Tag Archives: Metabolic Setpoints

Homeostasis And The Constancy Principle – We Are All Creatures Of Comfort Even When We Go Out Of Our Comfort Zone

It is autumn in our part of the world, and the first chills are in the air in the late evening and early morning, and the family discussed last night the need to get out our warm clothes from storage in readiness for the approaching winter, in order to be well prepared for its arrival. After sharing in the fun of Easter Sunday yesterday and eating some chocolate eggs with the children, a persistent voice in my head this morning instructed me to eat less than normal today to ‘make up’ for this out of the normal chocolate eating yesterday. It is a beautiful sunny day outside as I write this, and I feel a strong ‘urge’ to stop writing and go out on a long cycle ride because of it, and have to ‘will’ these thoughts away and continue writing, which is my routine activity at this time of morning. After a recent health scare I have been checking on my own physical parameters with more care than normal, and found it interesting when checking what ‘normal’ values for healthy folk are, that most healthy folk have fairly similar values for things like blood glucose, blood pressure, cholesterol concentrations and other such parameters, and that there are fairly tight ranges of values of each of these which are considered normal and a sign of ‘health’, and if one’s values are outside of these, it is a sign of something wrong in the working of your body that needs to be treated and brought back into the normal range either by lifestyle changes, medication, or surgical procedures. All of these got me thinking about the regulatory processes that ensure that the body maintains its working ‘parts’ in a similar range in all folk, and the concept of homeostasis, which as a regulatory principle explains and underpins the maintenance of this ‘safe zone’ for our body’s multiple activities, including the sensing of any external or internal changes which could be associated with the potential for one of the variables to go out of the ‘safe zone’, and initiates changes either behaviourally or physiologically which attempt to bring the variable at risk back into the ‘safe zone’ either pre-emptively or reactively.

Homeostasis is defined scientifically as the tendency towards a relatively stable equilibrium between inter-dependent elements. The word was generated from the Greek concepts of ‘homiois’ (similar) and ‘stasis’ (standing still), creating the concept of ‘staying the same’. Put simply, homeostasis is the property of a system whereby it attempts to maintain itself in a stable, constant condition, and resists any changes or actions on the system which may change or destabilize the stable state. It’s origins as a concept were from the ancient Greeks, with Empedocles in around 400 BC suggesting that all matter consisted of elements which were in ‘dynamic opposition’ or ‘alliance’ with each other, and that balance or ‘harmony’ of all these elements was necessary for the survival of the individual or organism. Around the same time, Hippocrates suggested that health was a result of the ‘harmonious’ balance of the body’s elements, and illness due to ‘disharmony’ of the elements which it was made up of. Modern development of this concept was initiated by Claude Bernard in the 1870’s, who suggested that the stability of the body’s internal environment was ‘necessary for a free and independent life’ and that ‘external variations are at every instant compensated for and brought into balance’, and Walter Cannon in the 1920’s first formally called this concept of ‘staying the same’ homeostasis. Claude Bernard actually initially used the word ‘constancy’ rather than homeostasis to describe the concept, and interestingly, a lot of Sigmund Freud’s basic work on human psychology was based on the need for ‘constancy’ (though he did not cross-reference this more physiological / physical work and concepts), and that everyone’s basic needs were for psychological constancy or ‘peace’, and when one had an ‘itch to scratch’ one would do anything possible to remove the ‘itch’ (whether it be a new partner, a better house, an improved social status, or greater social dominance, amongst other potentially unrequited desires), and further that one’s ‘muscles are the conduit through which the ego imposes its will upon the world’. He and other psychologists of his era suggested that if an ‘itch’, urge or desire was not assuaged (and what causes these urges, whether a feeling of inadequacy, or previous trauma, or a desire for ‘wholeness’, is still controversial and still not clearly elicited even today), the individual would remain out of their required ‘zone of constancy’, and would feel negative emotions such as anxiety, irritation or anger until the urge or desire was relieved. If it was not relieved for a prolonged period this unrequited ‘itch’ could lead to the development of a complex, projection or psychological breakdown (such as depression, mania, anxiety, personality disorder or frank psychosis). Therefore, as much as there are physical homeostasis related requirements, there are potentially also similarly psychological homeostasis related requirements which are being reacted to by the brain and body on a continuous basis.

Any system operating using homeostatic principles (and all our body systems do so) has setpoint levels for whatever substance or process is being regulated in the system, and boundary conditions for the substance or process which are rigidly maintained and cannot be exceeded without a response occurring which would attempt to bring the activity or changes to the substance or process back to the predetermined setpoint levels or within the boundary conditions for them. The reasons for having these set boundary conditions are protective, in that if they were exceeded, the expectation would be the system would be damaged if the substance or process being regulated (for example, oxygen, glucose, sodium, temperature, cholesterol, or blood pressure, amongst a whole host of others) was used up too quickly or worked too hard, or was allowed to build up to toxic / extremely high levels or not used enough to produce life-supporting substrates or useable fuels, which would endanger the life and potential for continued activity of the system being monitored. For example, oxygen shortage results in death fairly quickly, as would glucose shortage, while glucose excess (known as diabetes) can also result in cellular and organ damage, and ultimately death if it is not controlled properly. In order for any system to maintain the substance or process within homeostasis-related acceptable limits, three regulatory factors (which are all components of what is known as a negative feedback loop) are required to be components of the system. The first is the presence of a sensory apparatus that can detect either changes in whatever substance or process is being monitored, or changes in the internal or external environment or other systems which interact with or impact on the substance or process being monitored. The second is a control structure or process which would be sent the information from the sensory apparatus, and would be able to make a decision regarding whether to respond to the information or to ignore it as not relevant. The third is an ‘effector’ mechanism or process which would receive commands from the control structure after it had made a decision to initiate a response in response to the sensed perturbation potentially affecting the system it controls, and make the changes to the system decided upon by the control structure in order to maintain or return the perturbed system to its setpoint value range.

The example of temperature regulation demonstrates both the complexity and beauty of homeostasis in regulating activity and protecting us on a continuous basis from harm. Physiological systems in most species of animals are particularly sensitive to changes in temperature and operate best in a relatively narrow ranges of temperature, although in some species a wider range of temperatures is tolerated. There are two broad mechanisms used by different organisms to control their internal temperature, namely ectothermic and endothermic regulation. Ectothermic temperature regulators (also known as ‘cold-blooded’ species), such as the frog, snake, and lizard, do not use many internal body processes to maintain temperature in the range which is acceptable for their survival, but rather use external, environmental heat sources to regulate their body temperature. If the temperature is colder, they will use the sun to heat themselves up, and if warm, they will look for shadier conditions. Ectotherms therefore have energy efficient mechanisms of maintaining temperature homeostasis, but are more susceptible to vagaries in environmental conditions compared to endotherms. In contrast, endotherms (also known as ‘warm-blooded’ species), into which classification humans fall, use internal body activity and functions to either generate heat in cold environments or reduce heat in warm conditions. In endotherms, if the external environment is too cold, and if the cold environment impacts on body temperature, temperature receptors measuring either surface skin temperature or core body temperature will send signals to the brain, which subsequently initiates a shiver response in the muscles, which increases metabolic rate and provides greater body warmth as a by-product of fuel / energy breakdown and use. If environmental temperature is too warm, of if skin or core temperature is too high, receptors will send signals to brain areas which initiates a chain of events involving different nerve and blood-related control processes which result in increased blood flow to the skin by vasodilatation, thereby increasing blood cooling capacity and sweat rate from the skin, thus producing cooling by water evaporation. All these endotherm associated heating and cooling processes utilize a large amount of energy, so from an energy perspective are not as efficient as that of ectotherms, but they do allow a greater independence from environmental fluctuations in temperature. It must be noted that endotherms also use similar behavioural techniques to ectotherms, such as moving into shady or cool environments if excessively hot, but as described above, can tolerate a greater range of environmental temperatures and conditions. Furthermore, humans are capable of ‘high level’ behavioural changes such as putting on or taking off clothes, in either a reactive or anticipatory way. It is evident therefore that for each variable being homeostatically monitored and managed (on a continuous basis) there are a complex array of responsive (and ‘higher-level’ pre-emptive) options available with which to counteract the potential or actual ‘movement’ of the variable beyond its ‘allowed’ metabolic setpoints and ranges.

There are a number of questions still to be answered regarding how homeostasis ‘works’ and how ‘decisions’ related to homeostasis occur. It is not clear how the regulatory mechanisms know which variable they ‘choose’ to defend as a priority. Brain oxygen would surely be the most important variable to ‘defend’, as would perhaps blood glucose levels, but how decisions are made and responses initiated for these variables preferentially, which may impact negatively on other systems with their own homeostatic requirements, is not clear. Furthermore, there is the capacity for ‘conflict’ between physical and psychological homeostatic mechanisms when homeostatic-related decisions are required to be made. For example, one’s ego may require one to run a marathon to fulfill a need to ‘show’ one’s peers that one is ‘tough’ by completing such a challenging goal, but doing so (running the marathon) creates major physical stress for and on the physical body. Indeed, some folk push themselves so hard during marathons that they collapse, even if they ‘feel’ warning signs of impending collapse, or of an impending heart attack, and choose to keep running despite these symptoms. To these folk, the psychological need to complete the event must be greater than the physical need to protect themselves from harm, and their regulatory decision-making processes clearly valences psychological homeostasis to be of greater importance than physiological homeostasis when deciding to continue exercising in the presence of such warning symptoms. However, running a marathon, while increasing physical risk of catastrophic physical events during the running of it, if done on a repetitive basis has positive physical benefits, such as weight loss and increased metabolic efficiency of the heart, lungs, muscles and other organ structures, along with enhanced psychological well-being which would be derived from achieving the set athletic performance-related goals. Therefore, ‘decision-making’ on an issue such as running a marathon is complex from a homeostasis perspective, with both short and long term potential benefits and harmful consequences. How these contradictory requirements and factors are ‘decided upon’ by the brain when attempting to maintain both psychological and physical homeostasis is still not clear.

A further challenge to homeostatic regulation is evident in the examples of when one has a fever, where a high temperature may paradoxically be beneficial, and after a heart attack, where an altered heart rate and blood pressure setpoint may be part of compensatory mechanisms to ensure the optimal function of a failing heart. While these altered values are potentially ‘outside’ of the ‘healthy’ setpoint level range, they may have utilitarian value and would be metabolically appropriate in relation to either a fever or failing heart. How the regulatory homeostatic control mechanisms ‘know’ that these altered metabolic setpoints are beneficial rather than harmful, and ‘accepts’ them as temporary or permanent new setpoints, or whether these altered values are associated with routine homeostatic corrective responses which are part of the body’s ongoing attempt to induce healing in the presence of fever or heart failure (amongst other homeostatically paradoxical examples), is still not clear. Whether homeostasis as a principle extends beyond merely controlling our body’s activity and behaviour, to more general societal or environmental control, is also still controversial. For example, James Lovelock, with his Gaia hypothesis, has suggested that the world in its entirety is regulated by homeostatic principles, and global temperature increases result in compensatory changes on the earth and in the atmosphere that lead to eventual cooling of the earth, and this warming and cooling continues in a cyclical manner – and most folk who believe in global warming as a contemporary unique catastrophic event don’t like this theory, even if it is difficult to support or refute without measuring temperature changes accurately over millennia.

Homeostatic control mechanisms can fail, and indeed our deaths are sometimes suggested to be the result of a failure of homeostasis. For example, cancer cells overwhelm cellular homeostatic protective mechanisms, or develop rapidly due to uncontrolled cellular proliferation of abnormal cells which are not inhibited by the regular cellular homeostatic negative feedback control mechanisms, which lead to physical damage to the body and ultimately our death, for these or other reasons that we are still not aware of. In contrast, Sigmund Freud, in his always contrary view of life, suggested as part of his Thanatos theory that death in the ultimate form of ‘rest’ and is our ‘baseline’ constancy-related resting state which we ‘go back to’ when dying (with suicide being a direct ‘mechanism’ of reaching this state in those whose psyche are operating too far away from their psychological setpoints, whatever these are), although again this is a difficult theory to either prove or disprove. Finally, what is challenging to a lot of folk about homeostasis from a control / regulatory perspective is that it is a conceptual ‘entity’ rather than a physical process that one can ‘show’ to be ‘real’, much like Plato’s Universals (to Plato the physical cow itself was less relevant than the ‘concept’ of a cow, and he suggested that one can only have ‘mere opinions’ of the former, while one has absolute knowledge of the latter, given the physical cow changes as it grows, ages, and dies, while the ‘concept’ of a cow is immutable and eternal). It is always difficult scientifically to provide categorical evidence which either refutes or support concepts such as universals and non-physical general control theories, even if they are concepts which appear to underpin all life as we know it, and without which function we could not exist in our current physical form and living environment.

As I look out the window at the falling autumn leaves and wonder whether we will have a very cold winter this year and whether we have prepared adequately for it clothes-wise (pre-emptive long-term homeostatic planning at its best, even if perhaps a bit ‘over-the-top’), while taking off my jersey as I write this given that the temperature has increased as the day has changed from morning to afternoon (surely a reactive homeostatic response), and as I ponder my health-related parameters, and work out how I am going to get those that need improvement as close to ‘normal’ as possible (surely as part of behavioural homeostatic / health-optimization planning), I look forward to that bike ride now I have managed to delay gratification of doing so until I have completed writing this (and feel a sense of well-being both from doing so and by realizing I am now ‘free’ to go on the ride and by doing so can remove the psychological ‘itch’ that makes me want to do it and therefore return to a state of psychological ‘constancy’ / homeostasis). Contemplating all of these, it is astonishing to think that all of what I, and pretty much all folk, do is underpinned by a desire to be, and maintain life, in a ‘comfort zone’ which feels right for me, and which is best for my bodily functions and psychological state. Given that all folk in the world have similar physical parameters when we measure them clinically, it is likely that our ‘comfort zones’ both physically and psychologically are not that different in the end. Perhaps the relative weighting which each of us assigns to our psychological or physical ‘needs’ create minor differences between us (and occasionally major differences such as in folk with psychopathology or with those who have significant lifestyle related physical disorders), though at the ‘heart of it all’, both psychologically and physically, is surely the over-arching principle of homeostasis. While on the bike this afternoon, I’ll ponder on the big questions related to homeostasis which still need to be answered, such as how homeostasis-related decisions are made, how the same principle can regulate not just our body, but also our behaviour, and perhaps that of societal and even planetary function, and how ‘universals’ originated and which came first, the physical entity or the universal. Sadly I think it will need a very long ride to solve these unanswered questions, and remove the ‘itch that needs scratching’ which arises from thinking of these concepts as a scientist who wants to solve them – and I don’t like to spend too long out of my comfort zone, which is multi-factorial and not purely bike-focused, but rather is part bike, part desk, part comfy chair, the latter of which will surely become more attractive after a few hours of cycling, and will ‘call me home’ to my next ‘comfort zone’, probably long before I can solve any of these complex issues while out on the ride watching the autumn leaves fall under a beautiful warm blue sky, with my winter cycling jacket unused but packed in my bike’s carrier bag in case of a change in the weather.


Metabolic Activity Setpoint Regulation In The Body – Conundrum Of How We All Are So Similar Deep Inside

This week I have had a bad bout of flu, along with the rest of the family, and apart from feeling pretty miserable, everything in my body feels disjointed and not functioning well because of the illness. I have been researching how the brain and body works for more than 25 years, and while the old adage that the more one learns about something, the less one knows about it is certainly true in my case, each journal article I read, or data I examine on how the body and the brain ‘work’ and are regulated, I marvel still at what a brilliant piece of work the human body is, and ‘feeling’ my own body not working well this week reinforced this perception for me. One of the most fascinating things about the body is how all the different organs, systems and metabolic activity are regulated to ensure that all its activity functions in a synchronous way and successfully from an integrative perspective. Even at rest, vast numbers of anatomical and physiological functions are operative and interacting with each other continuously in order to sustain life as we know and ‘feel’ it, whatever life really is. When one moves or performs activity, all these variables and interactions change in both quantitative and temporal domains, with metabolic activity increasing and the interactions between different organs and physiological systems occurring at a faster rate. Given the large number of physiological processes and activities occurring at any one time in the body, one would expect large variability between different individuals for the value of any single substrate, metabolite or regulatory factor operating at the cellular, tissue, organ, or system level in the body. Furthermore, one would expect that this potential inter-individual variability in physiological function would alter continuously with time. But, astonishingly, the range of values for any metabolic variable or its activity, and baseline levels of activity for most physiological variables, is relatively similar in different folk who are healthy. For example, blood glucose concentrations are usually maintained between 4 and 6 mmol/l in all healthy individuals, and breathing rate between 12 and 16 breaths per minute. Therefore, a similar metabolic regulator appears to occur in all individuals, although what sets these similar metabolic ranges in all folk is still currently not well understood.

The first potential regulator of all our metabolic and physiological system setpoints is a control mechanism in the brain or central nervous system. If this is the case, the values of each metabolic setpoint level, and the requirement for every single physiological system at every level in the body, as well as mechanical restraints and cellular architecture are present in the brain. The hypothalamus, a small area of brain tissue at the base of the brain, which has been shown to regulate hormonal function and has signalling connections with the body, has been suggested to be the key area of the brain where metabolic regulation occurs, along with a host of other brain and brainstem regions. These potential areas in the brain have been suggested to have a collection of neural networks that contain a register of the set values for each metabolic and physiological constituent of the body which is ‘stored’ somewhere and somehow in the these brain neural networks. Two innovative researchers, Joseph Parvizi and Antonio Damasio, in the early 2000’s suggested that a ‘proto-self’ exists, as a collection of neural networks that ‘map’ the physical and physiological state of the body. In their theory, the proto-self is a first-order map describing the state of every physiological variable in the body, and when a change to the internal physiological milieu occurs, such as when one moves or performs exercise, these changes become a further first-order map in other neural networks. When the proto-self values in the one neural network is compared to this ‘change map’, the difference between the two become a second-order map, which is used by some regulatory process in the brain to initiate changes at either the psychological, physiological system or cellular level by either sending out efferent neural commands (brain signals flowing out to the muscles or organs of the body) or humoral (blood borne) hormonal changes, both of which would attempt to restore the altered metabolic variables to their proto-self values by reducing pace during physical activity or terminating the physical activity, or ingesting fuel or fluid as required to replace the increase in its use, or changing cardiac output or fuel utilization composition to as near what is routine / ‘normal’ as possible.

This is an attractive idea, but like all things related to the brain, there has been no real development in identifying the mechanisms or components of the brain that would be responsible for the storage of the metabolic proto-self maps and register of all the physiological and metabolic setpoint variables. Two distinct shortcomings of these proto-self and brain storage concepts are firstly, the level of requirement for ‘storage space’ given the huge number of variables that would have to be stored, and the intellectual brain activity required to occur continuously to integrate and manage all the different variables at the same time. Secondly, if the values were ‘stored’ in the neural circuits, one would have expected over the generations there would be slow but substantial changes to these values as part of normal genetic variation that occurs over time, which would create an increasingly diverse array of anatomical brain neural network variations and an associated diverse array of setpoint values with time. Therefore, it is likely that some other mechanism is responsible for the similarity between the metabolic setpoint variables of different folk.

An external agent or force, rather than an internal brain mechanism, may be responsible for establishing metabolic setpoints, either directly or by maintaining similar function in the brains of different individuals by preventing changes which would be produced by the evolutionary pressure of passing time. Each individual would need to respond to the external agent or energy force in the same way, and this similar response would set a similar internal physiological and metabolic state in all individuals. For this type of external regulation to occur, the external energy force would need to be consistently present to allow the physiological response to occur continuously in all individuals. A putative energy force which would fulfil these criteria is the force of gravity. Gravity occurs over the entire surface of the earth, and energy is continuously required by all humans to counteract the effect of gravity on body structures. For example, merely standing upright requires constant force and hence muscle activity, which requires as a result a certain continuous level of metabolic activity. Experiments performed in zero gravity environments show that physiological activity levels are profoundly altered by lack of gravitational force. Therefore, there is a strong possibility that gravity, or other electromagnetic forces around the earth such as the coriolus force, are, at least partly, responsible for maintaining the similar homeostatic setpoints found in all healthy individuals.

There are of course times and conditions when metabolic setpoint variables alter, and can be altered. After long term physical training, a number of setpoint levels are altered associated with increased ‘fitness’ induced by training. For example, resting heart rate is reduced, blood lipid and cholesterol profiles are reduced, and muscle enzymatic and mitochondrial setpoint functions are altered. These changes are probably due to adaptations in protein regulatory function at the genetic and molecular level, which alters the physical and neural structures associated with physiological activity by changing their size, number and efficiency of function. But, these alterations are maintained only as long as the training bouts are continued. Once the training stimulus is removed, the metabolic setpoint levels in the different physiological systems return to their original values associated with the ‘untrained’ state, and these reversions occur at a faster rate than do the changes associated with training, indicating that it is easier to return metabolic setpoint values to their untrained values, then it is to alter the setpoint values away from their untrained state.

Chronic disease can also alter resting metabolic values, and in a permanent manner, if the disease is permanent and related to some cellular death. For example when an individual suffers a big heart attack, there is permanent loss of heart tissue in the affected area, which results in the contractile state of the heart changing, which leads to a number of other changes occurring, such as increased (or decreased) heart rate or stroke volume, blood pressure changes, and alterations in the flow of blood and fluids between organs. If the body can tolerate these changes, the individuals will survive in this damaged state for a substantial period of time, with altered resting metabolic variables and setpoint values, until death occurs from some other pathology / disease process. One could describe this as being a functionally different setpoint state, and in complex system research terminology / parlance this is known as a functional bifurcation from the resting state, but it is an artificial state related to illness, and the individual is in effect not functioning in an optimal state, but rather in state of chronic systemic compensation. In diseases such as diabetes mellitus, there appears to be marked changes in the concentrations of blood glucose, with levels measured at different times of the day either being higher or lower than the concentrations present in healthy individuals. However, these changes appear to be caused by the increased variation in blood glucose concentration associated with changes in the gain (the capacity of the system to return to baseline), and time constant of the gain, of the blood glucose control system in individuals with diabetes, rather than by changes in the metabolic setpoint values themselves.

The metabolic setpoints can also alter in response to acute infection, as happened to my body this week, with increased baseline temperature levels, heart rate and cardiac output. Interestingly, in what has been called the ‘setpoint controversy’, during a bout of fever such as I have had, changes occur which are not immediately corrective and which return the core temperature to previous homeostatic setpoint levels, but rather create conditions which would lead to further increases in temperature, or maintenance of the raised temperature away from the routine setpoint levels. These include seeking a warm environment, increased vasoconstriction, and shivering, all which increase metabolic rate and increase generation of heat, despite the individual already having an increased core temperature. The usual response to an increased core temperature when one is in a hot environment, or when the body’s core temperature increases due to exercise or physical exertion (hyperthermia), would be to seek out a cold environment, reduce locomotion, increase vasodilation and reduce metabolic rate. Therefore the responses to hyperthermia and fever, which similarly cause core temperature to increase above baseline setpoint levels, induce directly opposite effects, which in the case of hyperthermia lead to a reduction in core temperature, and in fever, maintains the increase in core temperature, and these different responses are the nub of the setpoint controversy. The teleological value of the responses to fever would be to allow optimal function of the inflammatory and immune response to remove the threat caused by the organism or process (in my case a flu virus) which induced the fever. The teleological value of the responses to hyoperthermia would be to prevent catastrophic overheating of physiological systems. How the ‘decision’ is made by the brain and body to initiate either of these different metabolic setpoint related strategies in response to an increase in core temperature is not currently known.

In summary therefore, one of the most fascinating aspect of our hugely complex bodies, is that despite this complexity, the setpoint values for each metabolic or physiological function appears to be very similar across all individuals, unless there are differences in fitness or health levels. While these setpoint values may be determined in brain structures and circuits, it is more likely that they are set in response to an external system force, likely to be gravity or other such forces that operate in a chronic and continuous manner similarly in all of us. In a world where our perceived external individual differences are often used politically and socially to differentiate and define us, it is a surety that deep inside we are all very much the same, and all are responding to the same challenges and forces we face, and are all so similar in all aspects of our bodies makeup and physical function because of this. So apart from being fabulously complex and mechanistically brilliant, perhaps the deep workings of our bodies, in all their brilliance, can teach us also something socially from how they are made, and how they are operate, reacting to external stimuli in the same way, responding internally in a host of different physiological systems in the same way, and returning to the same baseline values in the same way. No matter how different we or others think we are, deep inside, we are all very much the same, and this similarity is perhaps the fundamental tenet which allows the ongoing existence of life as we know it. Who would ever have believed that gravity would perhaps be the ultimate force potentially underpinning all of our body’s functions, and ensuring the physiological similarity of all us residing on this planet of ours, as we rotate daily around the sun and go about our daily business, if indeed this is the case. Sadly though, it wasn’t able to prevent me developing an illness as a result of a nasty flu virus, which appears to have knocked everything out of kilter this week, including most of my metabolic setpoints, to say nothing of my psychic harmony!

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