Theme 1: Extreme Environments Flashcards

Question

Describe an experiment about the effects of spaceflight on arterial oxygen saturation.

Answer 1

(Blue, 2012): * Used a centrifuge to simulate spaceflight, at various Gz (head-foot) and Gx (front-back) G-force values * Studied 77 participants, aged 22-88 * 16 participants were studied using pulse oximetry * No reading below 89% was obtained during any centrifuge exposure * 8 had desaturation to 92% or below at least once (mostly related to peak +Gx) * 5 had repeat desaturations * +Gz did not result in significant changes in pulse oximetry * In summary, of those studied, half experienced desaturation to 89-92% (Blue, 2014): * Carried out a similar experiment in particular in participants with medical conditions (e.g. hypertension) * Combined +Gx and +Gz, with a peak of +6.0 Gx/+4.0 Gz * 69% got greyout * 6% got chest discomfort * Minimum arterial oxygen saturation was recorded was 90% and no clinical symptoms of hypoxia were noted at any time The studies established the difficulty of finger probe pulse oximetry was of limited utility due to difficulty in keeping the probe on. Also, there were few low SpO₂ readings regardless of G magnitude or direction, so it is unlikely that SpO₂ monitoring during commercial spaceflight will be of any greater utility.’

Answer 2

(Blue, 2017): * Used a centrifuge to simulate spaceflight * After the centrifuge stopped, auditory alarms sounded and subjects were verbally instructed to complete a series of tasks (total of 12 steps), including removing their harness, reorienting gondola air vents, signalling one of the gondola cameras, and replacing their harnesses. * Heart rate increased by 34% * On average, subjects made 3 mistakes * Only 28/137 (20%) made no mistakes during the scenario

Answer 3

(Pollock, 2021): * Used a centrifuge to stimulate spaceflight at Gx (front-back) values of +2, +4 and +6 * Performed all studies with normal air and also with 15% oxygen to simulate the way in which the cabin could be pressurised. * Arterial oxygen saturation fell at +4 and +6 Gx values. The saturation was overall lower when breathing 15% oxygen. * The arterial partial pressure of oxygen decreased and the alveolar-arterial gradient increased with increasing Gx force. These are evidence of impaired V/Q matching. * Ventilation was relatively unaffected until +6 Gx, when it began to increase slightly. This was because, although respiratory rate increased with Gx, the tidal volume decreased. * The neural respiratory drive increased greatly with Gx, as did the work of breathing. These results point to the idea that the Gx force compresses the lungs, impairing function. Thus, respiratory drive increases but there is persistent feeling of breathlessness. This could partly explain the anxiety that many participants experience. The respiratory problems are exacerbated by airline-style cabin pressurisation.

Answer 4

(Pollock, 2021): * Simulated spaceflight using a centrifuge * Divided the chest into 8 sections * As Gx (front-back) G force increased, the ventilation became more ventral * However, there was also more residual air left in the ventral areas of the lungs at the end of expiration

Answer 5

Temporary COPD and obesity (transient respiratory failure)

Answer 6

* Two compartment system: * The core (brain, thoracic and abdominal compartments containing the heat producing organs) * This region is held at ~37.0+/- 0.5\*C * The peripheral shell (this is cooler and allows for regulation of temperature) * Communication between the two compartments is achieved via the circulation as blood is allowed to move between the two compartments, and can do so in either direction

Answer 7

* This is an organism that maintains a constant body temperature through **metabolic processes** * This body temperature is often above that of the surrounding temperature * Humans are homeotherms

Answer 8

* This is the temperature range over which there is no 'active' temperature gain or loss * This means that the surrounding temperature is pretty well matched with our typical heat generation * If temperature drops below this zone, we start to increase heat production to maintain homeostasis * If the temperature increases above the thermoneutral zone, we begin to actively dissipate heat and begin cooler temperature-seeking behaviours

Answer 9

* Naked = 25-30\*C * Light clothing = 18-22\*C * Affects heat loss from the body therefore reduces the range

Answer 10

* Thyroid hormone * Testosterone * Growth hormone

Answer 11

* Thyroid hormones (**thyroxine**) can raise BMR to 50-100% above normal * Total loss of thyroxine will decrease BMR to 40-60% of normal levels [EXTRA] * Adaptation of the thyroid gland is seen in people living in different geographical locations * People living in arctic regions have a BMR 10-20% above those in tropical regions, allowing an increased generation of heat to deal with the colder environment

Answer 12

~10-50% increase in BMR

Answer 13

~15-20% increase in BMR

Answer 14

* Fat/carbohydrate meals cause BMR to increase by ~4% * Protein heavy meals can raise BMR up to 30% (hence the meat sweats due to raised body temp after raised BMR)

Answer 15

Between 36.1-37.8\*C in normal physiological parameters NB that this can differ from the peripheral temperature, which is (understandably) cooler

Answer 16

Between approx. 12\*C and 54\*C (this is larger than the range for the thermoneutral zone as heat loss and gain processes are considered)

Answer 17

* Circadian rhythms * Daily variations in body temperature occur, +/-0.5\*C * Minimum occurs in the early hours of the morning, peak in the late afternoon * Menstrual cycle * Rise of +1\*C is seen following ovulation

Answer 18

* 'For the vast majority of animals, an animal's metabolic rate scales to the 3/4 power of the animal's mass' * I.e. if q₀ is the animal's metabolic rate, and M the mass, then Kleiber's law states that q₀ =~M^3/4 * Essentially, larger animal = larger metabolic rate * Named after Max Kleiber, Swiss agricultural biologist * There is still some argument over the exact value of the power, with some claiming it to be 2/3, but the constant is relatively arbitrary

Answer 19

Physical exercise * ~7% of daily energy expenditure is due to 'non-exercise' activity (e.g. fidgeting, non-specific exercise, muscle tone required for holding posture) * As exercise increases/becomes more significant, there is a rapid increase in energy expenditure requirements

Answer 20

* Adipose tissue rich in mitochondria * Also contain the uncoupling protein 1 (UCP-1) * Heat is generated through the dissipation of the proton gradient across the inner mitochondrial membrane via UCP-1 * Role in adults is a topic of ongoing research (particularly in isolating treatments for obesity) but it has been shown to play a vital role in neonatal thermogenesis (as neonates are unable to shiver) * Found primarily between the shoulder blades and around the kidneys

Answer 21

* BAT is activated in resposne to low temperatures * Stimulation occurs via the release of noradrenaline from the sympathetic nervous system * Activation acts via multiple transcription factors, including PGC1alpha and the PPARs to increase mitochondrial proliferation and fatty acid metabolism * PPARs = peroxisome proliferation activated receptor

Answer 22

Stefan-Boltzmann law * Emissivity is the measure of a material's effective ability to emit and absorb thermal radiation, black objects have a high emissivity, white objects do not * **NB** That the temperature difference between the object and the environment is to the power of 4, therefore has a large effect on the equation * Also note that energy can only be lost from the body via radiation if the temperature gradient favours energy loss to the surroundings (i.e. they are cooler than the body) * If the surrounding temperature increases to exceed that of the body, radiation will occur in the other direction/heat is transferred to the body

Answer 23

* These are methods of allowing a separation between nutritional and thermoregulatory blood flow * These vessels bypass the capillaries and can increase or decrease blood flow to the periphery to facilitate or limit heat loss respectively * Flow through shunts can be 'on' or 'off' * Blood flow through the shunts can be **100-fold** greater than nutritional requirements * Shunts are controlled by **centrally mediated alpha-1 adrenergic receptors** * Although this is augmented by local alpha-2 adrenergic receptors in the periphery

Answer 24

* Primarily through nervous feedback systems from the periphery to the CNS * Centre in the brain: temperature regulating centers in the hypothalamus

Answer 25

Hypothalamus is area through which almost all temperature regulating mechanisms work

Answer 26

* The preoptic and anterior hypothalamus operates as the body's thermostat * This part of the brain has greater sensitivity to heat than to cold

Answer 27

* Spinal cord, abdominal viscera and great veins (**deep body sensors**) * Skin * Greater sensitivity to cold than hot

Answer 28

1. Hot 2. Cold

Answer 29

* They alter their discharge frequency * Sensors are rapidly adapting/will rapidly adapt to new static levels * This means that they are bad at sensing absolute temperature, but are very good at sensing changes in temperature

Answer 30

* Two bowls of water, one quite warm (35-40\*C), the other very cold (add ice, ~0\*C) * Put a hand in each boel and leave it there for 3-4 mins, then put the hand into a bowl of water at room temperature * Hand in ice water thinks that the bowl of room temperature water is really hot, hand in bowl of warmer water thinks that room temperature bowl is very cold * This shows that the change in temperature has shaped the response, not the actual temperature, or else the hands would experience the same sensation

Answer 31

* This part of the brain collates and combines the signals from the peripheral sensors and from the central sensors (in the anterior hypothalamus) * This leads to control over the heat-conserving and heat-producing reactions of the body

Answer 32

In newborn infants - this makes them far more susceptible to the cold and they instead rely upon the action of BAT

Answer 33

* Rapid (~50Hz) and unsynchronised muscular activity * This results in ATP cross-bridge cycling to facilitate contraction and production of heat as a byproduct of the metabolic reaction * Shivering is likely to result from a feedback oscillation of the muscle spindle stretch reflex mechanism * Random oscillation is overlaid on a **centrally controlled 4-8 cycle/min** of 'waxing and waning' * E.g. shivering cycles between more and less severe bouts

Answer 34

* Posterior hypothalamus signals the need for shivering after collating inputs from peripheral receptors and central receptors (anterior and preoptic hypothalamus) * This signal is translated to the anterior motor neurons

Answer 35

* With light stimulation, almost all of the Na+ and Cl- is reabsorbed (along with a lot of water) as the secretions travel along the duct * This leads to a concentrated solution made up of **urea, lactic acid** and **potassium** * With heavy stimulation, large volumes of sweat are produced * This results in poor reabsorption of NaCl and increased fluid loss (due to the subsequently less concentrated liquid secreted)

Answer 36

* Over 1-6 weeks of exposure to a hot climate, sweat production is upregulated * In response to the increased loss of NaCl caused by this change, the body also upregulates **aldosterone** secretion to increased Na+ reabsorption

Answer 37

* This is where continued exposure to cold temperatures causes the core body temperature to drop below **35\*C** * Energy expenditure **falls 13%** for every **1\*C drop** in core temperature * Loss of consciousness occurs at core body temp of **30\*C**

Answer 38

* Changes can be seen on the ECG, including bradycardia and prolongation of the PR and QT intervals * Ventricular fibrillation occurs at **28\*C**

Answer 39

* Neonates are particularly susceptible due to reduced behavioural adaptations possible (e.g. cannot put on clothes or move) and have a greater SA:Vol ratio than adults * They also cannot shiver, but do have BAT for thermogenesis * The elderly are also susceptible due to potentially reduced mobility and less efficient thermoregulatory mechanisms * Lessened mobility also makes them less able to move for heat generation and also slows the process to find and put on clothes

Answer 40

* Infection can lead to an elevation of the core body temperature set point, and therefore hyperthermia * This is caused either through the direct action of proteins/ protein breakdown products/lipopolysaccharide toxins released from bacterial cells (**pyrogens**) or by their action on macrophages, leukocytes and lymphocytes * This causes the release of cytokines (IL-1 and IL-6) * These pyrogens act to elevate **prostaglandin E2** synthesis in the hypothalamus (this raises the set point)

Answer 41

* Prostaglandin E2 (PGE2) * Acts on E2 receptors in the anterior hypothalamus to raise the set point of body temperature

Answer 42

* Drugs that act to reduce the elevated set point * Examples include: * Acetaminophen (paracetamol) * Aspirin and other NSAIDs

Answer 43

* Principally through their inhibition of the enzyme cyclooxygenase (COX), preventing the synthesis of inflammatory prostaglandins (including PGE2) * Recent studies on the mechanism of action have revealed effects independent of COX inhibition as well

Answer 44

* Heat exhaustion * Heat stroke

Answer 45

* AKA heat syncope * Occurs due to hypovolaemia following excessive sweating * Symptoms include hyperthermia, excessive sweating, dizziness, nausea, headache

Answer 46

* This is where body temperature \>40.6\*C * Thermoregulatory mechanisms fail at this point, causing the patient to become dizzy and confused * Loss of consciousness follows rapidly, then death * Treatment involves rapidly reducing body temperature * There is some disagreement over whether cold or cool water should be used * Cold water can induce vasoconstriction and shivering, which will instead elevate temperature

Answer 47

* Malignant hyperthermia is a pathological state where body temperature is overwhelmed by heat production * It is often fatal * Caused by drugs include the muscle relaxant suxamethonium and volatile anaesthetics including halothane * This is very rare (1 case per 100,000 in adult general anaesthetics) * Can be caused by mutations in ryanodine receptor 1 (RYR1), inherited in an AR fashion * **Dantrolene** is the reversal agent for MHS caused by anaesthetic agents, and so will be found in the collection of all anaesthetists * Some individuals with this condition can occasionally enter malignant hyperthermia after extreme exercise or heat stroke, as the condition is caused by over-activation of skeletal muscle and its contraction, causing excessive heat release

Answer 48

* Burns cause cell damage and a hypermetabolic state * This is characterised by increased energy expenditure and increased muscle protein catabolism, which can lead to a hyperthermia of sorts * If there is extensive skin loss, however, hypothermia can occur as the skin is essential for many energy- and heat-preserving behaviours * With increased energy expenditure, more heat will be lost and so burns can rapidly lead to hypothermia

Answer 49

* Sweat production can be increased by cholinergic sympathetic nerve fibres * The glands can also be stimulated by adrenaline/noradrenaline, e.g. during exercise to increase heat dissipation * This elicits the secretion of a primary fluid into the sweat duct * This fluid has a composition similar to that of plasma, just without plasma proteins * As regulation/reabsorption occurs along the tubule, if the demand for secretion increases and therefore the transit time decreases, then the time over which this secretion can be modified is rapidly decreased

Answer 50

* Severe form of hypothermia * Occurs when surface areas (commonly on peripheral parts of the body) freeze and there is formation of ice crystals * Commonly affects the hands, feet and ear lobes * If extensive formation of ice crystals occurs, this can lead to cell death * Therefore gangrene often follows thawing * Surgical removal of affected areas is necessary

Answer 51

* Individuals feel 'cold' despite core body temperature being above the normal level * This results in the recruitment of normal physiological responses to being cold, such as shivering * Upon restoration of a normal set-point, individuals experience a febrile 'rush' or 'crisis' where the body tries to restore a normal core temperature through sweating and vasodilation * This is seen at the end of illness, but there is also some evidence to suggest that this occurs cyclically throughout fever (bouts of breaking and shivering)

Answer 52

* Peripheral and central receptors detect temperature * It information is integrated in the hypothalamus, which has a set point that is dependent on multiple factors, such as pyrogens * The hypothalamus then outputs to effecotrs via the cerebral cortex, sympathetic nerves and motor nerves

Answer 53

Cold water immersion

Answer 54

* TRPM8 channels in the CNS and periphery * The identification of the molecular basis of temperature sensing could have therapeutic implications

Answer 55

(Keating, 1964): * Used a cold shower to simulate cold water immersion * P_CO2 decreased -\> This shows an increase in ventilation * Arterial pressure increased -\> This shows peripheral vasoconstriction (Cooper, 1976): * Water immersion leads to increased tidal volume and ventilation The peripheral vasoconstriction is useful but it is less clear why there is increased ventilation. The ventilation is significant because it increases the risk of water inhalation.

Answer 56

* Facial (trigeminal) immersion triggers the 'diving reflex’, which causes bradycardia, increase in stroke volume and peripheral vasoconstriction. * This is not necessarily useful for temperature regulation. It is more likely a residue evolutionary reflex.

Answer 57

(Heistad, 1968): * Measured heart rate and blood pressure in humans when holding breath and during facial immersion * Heart rate dropped mildly when holding breath and more severely during facial immersion * Blood pressure increased mildly when holding breath and more severely during facial immersion * Blood flow to the fingers decreased in both cases, but blood flow to the forearm decreased only during facial immersion

Answer 58

* During cold water immersion, the cold water reflex leads to sympathetic stimulation of the heart, while the diving response leads to parasympathetic stimulation of the heart * These opposing activities can pre-dispose to cardiac arrhythmias.

Answer 59

* No, habituation can happen with repeated exposure to cold water * (Tipton, 1988) studied heart rate and ventilation in response to cold water immersion. The response decreased when repeated for several days in a row.

Answer 60

* The effect seems to be mediated centrally (rather than at the level of the peripheral receptors) * (Tipton, 1998) exposed only the left half of the body to the cold, repeatedly. This led to habituation of both sides of the body to the cold, suggesting that habituation is a central process.

Answer 61

Several months

Answer 62

(Lunt, 2010): * Found that, for example, there may be a change in the response to hypoxia also after habituation to cold exposure * Thus, there may be adaptation that affects multiple stresses

Answer 63

There may be a psychological component to cold habituation, and/or some psychological benefit (van Tulleken, 2018)

Answer 64

* Behavioural: including exercise, which may be effective at heat production, but could increase convective heat loss * Vasoconstriction: cutaneous vasoconstriction is mediated by the sympathetic nerves, diverting blood away from the skin * Shivering: helpful for heat generation in the short term, but costly in energy and fuel usage (and not generally favoured by populations adapted to life in cold climates) * Non-shivering thermogenesis: heat generation by metabolic means other than muscle movement, mainly in brown adipose tissue in neonates, partly under hormonal control (thyroxine)

Answer 65

* When cold-induced peripheral vasoconstriction decreases blood flow to the extremities, such that there is an increased risk of cold damage. * Some groups (e.g. fishermen) may have down-regulated peripheral vasoconstriction in order to avoid this and maintain dexterity in the cold.

Answer 66

* A rare event similar to HAPE, except caused by cold water immersion * It may involve acute breathlessness and blood tinged sputum * It may be due increased central blood volume (peripheral vasoconstriction) and elevated wedge pressure (ventricular dysfunction), leading to ‘stress failure’ of pulmonary capillaries. * (Paz, 2020) provide a case report of a 58-year-old female athlete presenting with acute dyspnea during the swimming portion of a half-triathlon competition.

Answer 67

Brown adipose tissue

Answer 68

Yes, it was previously thought to be just in neonates, but it is now thought to also play an important role in responses to cold in adults.

Answer 69

(Vertanen, 2009): * Studies 5 adult volunteers studied with PET-CT scans using F-FDG (a radiotracer that marks the uptake of glucose) * Carried out a warm scan and cold scan * Prior to ‘cold’ scan, subjects’ feet were exposed to iced water intermittently for 2h, while sitting in a room at 17-19ºC * The cold scans showed greater glucose uptake than the warm scans, particularly in the brown adipose tissue -\> This is an indicator of its role in adaptive thermogenesis * Three volunteers had biopsies of the cold-induced areas of adipose tissue, which showed high expression of UCP1 protein -\> Thus UCP1 is expressed in BAT

Answer 70

Some groups (e.g. fishermen) may have down-regulated peripheral vasoconstriction in order to avoid frostbite and maintain dexterity in the cold.

Answer 71

(Cardona, 2014): * Carried out a GWAS of cold adaptation in indigenous Siberian populations * Found a number of genes on chromosome 11 that have been subject of positive selection (Clemente, 2014): * Studied the gene CPT1A, which is a regulator of cellular metabolism and helps to regulate brown adipose activity. * This gene may even have undergone positive selection despite some adverse effects on energy balance.

Answer 72

Topical menthol could stimulate thermogenesis.

Answer 73

* In 1999 the Swedish doctor Anna Bågenholm made a full recovery after being frozen for 80 min under a layer of ice (core temperature 13.7ºC), likely due to the cytoprotective effects of tissue hypothermia (Gilbert, 2000) * This is exploited for therapeutic benefit during neurosurgical or cardiac procedures, and therapeutic cooling (e.g. 33ºC) can improve neurological outcome following cardiac arrest (Lascarrou, 2019)

Answer 74

* The hyperthermic range is \>40ºC, when neurological manifestations occur including confusion, agitation and slurred speech. * Serious illness or death from ‘heatstroke’ is likely with prolonged exposures \>40.5ºC.

Answer 75

(Robinson, 1943): * Exposed subjects to a desert-like environment * Over 24 days of exposure, the subjects showed a fall in heart rate, skin temperature and core temperature * The majority of these changes occur within 7-10 days of the onset of exposures to heat, and they last several weeks after the exposure (Wyndham, 1968): * Carried out a similar experiment and showed that sweat rate also increases.

Answer 76

Periods of exercise (90-120 min) are required for rapid acclimation, and the exercise is much better tolerated after acclimation.

Answer 77

The shift to the left is due to central acclimation (lower threshold for sweating), while the increased gradient is due to peripheral acclimation (greater sensitivity).

Answer 78

(Epstein, 2019): * The sequence of events that leads to heat stroke involves a transition from a compensable thermoregulatory state to the noncompensable condition. * Heat stress initiates a thermoregulatory response to increased cardiac output and redistribution of blood flow. * When central venous pressure begins to decrease substantially, core temperature begins to increase rapidly and becomes noncompensable. * The thermoregulatory failure aggravates pathophysiological processes at the cellular level, including an inflammatory reaction, and multiorgan failure occurs as a result of the combination of high body temperature and circulatory collapse, and ultimately is expressed as heatstroke.

Answer 79

* In the presence of oxygen, it is hydroxylated and degraded * In the absence of oxygen, this does not happen

Answer 80

* Erythrocytosis -\> Advantageous (unless it is excessive, causing chronic mountain sickness) * Pulmonary arterial vasoconstriction -\> Maladaptive * Ventilatory acclimatisation -\> Advantageous

Answer 81

* Viscosity increases as haematocrit increases. * Cardiac work is relatively unaffected because the arterioles can dilate in compensation for the increased pressure.

Answer 82

(Juvonen, 1991): * Described a family with autosomal dominant erythrocytosis. * In in vitro cultures, performed using the methyl cellulose assay, the number of erythroid colonies was normal or marginally increased when a standard concentration of erythropoietin (Epo) was used, but at lower Epo concentrations, the investigated persons formed more colonies than the controls. The difference was generally greater the lower the Epo concentration became. * This finding indicates that the erythrocytosis in this family is caused by hypersensitivity of erythroid progenitors to Epo. * Many of the family reached an advanced age, and one of the affected family members has won several Olympic gold medals and world championships in endurance sports.

Answer 83

(Schuler, 2010): * The optimum haematocrit in mice is higher than the average normal haematocrit

Answer 84

(Hall, 1937): * High-altitude mammals do not have increased oxygen carrying capacity (i.e. haematocrit)

Answer 85

(Beall, 1998): * Aymara have high haemoglobin concentrations, but Tibetans do not

Answer 86

* Tibetans have a high allele frequency of a certain allele for the EPAS1 gene * This gene encodes HIF2α * The allele is associated with low haemoglobin concentration, which explains why Tibetans tend to have similar haemoglobin concentrations to sea level populations * However, the allele is also associated with improved oxygen transport

Answer 87

(Jacobson, 1957): * Stimulated erythropoeisis by either administering cobalt or causing bleeding in animals * Animals with their kidneys removed produced a smaller response (in terms of EPO production)

Answer 88

* The kidney is a good place for EPO production because PO₂ in the kidney is dependent on haematocrit, not blood flow * In other organs, if you increase blood flow, then PO₂ will increase because oxygen delivery is increased while oxygen consumption is unchanged * However, in the kidneys, most oxygen consumed is used for reabsorption of ions from the ultrafiltrate. If you increase blood flow, then oxygen delivery is increased but oxygen consumption is proportionally increased because more ultrafiltrate is produced and thus more energy is required to reabsorb the ions. * Therefore, only haematocrit can alter PO₂ in the kidneys since it affects oxygen delivery. This means that the kidneys are good at sensing a need for erythropoeisis.

Answer 89

* Swan Ganz catheter (in diagram) * Echocardiography of the right atrium * When the right ventricle contracts, there is a jet of blood that flows to the right atrium * Echocardiography allows the velocity of this to be calculated * Bernoulli's equation can be used to calculate pulmonary arterial pressure

Answer 90

(Dorrington, 1997): * Hypoxia leads to a two-stage rise in pulmonary vascular resistance over the first 3 hours -\> The slower second increase is due to HIF * At the end of hypoxia there is a sharp drop in PVR followed by a gradual return to baseline -\> This is evidence of some sensitization following hypoxia

Answer 91

(Ang, 2002): * Chuvash polycythemia is caused by homozygosity of an allele for VHL that causes loss of function * This means there is reduced clearance of HIF, leading to erythrocytosis, etc.

Answer 92

The HPV is more pronounced due to the lack of HIF degradation seen in Chuvash polycythemia. Even in normoxic conditions, the pulmonary arterial pressure is high.

Answer 93

* Tibetans have a high allele frequency of a certain allele for the EPAS1 gene * This gene encodes HIF2α * The allele is associated with low haemoglobin concentration (Petousi, 2014): * Han Chinese and Tibetans had their pulmonary hypoxic response tested before and after exposure to hypoxia for 8 hours * The Tibetans showed a lesser increase in pulmonary arterial pressure upon exposure to transient hypoxia -\> This is because HPV is partly mediated by HIF in response to sustained hypoxia.

Answer 94

(Smith, 2008): * Measured pulmonary hypoxic response before and after exposure to hypoxia for 8 hours * The group who received iron infusion prior to the 8 hours of hypoxia showed a smaller increase in pulmonary arterial pressure upon transient hypoxia compared to the group receiving saline infusion * This is suggested to be because iron is involved in hydroxylating HIF prior to degradation, so it promotes HIF degradation and therefore reduces HPV (Smith, 2009): * Sea level residents were taken to altitude and after 3 days either a placebo or iron was administered * The iron group showed a more marked and rapid fall in pulmonary arterial pressure

Answer 95

* A progressive rise in ventilation and fall in P_CO2that occurs over a number of days of exposure to high altitude. * It is associated with increased sensitivity to both CO₂ and hypoxia.

Answer 96

Some theories suggest so, but it could just be viewed as a consequence of of mechanisms of regulation of ventilation at sea level.

Answer 97

Peripheral chemoreceptor denervation leads to decreases in ventilation and increases in P_CO2 in response to altitude.

Answer 98

Theory 1 -\> pH-dependent: * Peripheral chemoreceptors detect the fall in P_O2 and there is compensatory hyperventilation * This leads to a respiratory alkalosis * In response, a compensatory metabolic acidosis (by excreting bicarbonate) develops, which is associated with a drop in pH in a certain body compartments * This drives the increased ventilation * A strength of this model is that ventilation is sensitive to acute changes in CO₂ and pH Theory 2 -\> pH-independent: * Ventilatory acclimatisation arises directly from the effects of P_O2and is not mediated through pH effects (e.g. it could work via HIF)

Answer 99

* When someone travels to altitude, there is an immediate increase in pH (respiratory alkalosis). * In the blood, bicarbonate falls (metabolic acidosis) along with P_CO2 sufficiently to maintain pH but not to lower it to normal. Therefore, it cannot be a peripheral pH sensor (peripheral chemoreceptors) driving acclimatisation in response to the pH returning to normal. * In the CSF, the bicarbonate falls more quickly so the pH returns to normal. Thus, this drives hyperventilation through the central chemoreceptors. (Forster, 1975): * HOWEVER, when looking at a larger number of individuals, this was not the case. The blood and CSF HCO₃^- fell approximately at the same rate. * The pH of the compartments was not compensated sufficiently to drive acclimatisation in the form of hyperventilation. Overall, the early results supported a pH-dependent model of ventilatory acclimatisation, but the later study supports a pH-independent model of ventilatory acclimatisation to altitude.

Answer 100

* Bisgard surgically removed one of a goat's carotid bodies and re-plumbed the second one so that the type of blood supplying the carotid body could be controlled independently of the blood supplying the rest of the body (Bisgard, 1985): * Only the carotid body was given hypoxic blood, while the rest of the body was given normoxic blood. * This was sufficient to drive ventilatory acclimatisation, showing the importance of the carotid bodies and that systemic hypoxia is not required for acclimatisation. Other experiments: * If the rest of the goat is given hypoxic blood, while the carotid body is given normoxic blood, there is no acclimatisation. * If the gas the goat breathes is high in carbon dioxide, then respiratory alkalosis (via hyperventilation) is prevented. When then carotid body receives hypoxic blood under these conditions, acclimatisation still occurs, showing that alkalosis is not required for acclimatisation. * If the stimulus at the carotid body is changed (e.g. to hypercapnia) or the carotid body is stimulated, this is insufficient to drive acclimatisation. Overall, this suggests that local hypoxia at the carotid body is both sufficient and necessary for ventilatory adaptation to altitude.

Answer 101

(Robbins, 1985): * Used a chamber to maintain one group isocapnic at all times, while the other group was allowed to have changes in blood CO₂ * Both groups were exposed to 8 hours of hypoxia and showed similar increases in ventilation * This suggests that hypocapnia is not required for ventilatory acclimatisation (Robbins, 1998): * Carried out a similar protocol and then plotted the ventilation against P_CO2 curves after acclimatisation * The isocapnic and poikilocapnic showed similar changes in their graphs Thus, this supports a pH-independent model of ventilatory acclimatisation.

Answer 102

(Hodson, 2016): * Studied mice * Conditional inactivation of Phd2 enhances ventilatory response to hypoxia in mice (since Phd2 usually degrades HIF) * Conditional or constitutive inactivation of HIF-2 alpha, but not HIF-1 alpha, abrogates ventilatory acclimation to hypoxia Chuvash polycythemia: * Patients with Chuvash polycythemia show higher increases in ventilation in response to acute hypoxia compared to normal patients * These patients have increased HIF activity Thus, HIF-2 alpha in particular is likely to underlie acclimatisation to altitude.

Answer 103

Longer-term residents show: * Higher values for alveolar P_CO2 * Blunted ventilatory responses to hypoxia (Severinghaus, 1966)

Answer 104

(Velarde, 2003): * Used dopamine and somatostatin to block the chemoreflex in loew-landers and those living at high altitude * At high oxygen concentrations, ventilation is only minimally blunted * At low oxygen concentrations, ventilation is blunted far more in the low-landers * This suggests higher chemoreflex activity in the low-landers, although it is suggested that both groups show similar levels of chemoreflex at their respective normal oxygen concentrations (it is just that the long-term altitude residents are exposed to greater hypoxia at rest)

Answer 105

* There is a claim that the blunting of ventilatory sensitivity to hypoxia by residence at high altitude is irreversible -\> This suggestion is controversial (Gamboa, 2002): * Compared low-landers (graph 1) with high-altitude individuals living at low altitude (graphs 2 and 3) * Exposed each group to hypoxia * Both groups showed significant, similar initial response to hypoxia, but the high-altitude individuals showed a more rapid decline of this response during the hypoxia * Thus, this partly supports the idea that blunted ventilatory response is irreversible. It also shows the situation is more nuanced. (Rivera, 2003): * When high-landers living at low altitude return to high altitude, they show similar acclimatisation as low-landers * In other words, the ventilatory response is not permanently affected in this way

Answer 106

* Both VAL and HAN have reduced end-tidal PCO2 and elevated ventilation at high altitude, but more so for VAL than HAN. * The underlying mechanisms very different: * VAL has augmented peripheral chemoreflex response to acute hypoxia * HAN has depressed peripheral chemoreflex response to acute hypoxia * Only the sustained component (not initial components) of HAN's response to hypoxia is irreversibly blunted. * HAN re-exposure to hypoxia induces same acclimatization response as for lowlander. See previous flashcards for more detail.

Answer 107

(Donoghue, 2005): * Found that even very small changes in P_O2 can alter the ventilatory chemoreflex sensitivity to hypoxia * This suggests that ventilatory acclimatisation is not just a characteristic of ascent to altitude, but it can also happen with small changes in altitude near sea level

Answer 108

(Pan, 1998): * Denervated the carotid bodies in a goat * Found that the ventilatory response to CO₂ decreased over the first 4 days and then slowly recovered to close to normal * This shows that the central chemoreflex is under the control of the peripheral chemoreceptors -\> The fact that the central chemoreceptors are unaffected is why the response can recover (Fatemian, 2003): * Studied patients with bilateral carotid body resection * Found that bilateral carotid body resection in humans elevates alveolar P_CO2 and suppresses ventilatory sensitivity to CO₂ * Thus it is clear that bilateral resection leads to alterations in the ventilatory set point

Answer 109

* Both ventilatory acclimatization to hypoxia and lifelong hypoxia alter the respiratory set point, and affect the acute chemoreflex sensitivities to hypoxia and CO₂ * Carotid body resection has permanent effects of the ventilatory set point and the respiratory sensitivity to CO₂, as well as removing the acute ventilatory response to hypoxia. * Although not so important for short-term regulation of breathing as CO₂, hypoxia may play a significant role in calibrating the ventilatory set point and chemoreflex sensitivities of the respiratory controller.

Answer 110

* Corollary I: hypoxia-sensing mechanisms exist to subserve functions at altitudes close to sea level – not sense reductions in environmental PO2 * Corollary II: to a substantial degree, it is a matter of chance whether physiological responses to the hypoxia of high altitude are beneficial or deleterious * As such, it may be beneficial to suppress activation of hypoxia-sensing mechanisms such as HIF at high altitude (and potentially also in hypoxia-related disease).

Answer 111

* When acutely exposed to hypoxia, humans hyperventilate -\> This is the acute chemoreflex * Upon prolonged exposure to hypoxia (e.g. at altitude), humans adapt so that ventilation is increased in response to altitude * This may happen by a pH-dependent system (where respiratory alkalosis is compensated by metabolic acidosis, so that the drop in pH in some compartment drives adaptation) or a pH-independent system (where low P_O2 itself drives adaptation directly). * Overall, the pH-independent model seems more likely since hypoxia at the carotid bodies is sufficient for acclimatisation, while hypocapnia is not required. * On a graph of Pa_CO2 against ventilation, a shift to the left is seen and can be explained by increased sensitivity of the central chemoreceptors to CO₂ and an increased gradient can be explained by increased sensitivity of the peripheral chemoreceptors to O₂. * It is likely that HIF-2 alpha drives acclimatisation to altitude.

Answer 112

* Peripheral chemoreceptors (carotid body) -\> Samples arterial blood for decreases in P_O2 or to a lesser extent increases in pH and P_CO2 * Central chemoreceptors (medullary) -\> Sample CSF pH, which is dependent on blood P_CO2and HCO₃^- These communicate with medullary respiratory neurons, which control breathing.

Answer 113

* Parallel shift of line to the left (shown on the left graph) * This is due to increased sensitivity of the central chemoreceptors to P_CO2 * This change in sensitivity may be due to prolonged alkalinisation of the body as P_CO2falls * The result is increased ventilation * Increased slope of the line (shown on the right graph) * This is due to an increase in the sensitivity of the peripheral chemoreceptors to P_O2 * The result is increased ventilation (Remember that this change only occurs over a few days as the body acclimatises to high altitude)

Answer 114

* It may be reduced CSF bicarbonate. * This can be explained this way: * At high altitude, there is hyperventilation * This leads to falls in P_CO2 in the body (respiratory alkalosis) * The kidneys excrete increased amounts of bicarbonate to compensate for this * So there are low levels of bicarbonate in the blood and CSF Note that this explanation assumes a pH-dependent model of acclimatisation, which may not be the case.

Answer 115

(Kellogg, 1963): * Saw that the graph shifted to the left AND increased in slope * Therefore, both types of shift occur

Answer 116

Evidence that peripheral chemoreceptors detecting P_O2is important: * (Howard, 1995) -\> Varied P_O2 without changing P_CO2. It turns out that there is a large increase in ventilation upon hypoxia when P_CO2 is kept constant. * (Bisgard, 1986) -\> Altered the blood supply to a goat's brain so that the peripheral chemoreceptors can be independently perfused. Induced hypoxia at the carotid bodies but not at the central chemoreceptors. It turns out that ventilation increases when only the peripheral chemoreceptors are hypoxic. Evidence that central chemoreceptors detecting P_CO2is important: * (Ren, 1999) -\> Asked patients to hyperventilate while keeping their P_O2 constant. In patients where P_CO2was allowed to drop, the line shifted to the left. In patients where CO₂ was supplied to keep P_CO2 constant, the line did not shift.

Answer 117

* Increased sensitivity of the peripheral chemoreceptors to P_O2 is likely to be the first response that kicks in, responsible for most of the acclimatisation. * Increased sensitivity of the central chemoreceptors to P_CO2 is likely to be slower because (in pH-dependent models) it relies on the kidneys excreting bicarbonate in order for CSF bicarbonate to fall. Also note that it is likely that the peripheral chemoreceptors influence the central chemoreceptors.

Answer 118

Assuming that there is a sudden change of altitude: * P_O2 drops and this hypoxia drives hyperventilation via the carotid bodies * This increases P_O2 and decreases P_CO2 * The fall in P_CO2 leads to alkalosis, which reduces ventilation via reduced stimulation of the central chemoreceptors * This leads to a balance between hypoxia and hypocapnia * Over several days, acclimatisation occurs, causing a shift towards hyperventilation

Answer 119

There are 3 main hypothesis: * Renal compensation * At high altitude, there is hyperventilation * This leads to falls in P_CO2 in the body (respiratory alkalosis) * The kidneys excrete increased amounts of bicarbonate to compensate for this * There is redistribution of bicarbonate from the CSF * Active transport out of the CSF (not fully believed) * At high altitude, there is hyperventilation, leading to respiratory alkalosis * As pH of the CSF fluid falls, bicarbonate is actively transported out of it * Lactacidosis * At high altitudes, there is cerebral tissue hypoxia * This leads to acidosis, which is buffered using bicarbonate

Answer 120

* The classic assumption is a pH-dependent system of ventilatory acclimatisation, which requires bicarbonate excretion in order to happen * The evidence for this includes, for example, the use of acetazolamide * However, there are also a number of studies that point towards a pH-independent system that relies only of low P_O2 to drive acclimatisation -\> For example, bicarbonate excretion does not appear to happen rapidly enough to drive pH changes * Overall, what we do know is the importance of the peripheral chemoreceptors in driving adaptation, followed by the central chemoreceptors * This can be seen in the shape of the Pa_CO2-ventilation graphs

Answer 121

* Sickness that occurs during an ascent, typically before you acclimatise * Risk factors include: * Speed of ascent * Final altitude * Individual predisposition

Answer 122

* Lake Louise Score * Defined as headache and Lake Louise Score \>3, in setting of recent ascent/hypoxia (\>6h)

Answer 123

(Hackett, 1976): * Trekkers were given a self-reported questionnaire in Pheriche (on Everest) during the return trek from base camp * Incidence of AMS was 52.5% in 278 trekkers * However, 20% of the subjects turned back on the way to Pheriche and some did not complete the questionnaire. Thus, AMS is likely to be under-reported here. * The AMS questionnaire was before the Lake Louise score system was created, so the definition of AMS is not standardised here.

Answer 124

* The cause is unclear but it is likely to involve a small degree of cerebral oedema. * (Berger, 2020) found 3 main causes of AMS: * Increased cerebral blood flow (due to vasodilation) * Cytotoxic oedema (extracellular water passes into cells, resulting in their swelling) * Vasogenic oedema (due to increased vascular permeability) * These factors lead to increased brain volume and intravascular pressure that activate the trigeminal nerve

Answer 125

* There are some suggestions that it may depend on the amount of space that individuals have around the brain for the brain to expand into * Also, there are factors that may affect the hypoxaemia experienced (and therefore the degree of AMS): * Metabolic demand (e.g. exertion) * Hypoxic ventilatory response * Pulmonary oedema

Answer 126

* It is difficult to predict. * (Hohenhaus, 1995) studied the ventilatory response to isocapnic and poikilocapnic hypoxia and calculated the ventilatory sensitivity to hypoxia. The tests lasted 7-10 min, and were terminated when the SpO2 reached 80%. This seemed to identify those known to be susceptible to high altitude pulmonary oedema, but not AMS. * (Burtscher, 2008) had a bit more success. They measured SpO2 after 20-30 min of hypoxia and had slightly more success in predicting who developed AMS. * The best predictor seems to be previous experience of AMS.

Answer 127

(Kayser, 2012): * Reviewed 24 studies of acetazolamide in preventing AMS * 250mg, 500mg and 750mg doses were all effective in preventing AMS * However, high doses tend to have more side effects A recent meta-analysis suggests 125mg twice daily is effective, with fewer side effects than higher doses. A more recent RCT suggests that 62.5mg twice daily is not effective (Lipman, 2021).

Answer 128

HAPE often co-exists with AMS and HACE because it drives hypoxaemia, which is a driver of AMS and HACE.

Answer 129

* Severe swelling of the brain due to fluid Causes: * Hypoxia leads to increased cerebral blood flow, increased cerebral blood volume and increased permeability of the BBB Symptoms: * Headache, malaise, ataxia, confusion and coma Treatment: * Descent * Decompression * Oxygen * Dexamethasone

Answer 130

* HACE is a more severe form of AMS * HACE includes confusion, ataxia and depressed consciousness (coma), making it more dangerous

Answer 131

(Hackett, 1998): * Used MRI to scan an individual with HACE before and after recovery * The before scan showed a high degree of vasogenic oedema, particularly in the corpus callosum (Kellenberg, 2008): * Found evidence of microbleeds (hemosiderin deposits) on MRI scans of patients recovering from HACE * This evidence was not found in controls who went to similar altitudes and had severe AMS * This gives radiological evidence for presence of cytotoxic as well as vasogenic oedema

Answer 132

* Best treatment is descent, which is rapidly effective, but may be difficult * If descent is not possible, oxygen or hyperbaria (using a Gamow bag) may be effective as holding measures * The most important pharmacological treatment is dexamethasone (but acetazolamide may also be given)

Answer 133

* Severe swelling of the lungs due to fluid accumulation Causes: * Widespread pulmonary vasoconstriction upon ascent to high altitudes Strong individual predisposition * Leading cause of death at high altitudes Symptoms: * Dry cough, then pink frothy sputum and progressive hypoxia Treatment: * Descent * Oxygen * Nifedipine -\> Calcium channel blocker that reduces vasoconstriction

Answer 134

* At altitude, there is some uneven hypoxic pulmonary vasoconstriction (HPV). * This can lead to capillary pressures in some areas that are high enough to damage to capillary walls. * Thus there is oedema in these parts of the lungs. * (West, 1992) suggested this idea of stress failure first.

Answer 135

It is patchy, unlike the oedema in heart failure.

Answer 136

(Grunig, 1997): * HAPE-susceptible volunteers have exaggerated HPV at sea level, suggesting that high pulmonary pressure may predispose to oedema at altitude

Answer 137

(Swenson, 2012): * Flushed the lungs of healthy and HAPE-prone subjects with a fluid * Measured the albumin concentration in this fluid, as well as the pulmonary arterial pressure * As expected, those who were most severely ill had the highest pulmonary arterial pressure and also had high levels of albumin in the fluid * This albumin is evidence of stress failure of capillaries causing the HAPE

Answer 138

* HACE is thought to be an inflammatory process that disrupts the BBB (secondary to the hypoxaemia of altitude) * HAPE is thought to be due to stress failure of capillaries during uneven HPV (hypoxic pulmonary vasoconstriction) These differences are evidenced by the presence or absence of inflammatory cells in the alveoli/brains of patients.

Answer 139

(Sartori, 1999): * Compared 16 climbers prone to HAPE with 16 climbers resistant to HAPE at 4556m * In the 16 susceptible climbers, endothelin-1 levels were significantly elevated * Endothelin-1 is a potent vasoconstrictor released by the endothlium

Answer 140

* Inhaled beta-2 agonists (i.e. salmeterol) reduce HAPE in susceptible individuals, perhaps by enhancing alveolar fluid clearance. * Intravenous iron infusion rapidly reduces pulmonary artery pressure at high altitude. This is in keeping with a role for hypoxia-inducible factor in the pulmonary vascular response to high altitude.

Answer 141

* High altitude pulmonary hypertension (subacute mountain sickness) * Chronic mountain sickness

Answer 142

* High altitude pulmonary hypertension involves remodelling of the pulmonary vasculature such that the vessels are narrowed and there is pulmonary hypertension * It is a chronic condition caused by chronic hypoxia * The hypertension can lead to right sided heart failure and enlargement

Answer 143

Brisket disease: * Lowland cattle taken to altitude in the early 1900s often died, with dependent oedema and poor exercise tolerance * This was not acute, but took a while to happen * Invasive measurements of pulmonary artery pressure revealed a progressive rise over weeks at altitude * The rise in pressure seems almost universal, but varies considerably in magnitude * In some cases it is severe enough to cause right heart failure (i.e. cor pulmonale)

Answer 144

Right heart failure at altitude does not reverse acutely with oxygen, but does resolve slowly after weeks at sea level.

Answer 145

(Groves, 1987): * The pulmonary vascular pressure gradient normally increases slightly as cardiac output increases * Studied 8 male volunteers by decompressing them in a hypobaric chamber for 40 days to a barometric pressure (PB) of 240 Torr, equivalent to the summit of Mt. Everest. * Took haemodynamic measurements at the equivalents of 3 heights. * With altitude, the relationship between cardiac output and pulmonary pressure steepens. * This suggests a progressively less distensible pulmonary circulation, which provides evidence that sub-acute mountain sickness is caused by vascular remodelling that leads to pulmonary hypertension.

Answer 146

* Endothelin antagonists (Chen, 1995) * Inactivationof HIF

Answer 147

* HAPE is an acute event, while high altitude pulmonary hypertension is subacute (since it takes some time for vascular remodelling to occur). * However, both conditions are related and feature hypertension since HAPE involves uneven HPV that raises pulmonary pressure.

Answer 148

* A condition seen in people living at high altitude for a long time, characterised by symptoms of headache, dizziness, fatigue and paraesthesia. There is also often severe pulmonary hypertension. * The mechanism involves excessive erythropoiesis such that the viscosity of the blood is increased.

Answer 149

Diagnosis is based upon elevated haemoglobin (≥19 g/dL in females, ≥21 g/dL in males) and severe hypoxaemia in high altitude natives (\>2500 m).

Answer 150

(Monge, 1987): * CMS is classically thought to be due to a loss of ventilatory adaptation to high altitude, such that hypoxaemia develops and so there is secondary erythrocytosis and pulmonary hypertension * When plotting haematocrit against ventilation, there is an inverse relationship between the two. * Patients with CMS are those with the lowest ventilation and highest haematocrit, suggesting that the erythocytosis is secondary to low ventilation. (Bermudez, 2020): * More recent data suggests that CMS may actually be the result of differences in gene expression that affect erythropoiesis. * Under normoxic conditions, SENP1 expression is equally low in both CMS patients and non-CMS patients * Under hypoxic conditions, SENP1 expression is very elevated, but only in CMS patients

Answer 151

* Intermittent or permanent relocation to lower altitude is effective at limiting erythrocytosis, but may be very difficult. * Venesection produces symptomatic benefit but the effects may be shortlived (and iron deficiency could exacerbate pulmonary hypertension) * Acetazolamide seems to produce improvements in oxygenation and haemoglobin in high altitude residents wit CMS (Richalet, 2008)

Answer 152

* Acute mountain sickness -\> A mild form illness upon first ascent to altitude, thought to be largerly due to changes in cerebral blood flow and a small degree of cerebral oedema * HACE -\> A more severe form of acute mountain sickness, with more severe cerebral oedema. Thought to involve inflammation. * HAPE -\> Oedema of the lungs, involving stress failure of capillaries due to uneven hypoxic pulmonary vasoconstriction (rather than an inflammtory process). * Subacute mountain sickness -\> A.K.A. High altitude pulmonary hypertension. Due to vascular remodelling causing the pulmonary vessels to become less compliant. * Chronic mountain sickness -\> Chronic condition that involves excessive erythopoiesis in hypoxic conditions.

Answer 153

* Tibetans have a very low prevalence of CMS, due to a high allele frequency of a certain allele for the EPAS1 gene, which encodes HIF-2α (Beall, 2010). The allele is associated with low haemoglobin concentration compared to the Han Chinese, but the allele is also associated with improved oxygen transport. These results suggest a degree of selection against HIF-driven erythropoiesis due to the high risk of chronic mountain sickness, although there is a possibility that selection happened against another aspect of the human phenotype that EPAS1 determines. * On the other hand, Andeans tend to show significantly greater erythropoiesis, which is associated with chronic mountain sickness.

Answer 154

In a lab: * Controlled conditions * Safe for participants and investigators * Easy troubleshooting * Predictability On a mountain: * Time efficiency * Local populations * International collaboration * Exciting for researchers * High impact

Answer 155

* Carried out a genome-wide allelic differentiation scan to compare Tibetans with Han Chinese * 8 SNPs achieved genome-wide significance close to EPAS1 * There was strong linkage disequilibrium between these SNPs and the SNPs within EPAS1 (i.e. these SNPs are co-inherited with EPAS1 because they are close to it on the chromosome) * These 8 SNPs formed an extended haplotype (set of a genes inherited together from a single parent) that had a frequency of 46% in the Tibetans but only 2% in the Han Chinese * This explains why Tibetans have a very low prevalence of CMS, due to a high allele frequency of a certain allele for the EPAS1 gene, which encodes HIF-2α * The allele is associated with low haemoglobin concentration compared to the Han Chinese, but the allele is also associated with improved oxygen transport. * Homozygotes for this allele have haemoglobin around 1g/dL than heterozygotes.

Answer 156

* Aimed to find genes that could be related to Tibetans' adaptation to high altitude * First, identified candidate genes by selecting genes with a known function that could be related to high altitude adaptation * Secondly, a genome-wide scan was conducted to identify regions that show strong evidence of local positive selection in high-altitude Tibetans ASK AND DD INFORMATION

Answer 157

1. Low haemoglobin concentration (Beall, 1998) 2. High birth weight at altitude (Moore, 2001) -\> There is usually a fall in birthweight with increasing altitude, but Tibetans experience a much smaller fall compared to Han Chinese 3. Low prevalence of chronic mountain sickness (Moore, 2001) 4. Low HPV (Groves, 1993) 5. High hypoxicventilatory response

Answer 158

* They have blunted physiological responses to hypoxia (due to genetic variation in the HIF pathway) * This is contrasted by patients at sea level with mutations in the HIF pathway that lead to exaggerated responses to hypoxia

Answer 159

(Yi, 2010): * Sequenced 50 exomes * Did not find any significant SNPs in the exos * However, they did find 2 highly divergent SNPs in the introns (very close to the exons which is why they were picked up) close to the EPAS1 gene * These SNPs could have an effect by being parts of promoter regions, etc.

Answer 160

(Petousi, 2014): * Found two SNPs in exon 1 of EGLN1 that are found in high frequency in Tibetans -\> The two SNP frequently co-occur * These variants are found in lower frequency in other Asians and are rare in Caucasians * Also studied the relationship between the genotype and phenotype * Found that those homozygous for the variant showed a more blunted erythropoietin response to hypoxia * However, studies of Hb at altitude showed mixed results (Lorenzo, 2014): * Found that the frequency of these variants in Tibetans increases with altitude

Answer 161

* EPAS1 variants are in the introns -\> This affects promoter regions, etc. * EGLN1 variants are in the exons -\> This affects the actual structure of the protein

Answer 162

* EGLN1 encodes PHD2, so logically it would make sense for it to be a gain of function mutation, since this would lead to reduced accumulation of HIF -\> This would explain the reduced response to hypoxia seen in Tibetans (except the increased ventilation) * (Lorenzo, 2014): * Showed that the existence of a gain of function mutation in EGLN1 in Tibetans * However, there is some contradictory evidence. * (Song, 2020): * Created a mouse model for the Tibetan EGLN1 mutation. * Found that right ventricular systolic pressure (a measure of pulmonary hypertension) was not affected by the EGLN1 (PHD2) mutation, but the EPAS1 (HIF2a) mutation (diagram B). * The EGLN1 mutation mice showed a higher hypoxic ventilatory response (diagram A) which suggests a loss of function mutation in the EGLN1 (PHD2). See next flashcard if unsure.

Answer 163

* It would seem that all of these effects should be either elevated or blunted since they are all under the control of the HIF pathway. * (Song, 2020): * Created a mouse model for the Tibetan EGLN1 mutation and compared it to a wild-type mouse. * Found that right ventricular systolic pressure (a measure of pulmonary hypertension) was not affected by the EGLN1 (PHD2) mutation, but the HIF2a mutation (diagram B). * The EGLN1 mutation mice showed a higher hypoxic ventilatory response (diagram A). * These results suggests that Tibetans have a loss of function mutation in ELGN1 (PHD2) leading to an elevated hypoxic ventilatory response and a loss of function mutation in EPAS1 (HIF2a) leading to reduced pulmonary hypertension and blunted haemoglobin.

Answer 164

* Whole body immersion exerts pressure that compresses the limbs -\> Increases venous return and central blood volume by around 700 ml * There is also decreased lung volume by compression (less so when using SCUBA, since the air is delivered at ambient pressure) * Right atrial and pulmonary arterial pressure increased by 15-20 mmHg * Stroke volume and cardiac output by up to 30% * The increased blood pressure leads to increased natriuresis and diuresis * The increased blood pressure is further exacerbated by cold-induced vasoconstriction

Answer 165

* Hydrostatic pressure at the start of the pulmonary arteries is increased (due to compression of the limbs and peripheral vasoconstriction causing increased central volume) * But the colloid pressure throughout the arteries is unchanged * Overall, Starling forces mean that there is a net outwards force that causes fluid movement out of the vessels and into the alveoli * This pleural effusion leads to stiffer lungs, increased pulmonary vascular resistance and increased pulmonary arterial pressure * Eventually, there is pleural oedema, leading to reduced surface for gas exchange

Answer 166

* Certain breathing systems can increase the work required to breathe, resulting in a low pressure in the alveoli * This low pressure affects Starling forces, causing more fluid to be dragged out from the blood vessels * For example, a back-mounted closed-circuit rebreather can involve the air bag being at higher pressure than the lungs * Over 40 years, 11 cases of IPO have been recorded in French navy divers, probably due to negative-pressure breathing

Answer 167

* Nifedipine * Sildenafil

Answer 168

* Hyper-hydration * Exertion * Cold-induced vasoconstriction * Hypertension * Increased gas density at depth * Work of breathing

Answer 169

For every 10m, the pressure increases by 1 atmosphere.

Answer 170

P₁V₁ = P₂V₂

Answer 171

* The amount of gas that will dissolve in a liquid is almost directly proportional to the partial pressure of that gas. * It is time-dependent and temperature-dependent, where higher temperature makes the gas less soluble.

Answer 172

No, because the diver is breathing air at ambient pressure.

Answer 173

* At the surface, your tissues are in equilibrium with the environment (i.e. your lungs) * As you descend, the partial presssure of the gases in your lungs increases, driving fluxes towards tissues * A new equilibirum is eventually established * Upon return to the surface, the fluxes are reversed

Answer 174

* Gas saturation changes exponentially with time (since gas fluxes take time to happen) * The body can be divided into several compartments (e.g. the Buhlmann ZH 16 algorithm) based on how long it takes for that tissue to become saturated * The nervous system and spine get saturated very fast (fast tissues), whereas fat and bonessaturate very slowly (slow tissues)

Answer 175

* When diving, the body's tissues become saturated with high partial pressure of gases being breathed in (including oxygen and nitrogen) since these are administered at ambient pressure * Many gases are mild anaesthetics and the effects are directly related to partial pressure * Thus, inert gas narcosis includes effects similar to alcohol * The mechanism is not known but is thought to maybe involve disruption of the lipid bilayer by the gas

Answer 176

* Subjects were exposed to gas at 1 atm and then at 6 atm * The average reaction time for the Stroop test was over 2 seconds slower at 6 atm and the accuracy was far worse * This shows that executive functions are impaired by inert gas narcosis [FIND REFERENCE]

Answer 177

* Acclimatisation can occur with subsequent dives * Effect is increased when PCO₂ is high (e.g. when exercising)

Answer 178

Lorrain Smith effect (Pulmonary oxygen toxicity): * Pulmonary oxygen toxicity can occur with piO2 values as low as 0.5 ATA if the exposure is sufficiently long * Can be found in ICU and hyperbaric medicine units * It involves damage to the lung epithelium and lung oedema (fibrosis etc.) since there is a lack of antioxidants -\> This results in hypoxaemia Paul Bert effect (CNS oxygen toxicity): * A grand mal seizure can occur if a subject breath oxygen at 3 ATA but can also occur at pO2 of 2 ATA (at rest) for a prolonged period * Signs of acute O₂ toxicity: visual disturbances, ringing in the ears, dizziness, mood swings, convulsions, coma

Answer 179

(Demchenko, 2007): * Studied the bronchoalveolar lavage fluid from rats after exposure to normobaric or hyperbaric oxygen. * The number of inflammatory cells increased gradually over 56hrs in the group at 1 ATA oxygen and much faster in the groups at 2, 2.5 and 3 ATA * Lactate dehydrogenase is a marker of cell damage * Similar trends of lactate dehydrogenase concentration were seen as with the inflammatory cells

Answer 180

Exsudative stage: * There is pulmonary oedema, with breakdown of the pulmonary epithelium and an inflammatory infiltrate Proliferative stage: * Occurs when the exudative stage resolves and there is fibrotic tissue Overall this means that the work of breathing increases and there is hypoxaemia.

Answer 181

* Reactive oxygen species (produced due to high partial pressures of oxygen) lead to: * Membrane disruption / inactivation of cell membrane transport * Protein / enzyme inactivation * Impaired electron transport * DNA and RNA damage * ROS react with NO to produce ONOO^-(peroxynitrite) that reacts with protein tyrosines to nitrate them -\> This is thought to be the cause of seizures (Chavko, 2003) * This can lead to lipid peroxidation and GABA metabolism is disrupted, contributing to seizure onset

Answer 182

(Chavko, 2003): * Used a Western blot to measure the number of nitrated tyrosines over time with exposure to hyperbaric oxygen * After exposures, brains were analyzed for protein nitrotyrosine (NT), with NT concentration increasing with time * An NOS inhibitor can be used to block this effect

Answer 183

Often a gas mixture is used that has less N₂ and O₂, helping to avoid the toxicity of these gases.

Answer 184

* Mixtures containing lots of O₂ and N₂ may only be used near the surface and at slight depths * Mixtures with less O₂and N₂may be used at greater depths but not near the surface so a second gas mixture must be carried

Answer 185

Barotraumas are injuries that are caused by changes in pressure in certain body compartments.

Answer 186

* Pulmonary over-inflation barotrauma is the second most common cause of death in divers aside from drowning * Caused by: * Breath-holding during ascent * Uncontrolled ascent * Inhaling while pushing the “purge” button * Air trapped in the lung * Symptoms: * Most (95%) cases show varying systemic neurologic signs but vital signs preserved * Few (5%) cases show apnea, unconsciousness and cardiac arrest

Answer 187

Decompression from saturation is associated with formation of inert gas bubbles (usually nitrogen) in the tissue and veins (venous gas emboli, VGE).

Answer 188

There are multiple theories of bubble formation, including: microbubbles/micronuclei (little direct evidence), crevice model, tribonucleation and differential bubble seeding depending upon substrate (e.g. fat/muscle)

Answer 189

There is less oxygen in veins so there is a large nitrogen gradient for the formation of N₂ bubbles.

Answer 190

Bubbles can be detected using Doppler ultrasound.

Answer 191

(Zhang, 2016): * Found that the numbers of bubbles correlate with decompression rate * The number of bubbles peaked about 20 minutes after decompression * The 3 minute ascent peaked at a bubble score of 4, while the 5 minute ascent peaked at a bubble score of 2 on average (Papadopoulou, 2015): * The higher the bubble grade, the high the risk of adverse effects

Answer 192

* Yes, significant inter-personal variability is seen under the same controlled conditions * Various factors can affect bubble formation: * Exact dive profile * Previous exposures * Hydration * Vascular health * Thermal comfort * Exercise/workload * State of mind * Silent bubbles (Papadopoulou, 2018)

Answer 193

* Activate innate immunity (complement) * Damage the endothelium, activating endothelial markers of stress: * There are increased levels of endothelin and decreased levels of NO * Subsequently, there is activation of inflammatory pathways (↑TNF-a, IFN-g and IL-6) Endothelial activation correlates with bubble number.

Answer 194

* Endothelial cells respond to microbubble contact via mechano-transduction responses * Bubble contact stimulates extracellular calcium entry -\> (Kobayashi, 2011) used fluorescence microscopy images to show that calcium entry occurs shortly after bubble contact * Superoxide and peroxynitrite ions are formed in endothelial cells and are involve in the attenuation of NO and cell death * Bubble contact and pressure change also drives the release of EMPs (Endothelial microparticles), which have a role in coagulation, inflammation, endothelial function, and angiogenesis

Answer 195

* Endothelial microparticles * These are complex vesicular structures shed from endothelial cells (100 nm to 1 μm in diameter) * Their release is driven by bubble contact and pressure changes * They have a role in coagulation, inflammation, endothelial function, and angiogenesis * They are proposed to be a cause of DVT during flying and can pass through the lugs and have secondary systemic effects

Answer 196

* They are mostly filtered out by the lungs * If there are too many bubbles (or under certain circumstances) these bubbles can bypass the lung filter and enter the arterial circulation * Arterialisation of gas emboli can lead to symptoms of decompression sickness (DCS)

Answer 197

1. Slow ascent 2. Switching to breathing a gas mixture with more oxygen (rather than nitrogen) during ascent -\> This encourages a lower partial pressure of gases in the venous circulation (since the oxygen is metabolised in tissues), so that nitrogen gas is dragged out from tissues and bubbles into the venous blood. This allows it to be breathed out. 3. Exercise before diving 4. Exercise during ascent (but NOT during descent) 5. Avoiding exercise after diving

Answer 198

* The difference between the partial pressure of oxygen in arterial blood and in body tissues. * It is caused by metabolic consumption of oxygen.

Answer 199

* Aerobic exercise immediately before diving reduces VGE formation * This is likely to be because exercise improves endothelial NO bioavailability * This leads to: * Improved endothelial health * Less local sheer stress-induced inflammation * Less bubble-mediated dysfunction * NOS inhibition increases bubble formation in experimental models [FIND REFERENCES]

Answer 200

* Exercise during compression: * The raised cardiac output increase gas loading (so tissues are more saturated), narcosis severity (CO₂) and O₂ toxicity * This increases the likelihood of VGE * Exercise during decompression (ascent) * Moderate swimming performed during a 3 min decompression stop reduces post-dive VGE and may reduce the number of nuclei from which bubbles form [FIND REFERENCES]

Answer 201

* It can increase the risk of VGE * This is because cardiac output may be increased to the extent that VGEs pass quickly through the lungs without being filtered out * Thus, arterialisation occurs, which is the cause of decompression sickness * (Eldridge, 2004): * Studied 24 men who were subjected to exercise of progressive intensity, up to VO₂_max. * Contrast echocardiography was used to detect the first % of the VO_2max at which shunting occurred. * In all cases, the intrapulmonary shunting developed at submaximal exercise levels.

Answer 202

* Decompression sickness (DCS) -\> Caused by the formation of intra-corporeal bubbles resulting in a drop in pressure * Decompression Illness (DCI) -\> A combination of DCS and arterial gas embolism (AGE) which can be as a result of barotrauma, shunt or rapid decompression.

Answer 203

It depends on where the arterialised bubbles end up, but symptoms include: * Joint pain * Neurological symptoms * Audio-vestibular symptoms * Cutaneous symptoms * Cardiopulmonary symptoms * Lymphatic symptoms * Girdle pain * Constitutional

Answer 204

Hypobaric Oxygen Treatment: * This is recompression with hyperbaric oxygen * Essentially, the patient experiences a bubble-crushing ‘dive’ with slow and controlled decompression

Theme 1: Extreme Environments Flashcards

(237 cards)