FAQ’s
How exactly does the Coping Capacity Test work?
There are a whole host of mediators released in response to
stress. Measuring a single mediator can be useful, but it does not tell the
whole story. The ideal stress indicator would be the sum of these mediators. This
test monitors the multifaceted effects of stress using the body’s leukocytes as
bio-indicators. These cells circulate throughout the body picking up and
responding to all of the signals of stress (indicated by the diagram below).
What happens when the cells are stressed?
When the cells are stressed, the mediators released by stress alters the responsiveness of the cells. We can pick up those subtle changes in reactivity, by a simple test.
What makes this test unique?
The test informs you how well the body is coping with both
physiological and psychological stressors (coping capacity). Adrenaline and cortisol and other hormones are useful indicators of stress, but the stress response is a highly complex response involving a cascades of mediators. Absolute values of individual mediators are difficult to interpret. For example cortisol is subject to diurnal rhythms, and increased level of adrenaline can be associated with excitement. Leukocytes have over 250 receptors which respond to the key mediators released during stress. They circulate throughout the body and can pick up even subtle changes in stress mediators. Because of their exquisite sensitivity to stress mediators, and their ability to respond to not only one, but hundreds of stress related mediators, they are ideal stress detectors. They circulate throughout the body, so act as bio-mediators. The cells responsiveness is altered during stress. This test defines how well the body is coping with those stressors. It does not require specialist laboratory equipment. It is simple to use, portable and affordable.
What information does the test provide?
Provides: an immediate indication that the body's cells are not coping
Provides: actionable data for tailor-made stress management
Warning of a compromised immune system, typically this occurs before opportunistic infections ensue
It is objective and quantifiable
Easy to use
Portable
Results are available within 10 minutes
Monitors the multifaceted effects of stress using the body’s cells as bio-indicators
Early intervention can be targeted
What is needed?
A single drop of blood from a finger or a thumb (obtained using lancing devices frequently used by diabetics)
How quickly are the results available?
10 minutes
What forms of ‘Stress’ does the CC Test measure?
Leukocytes have over 250 different types of receptors
and are exquisitely sensitive to all forms of what we call ‘stress’ – They respond to physiological and psychological stress.
In order to establish an absolute 'Richter' Scale for stress, many thousands of results are needed. We hope to announce this in 2008. Meanwhile, the test is exceptionally useful to monitor relative stress levels. Relative normal values can be established quickly if the test is taken regularly. This is particulary important when fitness is vital. For example in professional athletes.
Why measure stress when its effects are often obvious?
Stress has been described as 'the curse of the 21st century'. Both humans and animals are so immersed in it that it is often difficult to recognise the full extent of it's influence on health and well being. It can affect the quality of life. This test provides an early warning of a compromised immune system. A compromised immune system makes humans and animals more vunerable to opportunistic infections. Stress can also lead to long term illnesses, and make existing diseaeses worse. It has been estimated that over 5 0% hospital admissions are stress related. It has been described as a 'silent killer.' An objective measure and early warning system can prevent longer term health problems. How have Professionals used this test?
Professionals have used this test to: Adjust volumes and intensity of training sessions Monitor effects of lifestyle and other external stressors Help maintain a consistent level of general fitness Monitor recover of player between games and events Monitor recovery from injury For example an Olympic level coach used the CC test to modify the training and lifesytle of his athletes. Some went on to acheive lifetime bests.
Has the CC Test been accepted by the academic community?
The Test has been the subject of a number of
peer-reviewed publications. For example, the test was first reported in ‘Experimental
Physiology’, a publication of The Physiological Society (arguably the most
prestigious such group in the world), and reported in the publication was: “We conclude that the Leukocyte
Coping Capacity Test serves as a quantitative measure of stress” The journal article was peer reviewed and published (details below). Also, patent applications have been submitted to the patent offices of the U.S.,
Japan. The European and UK patent has been granted. Academic publications published and in preparation are cited below. The test is for research purposes only and not for therapeutic or diagnostic uses.
Leukocyte Coping Capacity: a novel technique for assessing the stress response in vertebrates McLaren GW, Macdonald DW, Georgiou C, Mathews F, Newman C, Mian R Experimental Physiology (2003) 88.4 541-546
Physiological
consequences of captive conditions in water voles (Arvicola terrestris) Journal of Zoology (2007) 271 19-26 T. P. Moorhouse, M. Gelling, G.W. Mclaren,
R. Mian & D. W. Macdonald
Technique reviewed in an invited book chapter appearing in
‘Stress and Health: New Research Ed K Oxington, Nova Science Publications New York Publication
date 2005 ISBN: 1-59454-244-9 ‘Of Stress Mice and Men’ R Mian, G McLaren, DW
Macdonald Chapter 3 pages 61-79
Quantifying Stress in Farmed Guanacos, Lama guanicoe:
Leukocyte Coping Capacity (LCC) compared fro traditional and modern methods of
restraint D.W. Macdonald, C. Bonacic,
P.J. Johnson & R. Mian (2008 In preparation)
Marathon runners, fitness and oxygen free radicals: Can neutrophils reveal the body’s state of fitness Graeme W McLaren, Greg G Whyte, Keith George, Robert Shave, David W Macdonald & R Mian (2008 In preparation).
Impact of handling on leukocyte coping capacity in wild
rodents.
M. Gelling, G W McLaren, F Mathews, R Mian, and D W
Macdonald (accepted for publication in press 2008)
Transient Psychological Stress: Changes to PMA-induced production of ROS in vitro. Shelton-Rayner, G., Mian, R. Chandler, S., Robertson, D, and Macdonald, D.W. (In preparation 2008)
Psychological Stress:
Biochemical Changes and the Effect on Circulating Leukocyte Activation. Graham
K Shelton-Rayner, David W Macdonald, Simon Chandler, Duncan Robertson, and Rubina
Mian (In preparation 2008)
Excerpts below from Invited book chapter appearing in ‘Stress and Health: New Research
Ed K Oxington, Nova Science Publications New York Publication date 2005
ISBN: 1-59454-244-9
Chapter 3 pages 61-79 Ed K Oxingon(2005)
Of stress, mice and men: a radical approach to old problems.
Rubina
Mian1, Graeme McLaren2 and David W. Macdonald2
Curses and Plagues: fact or fiction? A modern idiom speaks of people
making themselves sick with worry. As with so many aphorisms that are casually
used, this linkage of stress and illness embodies a deep truth, a truth that
may already have been familiar to the ancients. It is an archaeological fact that most tombs of the Pharaohs had a curse
written above the door, to deter intruders, warning that whoever opened or
entered the tomb would die. ‘Death will slay with his wings
whoever disturbs the peace of the Pharaoh.’ (Budge 2001) For centuries such curses have been
dismissed as superstitious nonsense, but recent evidence shows that unwittingly
or otherwise, the ancient Egyptians had harnessed a powerful tool: danger
whether real or perceived can have devastating effect psychology can have on
the immune system. Psychological stress may reduce the effectiveness of the
immune system, thus increasing the risk of infection or disease (Dhabhar et al., 1996; Kang et al., 1996). The ancient Egyptians may have in fact been familiar
with this. In 1999 the German microbiologist Gotthard Kramer analysed 40
mummies and found them contaminated with several varieties of potentially
dangerous mould spores, which when exposed to air and a suppressed immune
system could have caused fatal illness (Viegas 1999). It
is also tempting to speculate that the plague of boils mentioned in Book of
Exodus 9:8-12, in the Old Testament, the sixth plague to hit Egypt would have
been exacerbated by the psychological endured by those who had already
experienced plagues of blood, gnats, flies and diseases of livestock. The
psychological stress would have burdened only the Pharaoh and his people, thus automatically
excluding those who firmly they were divinely protected. Stress and disease Epidemiological studies show that those individuals who are more
psychologically stressed are more prone to opportunistic infections (Clover
1989; Galinowski, 1997). For example stress associated with family dysfunction
is significantly associated with increased incidence of upper respiratory tract
infection and influenza B (Clover 1989) and work- related stress results in DNA
damage in female workers (Irie 2001). Similarly persistent stress in elite
athletes has been associated with chronic immunosupression and hence
susceptibility to opportunistic infections (for review see Gleeson 2000). In
animal models of stress, the spread of Candida
albicans (an opportunistic fungal disease) is greater in stressed rats than
non-stressed animals (Rodriguez et al.,
2001). Results from studies associating psychological stress with an increased
cancer are contradictory: some suggest an increased risk of developing cancer
in those exposed to psychological stress (Irie et al 2001) others support no
such link (Johansen et al 1998)and most
are inconclusive (Kiecolt-Glaser 1999). Overall psychological and behavioural
factors may well influence the progression of cancer through psychosocial
influences on immune function. Current measures of stress Objective, quantitative and practicable measures of stress are pivotal
to studies in many branches of vertebrate biology, including animal welfare
(e.g. Dawkins, 1980; Bateson & Bradshaw, 1997). The stress response in
animals is currently assessed using a variety of techniques, including cortisol
measurement (e.g. Palme & Möstl, 1997; Creel, 2001), haematological values
(e.g. Millspaugh et al., 2000) and behavioural observations (reviewed by
Rushen, 2000). We have recently reported a novel technique to measure the
stress response (McLaren et al.,
2003), based on the capacity of circulating neutrophils to produce reactive
oxygen species in response to an external stimulus. The mechanisms
involved Being stressed elicits a psycho- physiological arousal which was
comparable to Canon’s fear –flight- fight- defence reaction, the so called
‘stress response’ which involves stimulation of the hypothalamus (Canon 1932;
Folklaw 1982), a change in peripheral resistance (Brod 1972) and an increase in
the release of stress hormones including catecholamines and cortisol (Seyle
1946) and increases in haematocrit and haemoglobin concentration (Maes et al., 1998). The increase in the numbers of circulating leukocytes during
the horror film is comparable to that reported by others. Changes in
circulating cell numbers reflects the cell trafficking between reservoir sites
including the liver, lungs, spleen, bone marrow and peripheral blood (Cruse
1995). This process is modified by receptors (Hou 1996; Ley 1996) on both the
endothelium (P-selectin; Intracellular Adhesion Molecule-1; Vascular cell
Adhesion Molecule-1) and leukocytes (L-selectin; integrins and P-Selectin
Glycoprotein Ligand-1 PSGL-1). Modification of the receptors on either the
endothelial cells or leukocytes can also dramatically alter the number of
adherent (and thus the number of free flowing) leukocytes (Ley 1995; 1996). The margination process is enhanced in vessels of a particular size by the aggregation of
erythrocytes, which tend to occupy the centre of microvessels and thus promote
margination (Firrell et al.,
1989). The increase in haematocrit and
haemoglobin concentration observed in this and previous studies (Maes et al., 1998) could thus selectively
promote margination in some vessels. Previous studies have demonstrated that
margination of leukocytes is not a uniform process, and occurs in particular
sized vessels within the microcirculation (Mian et al., 1993). In larger- sized vessels it is possible that the
shear stress of flowing blood might be sufficient to dislodge marginated
leukocytes, thus increasing the numbers of free-flowing leukocytes. The changes
in shear stress likely to have been brought about by the increased
haemoconcentration may also serve as a trigger mechanism for leukocyte
activation (Schmid-Schonbeim et al.,
2001). It has been recognised for some time that physiological
stressors such as exercise induce leukocytosis from marginal pools (Shephard & Shek, 1996; Gleeson et al., 1998). Current literature
indicates that exposure to hostile conditions or other psychological stressors
initiates the secretion of several hormones, including cortisol,
catecholamines, prolactin, oxytocin and renin (Van de Kar & Blair, 1999;
Toft et al., 1994)), any of which
could alter adhesion receptors on circulating leukocytes and thus contribute to
their altered distribution. Stimuli such as adrenaline that disrupt this
process (Iversen et al., 1993) and
increase the circulating numbers of leukocytes. Recent studies by Maes et al. (1999) have revealed that an
increase in the levels of pro-inflammatory cytokines, such as interleukin-6 and
tumour necrosis factor, result in the demargination of some leukocytes. It is
thus possible that the stress -induced production of adrenaline and cytokines
could orchestrate the increased numbers of leukocytes within the general
circulation. Non-physical stressors have now also been shown to influence
the number and distribution of leukocytes in the blood. Kang et
al., (1996, 1997) and Dhabhar (1996) reported that the mental stress of
academic examinations stimulated increases in the number and distribution of
leukocytes. These changes were found to
be both rapid and reversible. Neutrophils are
responsible for most of the ROS production seen in the blood samples (McLaren et
al. 2003, Mian et al. 2003) A model of the interactions between
neutrophils and other components of the stress response is outlined in Figure 3
and discussed below. Plasma factors Stress causes the release
of stress hormones including cortisol and adrenaline. A host of stress-related endocrine and
non-endocrine plasma borne factors could potentially modify the sensitivity of
circulating neutrophils to PMA and control their level of activation. For example,
neutrophil behaviour, including ROS, is modified by both cortisol (e.g. Kurogi
& Iida, 2002) and catecholamines (e.g. Bergmann & Sautner, 2002;
Benschop 1999). Non-endocrine
plasma-borne factors could also potentially control the response of neutrophils
in response to stress. In particular the
cytokines IL- 1 & IL- 6, which are known to be released from activated
endothelial cells, are known to affect neutrophil accumulation and
activation(e.g. Joseph et al., 1992).
Also, IL- 8 is an important chemo-attractant for neutrophils and can
also play a role in the production of ROS (McPhail & Harvath, 1993), and
thus may play an important role in the recruitment and activation of
neutrophils during stress. Glutamine Other factors that are
important for neutrophil function, such as glutamine (Furukawa et al.,
1997; 2000; Pithon-Curi et al., 2002) and glucose (Furukawa et al., 2000), could also
affect the response of neutrophils to stress.
In the case of glutamine, there is evidence to support the notion that
glutamine depletion is related to immunosuppression in athletes (Castell &
Newsholme 2001; Castell 2002). Neutrophil-endothelial cell interactions The adhesion of
neutrophils to the endothelium is another important component of neutrophil
activation during stress (Jean et al., 1998; Figure 3) and modification
of the receptors on either the endothelial cells or neutrophils can
dramatically alter the number of adherent (and thus the number of free flowing)
neutrophils and the distribution of leukocyte subsets (Ley, 1996; Maes
1999). Endothelial and neutrophil
derived adhesion molecules serve important roles in properly orienting
neutrophils temporally and spatially for activation along the endothelium (Park
& Lucchesi, 1999;). Important regulators in this process are TNFa, and
ICAM- 1. TNFa upregulates ICAM- 1, which
leads to increased neutrophil-endothelium interaction (Menger et al., 1999).
The selectin family of adhesion molecules, which includes E- and L-
selectin, mediate the first contact of neutrophils with the endothelium. (Ley,
1996). E- selectin is expressed on the surface of endothelial cells and L-
selectin is expressed on the surface of neutrophils. L- selectin can also influence the production
of reactive oxygen species (Nagahata et al., 2000). Furthermore, changes in shear stress, such as
those brought about by stress related increases in red blood cell numbers, can
modify neutrophil adhesion behaviour (Sheikh et al., 2003). In summary
stress-induced changes in leukocyte activation reflect changes occurring in the local
environment. A
working model of neutrophil behaviour in response to stress
2 Wildlife Conservation Research Unit,
Department of Zoology, Oxford
University,Abstract.
The tremendous destructive
capabilities of reactive oxygen species in stress related disorders has become
apparent only recently, although in early historical times the ancients may
have been aware of the devastating power of stress on well-being. This chapter
explores ancient myths and modern techniques surrounding stress-induced
immunosupression in species as diverse as mice and humans, investigating
techniques and mechanisms, and speculating on possible therapeutic
interventions.
PSGL-1 is
constitutively expressed on all lymphocytes, monocytes, eosinophils and
neutrophils Ley 1997. PSGL-1 has a glycosylation pattern enabling it to bind to
endothelial P-selectin (Ley 1997). This interaction results in the margination
of the leukocytes, which is the process by which leukocytes exit the central
blood stream, and initiate mechanical contact with the endothelial cells (Cruse
et al.,1995).A working model of neutrophil behaviour in
response to stress: The key players
Cytokines
Figure 3. This
diagram represents our working model of the interaction between stress and
neutrophil behaviour. Stress brings about a shift in the behaviour of
neutrophils, inducing the release of reactive oxygen species (ROS), and
initiating a sequence of events that leads to neutrophils binding to the blood
vessel endothelium, and (not shown) rolling along the endothelium and migrating
into the tissues. Cytokines (including
IL-1, IL-6, and IL-8) and stress hormones are likely to play a role in
initiating and maintaining this behaviour, as is shear stress. This shift in responsiveness is limited to a
subpopulation of neutrophils: those remaining in the circulation have a reduced
sensitivity to PMA (see text for details), and this can be used as a measure of
stress. A new look at stress-induced
production of oxygen free radicals: Therapeutic Possibilities. Phagocytic leukocytes play a pivotal role in the innate immune response
against bacteria, fungi foreign particles and stress induced
immuno-supression (Mian et al2003, McLaren et al. 2003). On the
surface of phagocytic leukocytes lies NADPH oxidase, multisubunit enzyme that
can assemble which when assembled can
‘shoot’ highly reactive oxygen
species (ROS) through the membrane. NADPH oxidases are tightly controlled and
thus generally do not blast highly reactive superoxide anions into healthy
tissues. It has recently been shown that
once ‘superoxide shooting’ commences, the leukocyte initiates a highly
coordinated sequence of events which
include fusion and release of several types of granules and activation of
antimicrobial enzymes (Bokoch 2002). The role of ROS is not thus just that
of a reactive oxygen free radical, but may be a signal for subsequent
alteration of electrons, movement of ions
and ultimately release of granular contents (Bokoch 2002). Thus an alteration of stress-induced ROS (Figure 4
from Bokoch 2002) may signal a sequence of more sinister alterations of immune
function.
Figure 4. The single electron reduction of molecular oxygen to form
superoxide anion by the phagocyte NADPH oxidase (OX), stimulated by bacterial
uptake (and possibly by substances e.g. adhesion molecules or cytokines
released by stress), results in the transfer of electrons into the enclosed
phagocytic vesicle. Dismutation of the superoxide generates OH-, and the accumulating
negative charge must be compensated by the influx of H+ and/or K+.
The hypertonicity resulting from K+ transport promotes the release
of inactive cationic granule proteases (P) bound to an anionic sulfated
proteoglycan matrix (cross-hatching). The released and active proteases (P*)
encounter the bacterium under optimal pH conditions within the phagocytic
vesicle and degrade it. Cytoskeletal elements associated with the phagocytic
vesicle (wavy lines) indirectly affect the killing process by modulating
vesicular volume. pH and movement of ions may well be affected by gas
signalling molecules. We speculate that this process may be intiated by stress.
Pharmacological intervention with any of the processes discussed may modulate
the production of ROS. Figure reprinted from Bokoch (2002), with permission from GM Bokoch and the
Nature Publishing Group. ROS production in disease states Understanding the relationships
between stress and ROS production is also important for disease studies. ROS have been implicated in a wide variety of
autoimmune diseases such as rheumatoid arthritis (Halliwel et al., 1992)
inflammatory bowel disease (Kruidenhier & Verspaget 2002) and systemic lupus erythematosus (SLE) (Ames
et al., 1999) and psoriasis (Pereira et al., 1999). Stress
related psoriasis has been documented (Alabadie et al., 1994). There is evidence that the occurrence of
psoriasis is related to increased ROS production and decreased antioxidant
capacity (Baz et al., 2003). In an interesting experiment Kabat-
Zinn et al., (1998) demonstrated that stress reduction by meditation (in conjunction with
ultraviolet light therapy) increased the rate at which psoriasis cleared in
patients. ROS have been linked to
such a variety of diseases because they of their potential for causing
wide-ranging tissue damage. ROS can
damage DNA and membranes and the oxidation products can induce protein damage,
apoptosis, and the release of pro-inflammatory cytokines (Briganti &
Picardo 2003), leading to serious tissue damage if antioxidant capacity is
insufficient. In patients with SLE the severity of the
disease is known to be related to daily psychological stress (Pawlak et
al., 2003), and given that oxidative stress is a known factor in this
disease (Ames et al., 1999), the relationships between psychological
stress, ROS production and disease onset and severity would be worth exploring
further. Concluding comments All mammals are subjected to psychological stress at some
point in their lives. Whether man or mouse the nature, duration and intensity
of the stress can result in a common endpoint : immunosupression and the
release of reactive oxygen species from circulating leukocytes. Even vicarious,
fictitious stress is sufficient to orchestrate what appears to be a basic
instinctive response – the preparation for ensuing bacterial invasions. If the
stress is of sufficient magnitude we appear to be hard wired to produce a
defined physiological response. We prepare ourselves for action or injury. In
anticipation, leukocytes prepare for battle and release their arsenal of
weapons. The response is regulated. If however the stress continues, then this
can have devastating consequences on the host (Irie 2003). Long term immunosupression
can result in an increased vulnerability to opportunistic infections. Perhaps
the ancient Egyptians were aware of the power of stress when they wrote curses
on the tombs of pharaohs to deter thieves Such words would doubtless terrify a superstitious, and already anxious,
tomb- raider. The resulting psychological stress, together with scattered
invisible moulds scattered on the bodies of the mummies, which could remain
dormant for thousands of years, could be a fatal combination. Believing in the
curse could indeed have been a self-fulfilling prophesy. Unwittingly or
otherwise than ancient Egyptians may have designed the first effective
psycho-immunodeterrents.
‘Moreover, as for him who shall destroy this inscription: He shall not reach his home. He shall not embrace his children. He shall not see success.” (Budge 2001)
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