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When using a new noninvasive method for measuring the efficiency of pulmonary gas exchange, a key measurement is the oxygen deficit, defined as the difference between the end-tidal alveolar Po2 and the calculated arterial Po2. The end-tidal Po2 is measured using a rapid gas analyzer, and the arterial Po2 is derived from pulse oximetry after allowing for the effect of the Pco2 on the oxygen affinity of hemoglobin. In the present report we show that the values of end-tidal Po2 and Pco2 are highly reproducible, providing a solid foundation for the measurement of the oxygen deficit. We compare the oxygen deficit with the classical ideal alveolar-arterial Po2 difference (A-aDO2) as originally proposed by Riley, and now extensively used in clinical practice. This assumes Riley’s criteria for ideal alveolar gas, namely no ventilation-perfusion inequality, the same Pco2 as arterial blood, and the same respiratory exchange ratio as the whole lung. It transpires that, in normal subjects, the end-tidal Po2 is essentially the same as the ideal value. This conclusion is consistent with the very small oxygen deficit that we have reported in young normal subjects, the significantly higher values seen in older normal subjects, and the much larger values in patients with lung disease. We conclude that this noninvasive measurement of the efficiency of pulmonary exchange is identical in many respects to that based on the ideal alveolar Po2, but that it is easier to obtain.

The oxygen deficit (OD) is the difference between the end-tidal alveolar Po2 and the calculated Po2 of arterial blood based on measured oxygen saturation that acts as a proxy for the alveolar-arterial Po2 difference. Previous work has shown that the alveolar gas meter (AGM100) can measure pulmonary gas exchange, via the OD, in patients with a history of lung disease and in normal subjects breathing 12.5% O2. The present study measured how the OD varied at different values of inspired O2. Healthy subjects were split by age (young 22–31; n = 23; older 42–90; n = 13). Across all inspired O2 levels (12.5, 15, 17.5, and 21%), the OD was higher in the older cohort 10.6 ± 1.0 mmHg compared with the young −0.4 ± 0.6 mmHg ( P < 0.0001, using repeated measures ANOVA), the difference being significant at all O2 levels (all P < 0.0001). The OD difference between age groups and its variance was greater at higher O2 values (age × O2 interaction; P = 0.002). The decrease in OD with lower values of inspired O2 in both cohorts is consistent with the increased accuracy of the calculated arterial Po2 based on the O2-Hb dissociation curve and with the expected decrease in the alveolar-arterial Po2 difference due to a lower arterial saturation. The persisting higher OD seen in older subjects, irrespective of the inspired O2, shows that the measurement of OD remains sensitive to mild gas exchange impairment, even when breathing 21% O2.

Fritz Rohrer (1888–1926) has a special place in the history of respiratory physiology for two reasons. The first is that he laid the foundations of modern pulmonary mechanics in the early 1900s. For example, his seminal paper on pulmonary dynamics, that is, the pressure-flow relationships in the airways, was published in 1915 in one of the top journals in the field. It included extensive measurements of airway dimensions in postmortem human lungs and a sophisticated analysis of the modes of airflow. This was closely followed by a very original analysis of lung statics, which included studies of airway pressures at normal, maximal, and minimal lung volumes in relaxed normal volunteers, and was published in 1916. Remarkably, both papers were essentially ignored at the time. Fortunately, in 1925 he was able to summarize his major findings in a chapter in an important handbook of physiology. However, he tragically died from pulmonary tuberculosis in the following year at the early age of 37. The second reason for his importance in the history of pulmonary mechanics is that inexplicably his very innovative research was essentially ignored for about 30 years. It was not until the 1940s that his work was rediscovered, although not in time to save investigators from duplicating his very original studies. Possible reasons why his work was ignored for so long are discussed. Even today it is not easy to recover some important features of his career, and some aspects of his very original research are still almost unknown.

The efficiency of pulmonary gas exchange is often assessed by the ideal alveolar-arterial partial pressure difference (A-aDO2). Through a combination of pulse oximetry and rapidly responding gas analyzers to measure the partial pressures of O2 and CO2 in expired gas, one can measure the oxygen deficit. Defined as the difference between the measured alveolar Po2 and the arterial Po2 calculated from [Formula: see text], the oxygen deficit is a substitute for the alveolar-arterial Po2 difference. The oxygen deficit is physiologically reasonable in that it increases with age in healthy subjects and is well correlated with the A-aDO2. To calculate arterial Po2 from saturation, the saturation should be below the very flat upper part of the O2-Hb dissociation curve; good estimates can be made provided the arterial O2 saturation is below ~95%. Since saturations at or above 95% imply reasonably well-maintained gas exchange efficiency, this limitation is of only minor concern. Calculations show that it is necessary to take into account the change in Po2 at a saturation of 50% of the O2-Hb dissociation curve based on the measured alveolar Pco2. As the measurement is designed to be noninvasive, determination of any base excess is not practical, but calculations show that the effect of assuming a zero base excess is modest, with a similar small effect from an abnormal body temperature. Taken together, these results show that a noninvasive assessment of pulmonary gas exchange efficiency can be obtained from subjects with below-normal arterial O2 saturations through a combination of expired O2 and CO2 measurements and [Formula: see text] made during quiet breathing. NEW & NOTEWORTHY The details and limitations of a noninvasive measurement of pulmonary gas exchange efficiency, the oxygen deficit, are described. The oxygen deficit, calculated from expired gas measurements made during quiet breathing coupled with pulse oximetry, is a good surrogate measurement of the ideal alveolar-arterial Po2 difference and does not require arterial blood gas sampling.

As earthlings, we take the oxygen in the air that we breathe for granted. Few people realize that this easy access to oxygen makes us unique in the whole universe. Nowhere else in our planetary system or in distant stars has stable oxygen ever been detected. However, the present plentiful supply of oxygen in our atmosphere was not always there. Long after the Earth was formed some 4.5 billion years ago, the Po2 in the atmosphere was near zero, and it remained so for millions of years. But about 2 billion years ago, the Po2 dramatically increased to as high as 200 mmHg during the Great Oxygen Event, due to the activity of microorganisms, the cyanobacteria. Subsequently, the oxygen level fell to the intermediate values that we have today. Here, we also look to the future, for example, the next 50 years. This period will be special because it will include the beginnings of human space exploration, initially to the Moon and Mars. Neither of these has atmospheric oxygen. Nevertheless, plans to visit and live on both of these are developing rapidly. We consider the fascinating problems of how to ensure that sufficient oxygen will be available for the groups of people. Although it is interesting to discuss these issues now, we can expect that major advances will be made in the next few years.

West, John B. High altitude limits of living things. High Alt Med Biol 00:000–000, 2021.—The tolerance of animals to high altitude is generally limited by the low partial pressure of oxygen (PO2) i...

History has been kind to Christian Bohr (1855–1911). His name is attached eponymously to three different areas of respiratory physiology. The first is the Bohr dead space, which refers to the portion of the tidal volume that does not undergo gas exchange. The second is the increase in oxygen affinity of hemoglobin caused by the addition of carbon dioxide to the blood. This is known as the Bohr effect and is a very important feature of gas exchange, both in the lung and in peripheral tissues. Both of these contributions by Bohr are familiar to most students. Bohr’s third contribution refers to the calculation of the changes in the Po2 of blood as oxygen is loaded in the pulmonary capillary, the so-called Bohr integration. This contribution is less well known now, partly because of the advent of digital computing, but it was important in its day. The analysis is challenging because the very nonlinear shape of the oxygen dissociation curve means that the Po2 difference between the alveolar gas and the capillary blood, which is the driving pressure for diffusion, changes in a complicated way. All three papers are in German, and two of them are long and tedious to read. English translations are available, but few people read the papers, despite the fact that the first two articles are very frequently cited. In the present article, Bohr’s contributions are reviewed, and some parts of the articles that are particularly difficult to understand are clarified.

A new noninvasive method was used to measure the impairment of pulmonary gas exchange in 34 patients with lung disease, and the results were compared with the traditional ideal alveolar-arterial Po2 difference (AaDO2) calculated from arterial blood gases. The end-tidal Po2 was measured from the expired gas during steady-state breathing, the arterial Po2 was derived from a pulse oximeter if the [Formula: see text] was 95% or less, which was the case for 23 patients. The difference between the end-tidal and the calculated Po2 was defined as the oxygen deficit. Oxygen deficit was 42.7 mmHg (SE 4.0) in this group of patients, much higher than the means previously found in 20 young normal subjects measured under hypoxic conditions (2.0 mmHg, SE 0.8) and 11 older normal subjects (7.5 mmHg, SE 1.6) and emphasizes the sensitivity of the new method for detecting the presence of abnormal gas exchange. The oxygen deficit was correlated with AaDO2 ( R2 0.72). The arterial Po2 that was calculated from the noninvasive technique was correlated with the results from the arterial blood gases ( R2 0.76) and with a mean bias of +2.7 mmHg. The Pco2 was correlated with the results from the arterial blood gases (R2 0.67) with a mean bias of −3.6 mmHg. We conclude that the oxygen deficit as obtained from the noninvasive method is a very sensitive indicator of impaired pulmonary gas exchange. It has the advantage that it can be obtained within a few minutes by having the patient simply breathe through a tube.

Alexander von Humboldt (1769–1859) was one of the most distinguished German scientists of the late 18th and early 19th centuries. His fame came chiefly from his extensive explorations in South America and his eminence as a plant naturalist. He attempted to climb the inactive volcano Chimborazo in Ecuador, which was thought to be the highest mountain in the world at the time, and he reached an altitude of about 5,543 m, which was a record height for humans. During the climb, he had typical symptoms of acute mountain sickness, which he correctly attributed to the low level of oxygen, and he was apparently the first person to make this connection. His ability as a naturalist enabled him to recognize the effect of high altitude on the distribution of plants, and by comparing his observations on Chimborazo with those in the European Alps and elsewhere, he inferred that the deleterious effects of high altitude were universal. During his return trip to Europe, he called on President Thomas Jefferson in Washington, where he was given a warm reception, and discussed conservation issues. He then returned to Paris, where he produced 29 volumes over a period of 31 years describing his travels. Here the effects of high altitude on the distribution of plants compared with animals are briefly reviewed. Following Humboldt’s death in 1859, there was extensive coverage of his contributions, but curiously, his fame has diminished over the years, and inexplicably, he now has a lower profile in North America.

A number of Healthcare Practitioners (HCPs), mostly from Black, Asian and minority ethnic (BAME) origin have died with COVID-19. This survey aimed to explore the views of an ethnically diverse sample of HCPs in the UK about COVID-19-related deaths among HCPs in general and BAME HCPs in particular.It is a cross-sectional prospective survey of HCPs in UK and was conducted online using Google Forms between 28th April and 4th May 2020.A total of 1119 UK HCPs (aged 45.0 ± 9.5 years, 56% males, 71% BAME) participated. Seventy-two per cent of respondents reported being worried about COVID-19 and 84% had concerns about personal protective equipment (PPE). Almost all (93%) respondents felt that inadequate PPE may be a contributory factor to HCP deaths. Half of the respondents, especially younger and BAME, reported feeling unable to say 'no', if asked to work without adequate PPE. BAME HCPs were considered at a higher-risk of acquiring coronavirus and dying with COVID-19. Reasons for excess BAME HCP deaths were believed to be comorbidities, inadequate PPE and working in high-risk areas. Majority (81%) of respondents felt that the government has been slow to respond to COVID-19 related deaths in HCPs and 67% HCPs were of the opinion that BAME workers with risk factors should be removed from direct clinical care.HCPs have significant COVID-19-related concerns. BAME HCPs are considered at increased risk due to comorbidities, working in high-risk areas, and inadequate PPE. BAME HCP should have a thorough risk assessment and high-risk HCPs may need work adjustment or redeployment. All HCPs must have appropriate training and provision of PPE.

When using a new noninvasive method for measuring the efficiency of pulmonary gas exchange, a key measurement is the oxygen deficit, defined as the difference between the end-tidal alveolar Po

The oxygen deficit (OD) is the difference between the end-tidal alveolar Po

Background It would be valuable to have a noninvasive method of measuring impaired pulmonary gas exchange in patients with lung disease and thus reduce the need for repeated arterial punctures. This study reports the results of using a new test in a group of outpatients attending a pulmonary clinic. Methods Inspired and expired partial pressure of oxygen (PO 2 ) and Pco 2 are continually measured by small, rapidly responding analyzers. The arterial PO 2 is calculated from the oximeter blood oxygen saturation level and the oxygen dissociation curve. The PO 2 difference between the end-tidal gas and the calculated arterial value is called the oxygen deficit. Results Studies on 17 patients with a variety of pulmonary diseases are reported. The mean ± SE oxygen deficit was 48.7 ± 3.1 mm Hg. This finding can be contrasted with a mean oxygen deficit of 4.0 ± 0.88 mm Hg in a group of 31 normal subjects who were previously studied ( P 2 to calculate the alveolar-arterial oxygen gradient. Conclusions The results previously reported in normal subjects and the present studies suggest that this new noninvasive test will be valuable in assessing abnormal gas exchange in the clinical setting.

We are developing a novel, noninvasive method for measuring the efficiency of pulmonary gas exchange in patients with lung disease. The patient wears an oximeter, and we measure the partial pressures of oxygen and carbon dioxide in inspired and expired gas using miniature analyzers. The arterial Po2 is then calculated from the oximeter reading and the oxygen dissociation curve, using the end-tidal Pco2 to allow for the Bohr effect. This calculation is only accurate when the oxygen saturation is 2 difference between the end-tidal and arterial values is called the “oxygen deficit.” Preliminary data show that this index increases substantially in patients with lung disease. Here we report measurements of the oxygen deficit in 20 young normal subjects (age 19 to 31 yr) and 11 older normal subjects (47 to 88 yr). The mean value of the oxygen deficit in the young subjects was 2.02 ± 3.56 mmHg (means ± SD). This mean is remarkably small. The corresponding value in the older group was 7.53 ± 5.16 mmHg (means ± SD). The results are consistent with the age-related trend of the traditional alveolar-arterial difference, which is calculated from the calculated ideal alveolar Po2 minus the measured arterial Po2. That measurement requires an arterial blood sample. The present study suggests that this noninvasive procedure will be valuable in assessing the degree of impaired gas exchange in patients with lung disease.

West, John B. Are permanent residents of high altitude fully adapted to their hypoxic environment? High Alt Med Biol. 18:135-139, 2017.-Millions of people live permanently at high altitude and many have been there for generations. It is sometimes claimed that these people have completely adapted to their environment, and certainly some remarkable genetic adaptations have recently been described. However there is now strong evidence that permanent residents are not completely adapted to the high altitude in the sense that they have fully compensated for the environmental hypoxia. By sea level standards, highlanders have severe chronic arterial hypoxemia. Furthermore, their maximum oxygen uptake increases if they descend, and recent measurements suggest that cognitive function is reduced in this population compared with a matched group at a lower altitude. Reproductive success is reduced at high altitude because neonatal mortality increases with altitude. The topic has recently gained importance because new technology enables the physiological altitude of permanent residents to be reduced by adding oxygen to the air of buildings on a large scale, a procedure known as oxygen conditioning. Its feasibility has been questioned, but in essence it is no different from air conditioning that is universally used to improve the well-being and productivity of millions of people in hot climates. Oxygen conditioning has the potential to do the same for permanent residents of high altitude.

One of the most interesting unanticipated findings by André Cournand and Dickinson Richards in their groundbreaking studies of cardiac catheterization was the very low pressure in the normal pulmonary circulation. At the time, in the 1940s, the significance of this was not appreciated. For example, in their speeches at the Nobel Prize ceremony, neither of these laureates referred to the low pressure, although they did discuss other features of the pulmonary circulation. It was up to the cardiologist, William Dock, to point out that these low pressures implied a very uneven distribution of blood flow in the lung, and in particular that in the normal upright lung, the blood flow to the apex would be extremely small. Dock went on to argue that this low blood flow at the top of the lung was responsible for the characteristic apical distribution of adult pulmonary tuberculosis. Since that time, it has been recognized that the low pressures in the pulmonary circulation have many implications in pulmonary pathophysiology. For example, if the vascular pressure is further reduced, such as in hemorrhagic shock, gas exchange is seriously affected because of the development of a large alveolar dead space. Furthermore, if humans are subjected to increased acceleration, such as in a high-performance aircraft, the distribution of blood flow becomes extremely abnormal, with much of the lung being completely unperfused. There are also diseases where distribution in the lung is affected by the uneven distribution of blood flow. These include alpha-1 antitrypsin deficiency and metastatic calcification of the lung.

Pulmonary gas exchange is the primary function of the lung, and during my lifetime, its measurement has passed through many stages. When I was born, many physiologists still believed that the lung secreted oxygen. When I was a medical student, the only way we had to recognize defective gas exchange was whether the patient was cyanosed. The advent of the oximeter soon showed that this sign could be very misleading. A breakthrough was the introduction of blood gas electrodes that could measure the PO 2, PCO 2, and pH of a small sample of arterial blood. It was soon recognized that the commonest cause of hypoxemia was ventilation‐perfusion inequality, and that this could also be responsible for CO 2 retention. In the early days, the understanding of the mechanisms of pulmonary gas exchange relied on graphical analysis because the oxygen and carbon dioxide dissociation curves are nonlinear and interdependent which precluded algebraic methods. However, with the introduction of digital computing, problems that had hitherto been impossible to tackle became amenable to study. A key advance was the development of the Multiple Inert Gas Elimination Technique. Now, noninvasive methods for measuring gas exchange show promise, and the whole subject continues to develop.

West, John B. Cognitive impairment of school children at high altitude: the case for oxygen conditioning in schools. High Alt Med Biol. 17:203–207, 2016.—The hypoxia of high altitude frequently affects cognitive function. Recent work has shown that high altitude impairs the neuropsychological function of children of school age when compared with a similar control group of children at low altitude. This implies that the learning process is compromised at high altitude. One option is to bus children down to a lower altitude for schooling, but this is generally impracticable. Recently the new technique of oxygen conditioning has been introduced. The procedure is similar to air conditioning except that instead of altering the temperature of the air, the oxygen concentration is increased, thus raising the PO2 in the inspired air of classrooms. The result is that the children are physiologically at a lower altitude. Just as in very hot or cold climates, it is now unacceptable to have schools that are n...

Large numbers of people visit, work, or reside at high altitude. The inevitable hypoxia reduces physical performance and, in many instances, impairs neuropsychological function. The new technique of oxygen conditioning raises the oxygen concentration in the air of buildings such as homes, schools, and hospitals. The result is to decrease the equivalent altitude and improve both physical and cognitive performance.

Frank N. Low (1911–1998) has the distinction of publishing the first electron micrographs showing the ultrastructure of the pulmonary capillary and particularly the blood-gas barrier. This work in 1952 and 1953 was enabled by the progress in fixation and staining of tissue made by George Palade and was part of the very rapid advance in electron microscopy during the previous 25 years. Low's micrographs clearly showed the three layers of the blood-gas barrier: capillary endothelium, extracellular matrix, and alveolar epithelium. The images immediately resolved the debate about the composition of the blood-gas barrier that had been raging for 100 years. The first published micrographs were rather poor, but the quality rapidly improved and a major event was the first electron micrograph of the human blood-gas barrier published in 1953. These images had an enormous influence on the development of pulmonary physiology and biology. For example, for the first time it became clear that the barrier separating the blood from the alveolar gas was vanishingly thin. The discovery of the extracellular matrix layer ultimately clarified how this barrier, despite its extraordinary thinness, was sufficiently strong to avoid mechanical failure. Despite the major advances made by Low, his name is almost unknown in pulmonary physiology and biology, and perhaps this tribute will help to give him his due.

Barcroft's bold assertion that everyone at high altitude has physical and mental impairment compared with sea level was very provocative. It was a result of the expedition that he led to Cerro de Pasco in Peru, altitude 4300 m. Although it is clear that newcomers to high altitude have reduced physical powers, some people believe that this does not apply to permanent residents who have been at high altitude for generations. The best evidence supports Barcroft's contention, although permanent residents often perform better than acclimatized lowlanders. Turning to neuropsychological function, newcomers to high altitude certainly have some impairment, and there is evidence that the same applies to highlanders. However the notion that permanent residents are impaired is anathema to many people. For example the eminent Peruvian physician Carlos Monge took great exception to Barcroft's remark and even attributed it to the fact that Barcroft was suffering from acute mountain sickness when he made it! Monge referred to 'climatic aggression', by which he meant the negative consequences of the inevitable hypoxia of high altitude. Recent technological advances such as oxygen enrichment of room air can overcome this 'aggression'. This might be useful in some settings at high altitude such as a nursery where newborn babies are cared for, and possibly operating rooms where the surgeon's dexterity may be enhanced. Other situations might be dormitories, conference rooms, and perhaps some school rooms. These constitute possible ways by which the effects of Barcroft's assertion might be countered.

High-altitude physiology can be said to have begun in 1644 when Torricelli described the first mercury barometer and wrote the immortal words "We live submerged at the bottom of an ocean of the element air." Interestingly, the notion of atmospheric pressure had eluded his teacher, the great Galileo. Blaise Pascal was responsible for describing the fall in pressure with increasing altitude, and Otto von Guericke gave a dramatic demonstration of the enormous force that could be developed by atmospheric pressure. Robert Boyle learned of Guericke's experiment and, with Robert Hooke, constructed the first air pump that allowed small animals to be exposed to a low pressure. Hooke also constructed a small low-pressure chamber and exposed himself to a simulated altitude of about 2400 meters. With the advent of ballooning, humans were rapidly exposed to very low pressures, sometimes with tragic results. For example, the French balloon, Zenith, rose to over 8000 m, and two of the three aeronauts succumbed to the hypoxia. Paul Bert was the first person to clearly state that the deleterious effects of high altitude were caused by the low partial pressure of oxygen (PO2), and later research was accelerated by high-altitude stations and expeditions to high altitude.

AimTo evaluate the frequent use of ProTaper Next (PTN; Dentsply Maillefer, Ballaigues, Switzerland) systems on shaping ability of root canal utilizing Solidworks (2014, Dassault Systèmes) software.Materials and methodsThirty-six root canals in clear resin blocks (Dentsply-Maillefer) were allocated into six experimental groups (n = 36). Six new sets of PTN instruments (Dentsply Maillefer, Ballaigues, Switzerland) were used six times to shape the resin blocks. A #15 K-file was inserted to the working length (WL), followed by ProGlider (PG) to create a glide path. Sequential use of PTN instrumentation in a crown-down technique was used to reach size (30/07) apically. Macroscopic photos of the blocks were taken before and after instrumentation, layered by Paint Shop Pro 9 from JascSoftware®, and then canal transportation was measured using Solidwork 2014. The data were analyzed by SPSS software version 22. Multivariate statistical analysis general linear model (GLM) was also applied. Bonferroni correction test was used in multiple comparisons and the statistical significance was set to 0.05.ResultsThere was no difference in canal transportation resulted from utilizing PTN files after six multiple uses; in addition, the PTN files showed ability to maintain the original canal anatomy, especially in the apical level, where lowest total mean value of canal center displacement was seen (3 mm level) (0.019 ± 0.017).ConclusionProTaper Next files can be used to prepare single and multiple canals in a single furcated tooth.Clinical significanceProTaper Next nickel-titanium (NiTi) file system is a safe instrument that respects the canal shape, allows practitioners to treat difficult cases with good results, and low risk of separation.How to cite this articleElemam RF, Capelas JA, Vaz MAP, Viriato N, Pereira ML, Azevedo A, West J. Evaluating Transportation by Comparing Several uses of Rotary Endodontic Files. J Contemp Dent Pract 2015;16(12):927-932.

Humphry Davy (1778–1829) has an interesting place in the history of respiratory gases because the Pneumatic Institution in which he did much of his early work signaled the end of an era of discovery. The previous 40 years had seen essentially all of the important respiratory gases described, and the Institution was formed to exploit their possible value in medical treatment. Davy himself is well known for producing nitrous oxide and demonstrating that its inhalation could cause euphoria and heightened imagination. His thinking influenced the poets Samuel Taylor Coleridge and William Wordsworth, and perhaps we can claim that our discipline colored the poetry of the Romantic Movement. Davy was also the first person to measure the residual volume of the lung. The Pneumatic Institution was the brainchild of Thomas Beddoes, who had trained in Edinburgh under Joseph Black, who discovered carbon dioxide. Later Davy moved to the Royal Institution in London formed, in part, to diffuse the knowledge of scientific discoveries to the general public. Davy was a brilliant lecturer and developed an enthusiastic following. In addition he exploited the newly described electric battery to discover several new elements. He also invented the safety lamp in response to a series of devastating explosions in coal mines. Ultimately Davy became president of the Royal Society, a remarkable honor for somebody with such humble origins. Another of his important contributions was to introduce Michael Faraday (1791–1867) to science. Faraday became one of the most illustrious British scientists of all time.

Neonatal mortality increases with altitude. For example, in Peru the incidence of neonatal mortality in the highlands has been shown to be about double that at lower altitudes. An important factor is the low inspired PO2 of newborn babies. Typically, expectant mothers at high altitude will travel to low altitude to have their babies if possible, but often this is not feasible because of economic factors. The procedure described here raises the oxygen concentration in the air of rooms where neonates are being housed and, in effect, this means that both the mother and baby are at a much lower altitude. Oxygen conditioning is similar to air conditioning except that the oxygen concentration of the air is increased rather than the temperature being reduced. The procedure is now used at high altitude in many hotels, dormitories and telescope facilities, and has been shown to be feasible and effective.

Measurement of the gas exchange efficiency of the lung is often required in the practice of pulmonary medicine and in other settings. The traditional standard is the values of the PO2, PCO2, and pH of arterial blood. However arterial puncture requires technical expertise, is invasive, uncomfortable for the patient, and expensive. Here we describe how the composition of expired gas can be used in conjunction with pulse oximetry to obtain useful measures of gas exchange efficiency. The new procedure is noninvasive, well tolerated by the patient, and takes only a few minutes. It could be particularly useful when repeated measurements of pulmonary gas exchange are required. One product of the procedure is the difference between the PO2 of end-tidal alveolar gas and the calculated PO2 of arterial blood. This measurement is related to the classical alveolar-arterial PO2 difference based on ideal alveolar gas. However that traditional index is heavily influenced by lung units with low ventilation-perfusion ratios, whereas the new index has a broader physiological basis because it includes contributions from the whole lung.

This review examines an array of physiological responses to low cellular oxygen tensions and discusses the effect of increasing oxygen tensions, through oxygen conditioning, on such responses.

The early history of cardiac catheterization has many interesting features. First, although it would be natural to assume that the procedure was initiated by cardiologists, two of the three people who shared the Nobel Prize for the discovery were pulmonologists, while the third was a urologist. The primary objective of the pulmonologists André Cournand and Dickinson Richards was to obtain mixed venous blood from the right heart so that they could use the Fick principle to calculate total pulmonary blood flow. Cournand’s initial catheterization studies were prompted by his reading of an account by Werner Forssmann, who catheterized himself 12 years before. His bold experiment was one of the most bizarre in medical history. In the earliest studies that followed, Cournand and colleagues first passed catheters into the right atrium, and then into the right ventricle, and finally, the pulmonary artery. At the time, the investigators did not appreciate the significance of the low vascular pressures, nor that what they had done would revolutionize interventional cardiology. Within a year, William Dock predicted that there would be a very low blood flow at the top of the upright lung, and he proposed that this was the cause of the apical localization of pulmonary tuberculosis. The fact that the pulmonary vascular pressures are very low has many implications in lung disease. Cardiac catheterization changed the face of investigative cardiology, and its instigators were awarded the Nobel Prize in 1956.

I had arranged to spend a sabbatical year in the University of Buffalo where Hermann Rahn was the head of the department of physiology. He had been one of the major contributors in the area of pulmonary gas exchange. In the event, the year was not particularly productive in terms of research, but there were several interesting events. One was that I gave a seminar at the Massachusetts General Hospital in Boston, and was subsequently offered a position on the faculty of Harvard Medical School. We submitted a large application to the NIH to have a cyclotron installed at the Hospital and remarkably this was funded. However for various reasons I decided not to take up the position, and this astonished many people. But the next 5 years at Hammersmith Hospital turned out to be enormously productive. We concentrated on studying the effects of gravity on the lung, with much of the work being done using an isolated lung preparation. I collaborated with many excellent postdoctoral fellows, and many influential articles were published. However the most important event was my marriage to Penelope in October 1967. Our time together has been extremely happy and I could not have accomplished what I have done without her.

This chapter describes my period as a medical student in the University of Adelaide. Unfortunately the course was not well taught because these were the days before academic departments of medicine and surgery. This changed shortly after I graduated. I wanted to take part in a research project but the opportunity was not available. However I took full advantage of all the other opportunities. For example I had a wonderful group of friends who were very talented and musical, and with whom I have kept in touch. I captained the field hockey team and we played in several competitions in other states. After graduation I spent a year doing a medical residency, but shortly after that I left for London.

In the mid-1960s I was fascinated by the developing NASA space program. We had been working on the effects of gravity on the lung, and it was natural to wonder what would happen in the absence of gravity in space. I therefore decided to try to get my foot in the door. With the help of John Billingham at the NASA Ames Research Center, I was awarded a 1-year fellowship to work in that institution. We flew to San Francisco at the end of 1967 and spent the year in Palo Alto. The most productive project of the year was exploiting the excellent digital computing facilities of the Center to analyze pulmonary gas exchange. I carried out a study looking at the effects of ventilation-perfusion inequality on pulmonary gas exchange that was very innovative at the time. However a remarkable opportunity occurred when I was invited to give a seminar at the new medical school being developed by the University of California in San Diego. Dr. Eugene Braunwald who was chief of medicine was looking for someone to take charge of the physiology course for first-year medical students. This was to be taught out of the department of medicine. My skills fitted this well and I agreed to take up the position. As a consequence, Penelope and I returned to London to sell our house and make other arrangements.

In London I found a cheap bed-sitter flat in Earls Court which was a favorite area for Australians. Remarkably I was able to become registered as a medical practitioner after one week which demonstrated one of the great advantages of being in the British Commonwealth at that time. For the first couple of months I did locums in various London hospitals. I bought a very small used car, an Austin Seven, and then spent 10 weeks touring Europe and staying in youth hostels, reaching as far south as Venice. A highlight was a week in Bayreuth where I heard Wagner’s Ring and also Parsifal. On return to London I attended some postgraduate courses and eventually was accepted as a house physician at Hammersmith Hospital, where the Postgraduate Medical School was located. One of the senior physicians there, Charles Fletcher, told me of an upcoming new program in pulmonary medicine at Hammersmith, and he recommended that I spend a year at the Medical Research Council (MRC) Pneumoconiosis Research Unit in South Wales. There I was exposed to modern respiratory physiology for the first time. I fell in love with it, and decided to concentrate on that area.

This chapter describes my family background in Adelaide, Australia including my father who was an orthopedic surgeon, and my mother who was a nurse from a rural community. My schooling was at Prince Alfred College, and in my senior years I concentrated on science including physics, chemistry and mathematics. We were fortunate to have an excellent science teacher. I was the first editor of the PAC Science Journal which appears annually and is written by students. It is still going strong 73 years later. I took part in the usual sports including cricket, football and athletics, and was a member of the Boy Scout troop and the school debating society.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

As already related, my application to NASA to make measurements of common root function in astronauts in space was funded, and the first funds were available on the day I started at UCSD. However it took some time to prepare the experiments for this unique environment. The first measurements were made in 1977 when we looked at the effects of short periods of weightlessness obtained in aircraft during parabolic flights. These occur when an aircraft first climbs, and then the pilot puts the nose down and there is a period of as much as 27 s of zero gravity. We made these measurements at the Ames Research Center and showed dramatic changes in the distribution of ventilation and blood flow as would be expected from the known of effects of gravity on the lung. However the main experiments were planned for SpaceLab which was carried upt by the Shuttle. Preparations for these experiments were protracted because of their complexity. Also the program was set back by 2 years because of the Challenger accident in 1986. However eventually we had experiments on SpaceLabs SLS 1, SLS 2, LMS and Neurolab. Kim Prisk was responsible for superintending the actual experiments. A remarkable feature of the experiments was that most of the data was available in real time and we could access this at the Johnson space Center near Houston. Large amounts of data were obtained in an environment where none were available before, and these were reported in many publications. As expected the function of the lung was altered in microgravity but we were relieved to find that gas exchange could still be easily accomplished. When the International Space Station became available, measurements that were made there showed that even after 6 months in space, the astronauts rapidly the lung function of the astronauts rapidly returned to normal after a few days. The upshot was that as far as we can tell, changes in pulmonary function will not be a serious problem during long-term spaceflight, for example in a 3-year mission to Mars. However such a mission has other serious dangers such as harmful radiation.

On my return to London I learned by chance that Sir Edmund Hillary was planning a combined scientific and mountaineering expedition to the Himalayas, and that the physiological program would be the responsibility of Griffith Pugh whom I vaguely knew. I applied to join this, and to my astonishment was accepted even though I had never done any climbing before. The expedition was in three parts. In the fall of 1960, the components of the structure that we were to live in during the winter were carried in. This was the so-called Silver Hut that was eventually located at an altitude of 5800 m (19,000 ft) about 15 km south of Mount Everest. The second part was the wintering period when 8 physiologists lived in the hut for up to 5 months. Probably no one had lived so high for so long before. We carried out an extensive research program with an emphasis on the physiology of exercise and blood changes. For example I found that the oxygen saturation of the arterial blood fell dramatically on exercise, and also that the altitude caused essentially no change in the diffusing capacity of a lung as measured with carbon monoxide. For the third part of the expedition we took a high level route across to Mt Makalu, altitude 8481 m (27.8200 ft). The climbers had planned to ascend this without supplementary oxygen but were unsuccessful and we had great difficulties in rescuing one of the climbers who collapsed near the summit. I spent several days on the Makalu col at an altitude of 7440 m (24,400 ft) and there we made the highest measurements of maximal oxygen consumption that have been reported to date. The scientific return of the expedition was outstanding and it started my lifelong interest in high altitude physiology.

Most of this biography has been written without technical details so that the nonscientist can understand it. However some readers might wish to learn more about the science, and this chapter therefore includes my important my most important scientific papers with brief comments on their significance.

I returned to Hammersmith Hospital in the spring of 1956 to join the new program in respiratory physiology. We had the first mass spectrometer that had been specifically designed for respiratory research. It had just been constructed there by Kemp Fowler, another Australian. We took full advantage of this to study to obtain as much information as we could from expired gas, including a measurement of ventilation-perfusion inequality in patients with lung disease. However another very exciting development soon occurred. The MRC had built a medical cyclotron at Hammersmith, and among other things it produced radioactive oxygen 15 with a half-life of only 2 min. When we inhaled this, we were astonished to find that there was a dramatic difference of pulmonary blood flow from the top to the bottom of the upright lung. This opened up the whole new area of research on the effects of gravity on the lung. One example was a calculation of the regional differences of gas exchange down the lung. An intermission at this time was that my father sent me an air ticket to make a short visit to Australia, and I decided to go and return through the United States. I visited many of the major centers working on respiratory physiology, and was duly impressed by the opportunities there.

Penelope and I flew from London to San Diego with 6 month old Robert to enable me to start at UCSD on April 1, 1969. We had been pleasantly surprised to receive a letter from a realtor asking us what kind of house we would like. The result was that we chose one in the La Jolla Farms area adjacent to the campus which turned out to be a very auspicious move. I could not afford the down payment but my father helped. The medical school was in its infancy at the time with the first medical students having arrived in the previous fall. Only the most senior professors had been recruited, and each time another person joined the faculty the Dean threw a party, and also the new recruit gave an introductory lecture to all faculty in the school. There were a number of stellar academics and a wonderful intellectual atmosphere and esprit de corps. As mentioned above a major obligation of mine was to teach physiology to first-year medical students. I had never done this before and found it stimulating but challenging. The result was that I wrote my book “Respiratory physiology: the essentials” which has since become a standard textbook for medical students and is now in its 10th addition. Another obligation was to obtain external funding. While I was at the Ames Research Center I had put in an application to study pulmonary function in astronauts in space. Miraculously it was funded and the first check arrived the day I started and funding continued for over 30 years. Subsequently I was able to obtain an NIH training grant, and later a Program Project grant. These were the days when funding was much easier to obtain than now. An important early event was recruiting Peter Wagner who came as a postdoctoral fellow from Sydney. He is still in the Division and has been a tower of strength. Our daughter, Joanna, was born in 1971, and we moved to a larger house in the Farms area that was in the process of being built. The area had been an army camp, and the soil was solid clay. However over the years, Penelope, who is a keen gardener, has done wonders and we now have a beautiful garden. Another unexpected dividend of the location was the Torrey Pines Glider Port only some 10 min away. I have much enjoyed flying radio-controlled gliders there.

The avian pulmonary circulation has many interesting features and much information can be gained by comparing the avian and mammalian systems. Two features are primarily responsible for the unique features of avian capillaries. First, the avian lung has separated the ventilation and gas exchange functions. Second, the avian lung uses a flow-through process for ventilation rather than the reciprocal pattern adopted by mammals. As a consequence, the environment of the pulmonary capillaries is very different in the avian compared with the mammalian lung. The avian capillaries are nested in a syncytium of air capillaries, whereas the capillaries of the mammalian lung are strung out along the alveolar walls. This means that the mechanical support of the categories is very different in birds compared with mammals. A consequence of this is that the walls of the capillaries are very different. In the avian lung, the blood–gas barrier is extremely thin and uniform throughout the capillaries. Contrast this with the mammalian lung where a type I collagen cable is required for the support of the capillaries, and as a result the blood–gas barrier is much thicker in places and the diffusion characteristics are therefore inferior. Another striking difference is that avian pulmonary capillaries are remarkably rigid unlike those in mammals, which undergo recruitment and distention when the cardiac output rises. The implications of this for pulmonary vascular resistance during intense exercise such as flying are still unclear.