By Ilia Stambler
Introduction
Various means of therapeutic interventions into degenerative aging processes are now gaining increasing interest. The interest is largely due to the mounting challenges of the rapidly aging world population and the correspondingly increasing desire to seek solutions.[1] Yet, when searching for means to intervene into degenerative aging processes, the emphasis is often placed either on traditional means of life-style improvement (rest, exercise, moderate and balanced nutrition) or various pharmacological means (the so-called geroprotective or anti-aging drugs)[2] or gene-therapeutic or cell-therapeutic means (the so called regenerative medicine).[3] Yet, additional classes of potential interventions may be possible. Anti-aging and life-extending interventions do not necessarily need to be behavioural, biochemical or biological, but can also be physical, in particular as relates to various resuscitation technologies for the elderly, for example hypothermia and suspended animation,[4] electromagnetic stimulation,[5] or oxygenation (also in a sense a “biochemical” intervention, but with a stronger emphasis on physical energy metabolism and physical properties, such as gas pressure). Such technologies represent some of the most veritable means for life extension, demonstrably saving people from an almost certain death. But similar principles could perhaps be used for more preventive treatments and in less acute cases.
This work will focus on means of oxygenation, in particular hyperbaric (high pressure) oxygenation. It may be stated that 100% cases of death, including aging-related deaths, ultimately are caused by a lack of oxygen supply. Hence, various means of oxygenation may be considered as anti-aging means. On the other hand, oxidative damage has been long associated with the aging process.[6] From early times, human life has been likened to a burning candle: too much and too fast burning (oxygenation) could lead to an early death.[7] Hence efficient oxygen supply management may be needed to maintain healthy longevity. This article draws attention to the issue of oxygenation, in particular the use of hyperbaric oxygen therapy. It is not intended as a clinical guideline, but as a reflection on a potentially important issue and an invitation for further consideration of physical, energy-modulating means for anti-aging and life-extension, in particular oxygen management by such means as hyperbaric oxygenation therapy.[8] Some other physical means, such as temperature manipulation and electromagnetic stimulation, are also briefly considered with the same purpose to stimulate further interest.
The use of hyperbaric oxygen against acute and chronic diseases
Insofar as many (perhaps ultimately all) of the cases of death are ultimately due to various forms of oxygen deficit, a powerful means of life extension may be by improving oxygen supply. One form of oxygen supply can be in the form of Hyperbaric Oxygenation (using Oxygen Pressure Chamber or Barochamber). Such therapy was indicated as beneficial against a variety of life-threatening acute conditions, such as traumas and injuries, including severe brain and chest injuries, and could also improve a variety of degenerative and aging-related conditions, from neurological impairments, such as cerebral palsy and strokes, to diabetes.[9]
However, in high concentrations, oxygen can be cytotoxic. On the positive side, oxygen toxicity against bacteria may partly explain beneficial effects of hyperbaric oxygenation for treating acute infections, as well as wound, burn and fracture healing, where infections can be a major obstacle to effective healing.[10] The cytotoxic effects may be also involved in anti-cancer treatment, to destroy cancer cells by high oxygen concentrations.[11] Yet, the oxygen cytotoxic effect can be problematic, when either the oxygen dose or time of exposure to oxygen exceed a desirable physiological threshold.[12] Oxygen can lead to excessive cell and tissue stimulation, exhausting cell replicative potential, increasing the amount of reactive oxygen species and hastening the transition to apoptotic cell death via mitochondria activation.[13] The thresholds of oxygen toxicity have been uncertain even regarding single time applications of hyperbaric oxygenation.[14] And long-term effects of hyperbaric oxygenation on human life span apparently have not been studied.
Mechanisms of action of hyperbaric oxygenation against aging-related conditions
The mechanisms of potential general protective and/or anti-aging (geroprotective) effects of hyperbaric oxygenation, if such are indeed present, are yet to be elucidated. The question of dosages may be also crucial for determining the mechanisms of such anti-aging effects. High dosages of hyperbaric oxygen should intuitively induce oxidative stress, with high reactive oxygen species (ROS) production, which has been long seen as one the major sources of molecular damage in aging.[6] Indeed, oxidative damage has been observed under hyperbaric oxygen treatment, among other effects potentially contributing to cataract development.[15] Yet, it is also appreciated that, at certain levels, ROS may stimulate tissue regeneration.[16] And yet at certain dosages, hyperbaric oxygen may produce stimulatory “hormetic” effects (i.e. stimulation by a low dose, as opposed to inhibition by a high dose of the same factor), which may in fact increase anti-oxidant protection, via stimulation of anti-oxidant defense systems.[17] The protective effects of hyperbaric oxygen by stimulating heat shock protein expression[18] and stem cell mobilization[19] have also been suggested. In a related way, chronic systemic inflammation has been long implicated as a major source of aging-related damage.[20] Furthermore, excessive neuro-inflammation has been a sustained therapeutic target.[21] Hyperbaric oxygenation has been commonly reported to produce an anti-inflammatory effect, which has been suggested as one of its major therapeutic mechanisms, for both age-related chronic and acute conditions (like acute ischemic stroke).[22] Yet, there is also a growing realization that pro-inflammatory effects may be essential for tissue regeneration, including neuro-regeneration.[23]
Closely related to the phenomenon of hormesis (low dose stimulation), hyperbaric oxygenation may exert protective anti-ischemic effects through ischemic preconditioning, that is applying a certain sub-threshold dosage of hyperbaric oxygen that would induce a transient, mild ischemia that would confer tolerance to subsequent, more severe ischemia.[24] This mechanism opens the possibility for using hyperbaric oxygenation as a preventive therapy for the elderly. Some of the mechanisms of preconditioning were associated with enhanced expression of protective enzymes, such as Sirtuins,[25] enhanced Mitogen-activated protein kinases (MAPKs) and autophagy[26] and inhibiting the mTOR pathway.[27] Thus, the mechanisms of preconditioning by hyperbaric oxygenation may be similar with the application of other geroprotective medicines (e.g. Sirtuin-stimulating or mTOR inhibiting drugs),[28] producing a general improvement of energy metabolism, yet potentially with fewer pharmacogenic side effects. However, this possibility will yet require extensive investigation, necessitating a very careful consideration of the dosages. The short vs. long term effects should be considered when studying the mechanisms of action of hyperbaric oxygenation.[29] Indeed, there may be a need for a systemic, long term evaluation of oxygen therapy effects, as a part of a whole-organism whole-life-course model of energy resources expenditures. Such models are currently only emerging,[30] and are in great need of elaboration, both experimental and theoretical.
Supplementing Hyperbaric Oxygenation with additional treatment modalities
Hyperbaric Oxygenation can be seen as a potentially effective therapeutic or stimulating means, but it is unclear to which extent it can serve as a lifespan-extending means. Hence, the therapeutic modality of Hyperbaric Oxygenation may be supplemented or followed by additional modalities particularly designed to serve life-prolonging, rejuvenative and reparative functions. Pressure chamber could in principle provide a convenient environment to implement such modalities, insofar as it provides a protected, isolated and enclosed space unit, which can be easily manipulated and monitored for a variety of purposes. Some of the potential reparative applications can be as follows.
O2/CO2 Balance
For the life-span and health-span extension, rather than applying hyperbaric oxygenation, actually reducing oxygen partial pressure may be beneficial. Thus people living at high altitudes (with reduced oxygen pressure) are noted for high longevity, presumably due to either reduced metabolic rate or long-term adaptations. Some of the potential beneficial adaptations may include increased production of red blood cells, formation of new capillaries and increase in respiratory enzymes, and other mechanisms.[31]
Also, increased CO2 can be beneficial, insofar as persistent hypercapnia (enhanced CO2 level) has been associated with an increased life-span in animal models. This may presumably be due to increasing blood alkalinity (through liberating bicarbonate reserves) which may in turn positively affect proteins’ isoelectric stability.[32]
Interestingly and seemingly paradoxically, both hyperbaric oxygenation therapy and its apparent opposite – therapeutic hypoxia or hypoxic training (for example intermittent hypoxia) have been suggested to produce positive preconditioning effects against ischemic aging-related conditions, such as heart disease and neurodegenerative diseases.[33] The apparent paradox may be once again explained by the phenomenon of “hormesis” – namely the activation of anti-hypoxic/anti-ischemic protective mechanisms by certain extents of both deficit and excess of oxygen (in the latter case possibly increasing reactive oxygen species levels to induce a protective counter-effect), as well as possibly by other mild stressors (chemical, mechanical or electrical). The precise dosages and thresholds of such similar protective effects by seemingly diverse means, as well as their potential common central neuro-humoral regulatory mechanisms, yet require elucidation.
Besides hyperbaric oxygen therapy, normobaric (normal pressure) oxygen therapy, or just oxygen therapy generally (increasing oxygen supply) has been a widely applied means of therapy and resuscitation.[34] While hyperbaric oxygenation (using a pressure chamber) may be more effective to achieve rapid oxygen delivery to deep vital tissues, normobaric oxygenation (e.g. using an oxygen mask) may be more conveniently applicable and less expensive. Yet for normobaric oxygenation too, the appropriate balance of O2/CO2 levels may be critical. The pressure chamber may provide an ideal environment to control both O2 and CO2 levels and pressures, for acute therapeutic or prolonged restorative regimens. Still, with regard to CO2 manipulation, its long term effects as well as its effects on immediate daily performance will yet need to be established.
The issue of optimal thresholds or O2/CO2 balance will be vital, insofar as excessive O2 application may lead to a “burnout,” while excessive CO2 application may lead to a “death zone.” Both acidosis and alkalosis may be produced by O2/CO2 imbalance. Perhaps the most beneficial therapeutic regimen may be maintaining and/or rapidly restoring the physiological O2/CO2 balance. The normal (balanced) concentration of alveolar CO2 is often assumed to be about 6.5%, yet may vary according to particular metabolic requirements of every individual.[35]
Monitoring
In order to personalize the therapy, and to ensure its safety and efficacy, the treatment modalities should be related with a thorough array of monitoring and evaluation modalities, in particular for the evaluation of the organism’s energy metabolism, before, during and after the treatment. In performing oxygen therapy (in particular hyperbaric oxygenation), reference need to be made for Oxygen and CO2 balance (supply vs. demand), as well as for the supply and demand of macroergic (energy-rich) substances, in the entire organism and particular organs.[36] Measurement modalities may include oxygen measurement by mitochondrial cytochrome a,a3 reflectance spectrophotometry, mitochondrial NADH redox state by NADH fluorometry, tissue blood flow by Laser Doppler Flowmetry, hemoglobin oxygen saturation by reflectometry, DC potential and various ionic levels by micro-electrodes, gas partial pressure (O2, CO2, NO, etc) and pH levels by micro-electrodes and optodes, up to more advanced methods such as functional magnetic resonance imaging (fMRI) or using sequential single photon emission computerized tomography (SPECT) scans, etc.[37]
The monitoring of the gas composition (PaO2 and PaCO2) of the arterial blood may be seen as a necessary condition to perform effective hyperbaric oxygen therapy against life-threatening situations in patients with deteriorating cardiorespiratory functions, especially for the elderly patients.[8] This is necessary in order to control and maintain adequate levels of lung gas exchange, with regulated parameters of oxygen supply and controlled oxygen concentration. The speed of the blood flow and blood pressure in vital organs are also among the critical vital signs that need to be known. The basic parameters of cardiorespiratory function need to be monitored, such as: PaO2 mmHg – arterial partial pressure of oxygen; PaCO2 – arterial partial pressure of CO2; PaO2/FiO2 – the ratio of the partial pressure of oxygen to the fraction of inspired oxygen; SVI ml/m2 – stroke volume index; CI L/min/m2 – cardiac index; pH – blood acidity level. Such measures of cardio-respiratory function can help reference the normal balanced O2/CO2 levels in the blood and favorable blood electric charge and hemodynamic conditions.
The anatomical and physiological effects of aging on the heart and lungs are also vitally important parameters, including such indicators as the rise of arterial pressure and resistance with aging due to the increasing arterial stiffness, reduced contractility and relaxation of the heart, a reduction of lung vital capacity, impairment of gas mixture in the lungs, and other harmful anatomical and physiological effects of aging. All the deteriorative changes in the cardio-respiratory system generally show in the reduction of maximal oxygen uptake (VO2max) which has been considered one of the most informative parameters for biological age evaluation.[38]
The above parameters of cardiorespiratory function are practically indispensable in emergency and intensive care medicine, when treating acute and often life-threatening conditions. Yet, arguably, the cardio-respiratory parameters routinely employed in emergency and intensive care medicine may be good candidates for biomarkers of aging as they have proved their utility as real-time indicators of the organism’s vitality and energy. Often, in general frailty assessments, energy levels in the elderly are evaluated simply by asking the question “Do you feel full of energy?”[39] Yet, there may be more objective measures of the aging organism’s energy level, by such means as spirometry, oximetry, hemodynamic, electrochemical and spectroscopic energy metabolite measurements, as well as other structural and functional parameters of the cardiorespiratory system, that can provide improved indication for therapy.[40] Arguably, such cardio-respiratory “physiomic” parameters or markers of aging may be clinically valuable and conveniently interpretable for a practicing physician, alongside the many “biomarkers of aging” based on predominantly molecular-biological, e.g. genetic, epigenetic and other “omic” age-related alterations that are currently investigated. [41]
The main clinical utility of biomarkers or diagnostic parameters of aging is that their changes can help evaluate the effectiveness of particular therapeutic regimens, especially the effectiveness of particular therapeutic dosages. Yet curiously, in hyperbaric oxygen therapy, the concept of dosage is only rudimentary and there is no commonly agreed way to define the dosage. Moreover, there is no agreed way to evaluate the effects of this kind of therapy, and correspondingly no agreed way to correlate between the dose and the effect. The same may be said regarding other potential “energy-modulating” interventions into aging, whose definition is yet very nebulous. In certain studies, it was suggested to define the dose of hyperbaric oxygen therapy as the product of intra-barochamber pO2 (ATA), the duration of a single hyperbaric oxygenation exposure (hours), and the number of hyperbaric oxygenation treatments, yielding the dose unit: (ATA*h*N).[8,12] In those studies, the efficacy of hyperbaric oxygenation therapy was evaluated according to the number of patients who showed a significant clinical improvement in their neurological state in the course of the treatment (the percent of the total number of patients). The level of the therapy efficacy was compared with a corresponding value of the dose. For the treatment of acute ischemic stroke, a higher efficacy was indicated with increasing the average total hyperbaric oxygenation dose, reaching the maximum efficacy with the average doses of no less than 30 units (ATA*h*N).[12] However, such a definition of the dosages has not become consensus, and the definition of the therapy effects and of the dose-effect relations are rather vague and yet require a thorough elaboration and clarification. Hopefully, thanks to refinement of the definitions and massive additional data collection on dose-effect relations, including the evaluation of long-term effects and differential personalized effects in different patient groups (e.g. the elderly vs. the young) – oxygen therapy, hyperbaric oxygen therapy particularly, or “energy-modulating therapy” more generally – can become efficient means to alleviate aging-related conditions and increase healthy and productive life.
It is also necessary to note, that the obtained datasets of biomarkers, diagnostic parameters, and dose-effect relations, will be not only necessary for monitoring and personalizing treatment regimens, but will also be able to provide invaluable information for many yet unforeseen “quantified health” and “quantified longevity” applications – collecting a vast amount of health data on aging-related changes and their possible improvements to enable planning better informed therapeutic and life-style regimens and strategies to achieve healthy longevity.
Comprehensive physiological manipulation unit
Enhancing blood supply: The main purpose of oxygenation therapy (in particular hyperbaric oxygen therapy) is to directly enhance the supply of potentially deficient oxygen to the tissues that need it (while necessarily watching out against “burning out” and “oxygen toxicity”). However, oxygen supply can be improved by more indirect means, such as improving blood supply to the tissues. Historically, improved blood supply to the tissues (also for the purposes of rejuvenation) has been persistently sought. For example, the whole-body increase of the blood flow (hyperemia) has been achieved by various means ranging from hormone replacement therapy (by supplements, tissue transplants, and even operations on the endocrine organs) through diathermy (tissue heating), massage, exercise and baths.[1] The problems of oxygen delivery to the vital tissues have been also tackled from additional angles, such as oxygenated microparticles and “artificial blood”,[42] various forms of heart-lung machines, artificial hearts and other assisted circulation devices,[43] or pharmacological means to improve energy metabolism.[28] The blood flow can be also stimulated by electromagnetic devices.
As briefly mentioned above, recording electrodes and magnetic resonance devices may be employed for monitoring (for example during the course of oxygen therapy). Yet, in addition, stimulation electrodes may be also used for physiological manipulation purposes, in particular to stimulate nervous activity and blood flow, even to stimulate tissue regeneration, in particular blood vessels growth (angiogenesis – another potential means to improve tissue blood supply and oxygenation, but also requiring caution to avoid uncontrolled growth).[44] Such electromagnetic therapeutic devices have been sometimes termed “electroceuticals.”[45] They can be incorporated into the therapeutic regimens, either within the pressure chamber or as a part of accompanying regimens.
The incorporation or fitting of the additional therapeutic modalities within the pressure chamber can provide additional benefits. The ability provided by the pressure chamber to control and manipulate pressure, gas concentrations and temperature, can produce a convenient environment for physiological manipulation. Furthermore, with the addition of an infusion apparatus for delivering medications, including various regenerative and anti-aging medications (depending on the costs involved), this can become a multifunctional treatment unit. Some of its functions can be as follows.
“Resting state” induction: One possibility may be inducing a restorative “resting state” through a variety of physical means (pressure, temperature, oxygen and carbon dioxide concentration) as well as by electromagnetic and pharmacological means. Thus both reversible hypothermic and pharmacological resting states (reversible coma) are already becoming widely used clinical methods for recuperation and resuscitation, and can be incorporated into the chamber.[46] Just by using such physical manipulation means that are available in the pressure chamber – such as pressure, temperature, O2 and CO2 concentrations – a resting state can be induced insofar as rest and sleep are characterized by particular breathing and temperature patterns.[47] Temperature control can be another powerful means of physical manipulation. Thus, lower core body temperature has been correlated with longer lifespans.[48] In particular, lowering the body temperature (hypothermia) during hyperbaric oxygenation treatment could reduce energy (oxygen) demand by the organism and thus potentially lower oxygen toxicity. On the other hand, increased blood flow through heating may be used for therapeutic stimulation purposes. Within the chamber, temperature can be manipulated in both directions. The electric charge of the breathing mixture (e.g. negative ionization) can be also significant for recuperation vs. stimulation.[49]
Sleep enhancement: Sleep enhancement can be yet another promising restorative modality (in fact a form of “resting state”). In particular, slow-wave sleep (Stage 3, with synchronized EEG activity, showing slow waves with a frequency of less than 1 Hz) has been known to be vital for recuperation, presumably due to enhanced growth hormone production[50] or synchronization of physiological functions. [51] The restorative effects of sleep generally, and deep sleep in particular, may be also possibly due to activation of the immune response during sleep, or elimination of toxins, or other mechanisms.[52] This stage can be induced by a variety of methods, including: transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS),[53] other forms of sensory sleep stimulation[54] and a variety of slow-wave sleep enhancing drugs.[55] Sleeping in a hyperbaric chamber has already been practiced, and this combination of therapeutic modalities can be further explored and expanded if proven safe and effective.
All such technologies are yet extremely experimental, dose responses have not been thoroughly studied, hence side effects may be unpredictable. Both their short and long term effects are largely unknown, and the introduction of such additional technologies may become prohibitively expensive and unwieldy. They are mentioned here only as possibilities that can be further investigated and prospectively included within a potential “comprehensive restorative chamber” or “survival chamber.”
References and notes
[1] Ilia Stambler, A History of Life-Extensionism in the Twentieth Century, Longevity History, 2014, http://www.longevityhistory.com/.
[2] Ilia Stambler, “Human life extension: opportunities, challenges, and implications for public health policy,” in: Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 535-564, http://pubs.rsc.org/en/content/ebook/978-1-78262-435-6#!divbookcontent;
Alexander Vaiserman, Oleh Lushchak, “Anti-aging drugs: where are we and where are we going?” in: Alexander Vaiserman (Ed.), Anti-aging Drugs: From Basic Research to Clinical Practice, Royal Society of Chemistry, London, 2017, pp. 3-10, http://pubs.rsc.org/en/content/ebook/978-1-78262-435-6#!divbookcontent.
[3]. Anthony Atala, “Extending life using tissue and organ replacement,” Current Aging Science, 1(2), 73-83, 2008, http://www.eurekaselect.com/95101/article;
Giuseppe Orlando, Shay Soker, Robert J. Stratta, Anthony Atala, “Will Regenerative Medicine Replace Transplantation?” Cold Spring Harbor Perspectives in Medicine, 3(8), a015693, 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721273/.
[4] Ronald Bellamy, Peter Safar, Samuel Tisherman, …, Harvey Zar, “Suspended animation for delayed resuscitation,” Critical Care Medicine, 24(2Suppl), S24-47, 1996, http://www.ncbi.nlm.nih.gov/pubmed/8608704.
[5] Yury P. Gerasimenko, Daniel C. Lu, Morteza Modaber, …, V. Reggie Edgerton, “Noninvasive Reactivation of Motor Descending Control after Paralysis,” Journal of Neurotrauma, 32(24), 1968-1980, 2015, http://online.liebertpub.com/doi/abs/10.1089/neu.2015.4008;
Max Schaldach, Electrotherapy of the Heart: Technical Aspects in Cardiac Pacing, Springer-Verlag, Berlin, 2012.
[6] Denham Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of Gerontology, 11, 298-300, 1956, http://www.uccs.edu/Documents/rmelamed/harman_1956_13332224.pdf;
Rajindar S. Sohal, “Role of oxidative stress and protein oxidation in the aging process,” Free Radical Biology and Medicine, 33(1), 37-44, 2002, http://www.sciencedirect.com/science/article/pii/S0891584902008560;
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Toren Finkel, Nikki J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, 408(6809), 239-247, 2000, https://www.nature.com/nature/journal/v408/n6809/full/408239a0.html.
[7] Gerald J. Gruman, A History of Ideas about the Prolongation of Life. The Evolution of Prolongevity Hypotheses to 1800, Transactions of the American Philosophical Society, Vol. 56 (9), Philadelphia, 1966.
[8] Gennady G. Rogatsky, Ilia Stambler, “Hyperbaric oxygenation for resuscitation and therapy of elderly patients with cerebral and cardio-respiratory dysfunction,” Frontiers In Bioscience (Scholar Edition), 9, 230-243, June 1, 2017, http://www.bioscience.org/2017/v9s/af/484/2.htm, https://www.bioscience.org/special-issue-details?editor_id=1746, https://www.ncbi.nlm.nih.gov/pubmed/28410116.
[9] The standard indications for the use of hyperbaric oxygenation, as established by the US-incorporated Undersea and Hyperbaric Medicine Society (UHMS), include: 1. Air or Gas Embolism, 2. Carbon Monoxide Poisoning, 3. Clostridial Myositis and Myonecrosis (Gas Gangrene), 4. Crush Injury, Compartment Syndrome and Other Acute Traumatic Ischemias, 5. Decompression Sickness, 6. Arterial Insufficiencies, 7. Severe Anemia, 8. Intracranial Abscess, 9. Necrotizing Soft Tissue Infections, 10. Osteomyelitis (Refractory), 11. Delayed Radiation Injury (Soft Tissue and Bony Necrosis), 12. Compromised Grafts and Flaps, 13. Acute Thermal Burn Injury; 14. Idiopathic Sudden Sensorineural Hearing Loss.
(Undersea and Hyperbaric Medicine Society (UHMS), “Indications for Hyperbaric Oxygen Therapy,” https://www.uhms.org/resources/hbo-indications.html.)
Yes, there is good evidence for the possible use of this treatment against other severe and chronic conditions. See for example:
Gennady G. Rogatsky, Avraham Mayevsky, “The life-saving effect of hyperbaric oxygenation during early-phase severe blunt chest injuries,” Undersea and Hyperbaric Medicine, 34(2), 75-81, 2007, http://archive.rubicon-foundation.org/xmlui/bitstream/handle/123456789/6468/17520858.pdf?sequence=1;
Ning Gu, Fumiko Nagatomo, Hidemi Fujino, Isao Takeda, Kinsuke Tsuda, Akihiko Ishihara, “Hyperbaric oxygen exposure improves blood glucose level and muscle oxidative capacity in rats with type 2 diabetes,” Diabetes Technology & Therapeutics, 12(2), 125-133, 2010, http://online.liebertpub.com/doi/abs/10.1089/dia.2009.0104;
Majid Kalani, Gun Jörneskog, Nazanin Naderi, Folke Lind, Kerstin Brismar, “Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers: Long-term follow-up,” Journal of Diabetes and its Complications, 16(2), 153-158, 2002, http://www.jdcjournal.com/article/S1056-8727(01)00182-9/fulltext .
Michael H. Bennett, Jan P. Lehm, Nigel Jepson, “Hyperbaric oxygen therapy for acute coronary syndrome,” Cochrane Database of Systematic Reviews, 2015(7), CD004818, 2015, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004818.pub4/full;
Peter Kranke, Michael H. Bennett, Marrissa Martyn-St James, Alexander Schnabel, Sebastian E. Debus, “Hyperbaric oxygen therapy for chronic wounds,” Cochrane Database of Systematic Reviews, 2015(6), CD004123, 2015, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004123.pub3/abstract;
Michael H Bennett, Barbara Trytko, Benjamin Jonker, “Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury,” Cochrane Database of Systematic Reviews, 2012(12), CD004609, 2012, http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004609.pub2/abstract;
Richard A. Neubauer Research Institute, “Resources,” www.ranri.org/resources.html.
[10] Escobar S.J., Slade J.B., Hunt T.K., Cianci P., “Adjuvant hyperbaric oxygen therapy (HBO2) for treatment of necrotizing fasciitis reduces mortality and amputation rate,” Undersea and Hyperbaric Medicine, 32(6), 437–43, 2005, http://dspace.rubicon-foundation.org/xmlui/bitstream/handle/123456789/4061/16509286.pdf?sequence=1.
[11] Ingrid Moen, Linda E. B. Stuhr, “Hyperbaric oxygen therapy and cancer – a review,” Targeted Oncology, 7, 233–242, 2012, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510426/.
[12] Gennady G. Rogatsky, Edward G. Shifrin, Avraham Mayevsky, “Optimal dosing as a necessary condition for the efficacy of hyperbaric oxygen therapy in acute ischemic stroke: a critical review,” Neurological Research, 25(1), 95-98, 2003, http://www.tandfonline.com/doi/abs/10.1179/016164103101201003; Optimal_dosing_as_a_necessary_condition_for_the_efficacy_
of_hyperbaric_oxygen_therapy_in_acute_ischemic_stroke_A_critical_review.
[13] Elena Afrimzon, Naomi Zurgil, Yana Shafran, Pnina Leibovich, Maria Sobolev, Larissa Guejes, Mordechai Deutsch, “The use of sequential staining for detection of heterogeneous intracellular response of individual Jurkat cells to lysophosphatidylcholine,” Journal of Immunological Methods, 387(1-2), 96-106, 2013, http://www.sciencedirect.com/science/article/pii/S0022175912002992.
[14] Efouni S.N., et al., “Hyperoxia. Patofiziologicheskie aspekty lechebnogo i toxicheskogo vozdeystvia hyperbaricheskogo kisloroda (Hyperoxia. Pathophysiological aspects of therapeutic and toxic effects of hyperbaric oxygenation), in: EShfouni S.N. (Ed.), Rukovodstvo po Hyperbaricheskoy Oxygenazii. Teoria I Praktika Klinicheskogo Primenenia (Hyperbaric Oxygenation: a manual. The theory and practice of clinical application), Akademia Medizinskikh Nauk SSSR (Academy of Medical Sciences of the USSR), Medizina, Moscow, 1986, pp. 29-56;
Richard D. Vann, Oxygen Toxicity Risk Assessment, Office of Naval Research, Arlington VA, 1988, https://www.researchgate.net/publication/235051634_Oxygen_Toxicity_Risk_Assessment;
Noemi Bitterman, “CNS oxygen toxicity,” Undersea and Hyperbaric Medicine, 31 (1), 63-72, 2004, http://dspace.rubicon-foundation.org/xmlui/bitstream/handle/123456789/3991/15233161.pdf?sequence=1.
[15] Yi Zhanga, Shan OuYanga, Lan Zhangb, XianLing Tanga, Zhen Songa, Ping Liua, “Oxygen-induced changes in mitochondrial DNA and DNA repair enzymes in aging rat lens,” Mechanisms of Ageing and Development, 131(11-12), 666-673, 2010, http://www.sciencedirect.com/science/article/pii/S0047637410001740.
[16] Carole Gauron, Christine Rampon, Mohamed Bouzaffour, Eliane Ipendey, Jérémie Teillon, Michel Volovitch, Sophie Vriz, “Sustained production of ROS triggers compensatory proliferation and is required for regeneration to proceed,” Scientific Reports, 3, 2084, 2013, https://www.nature.com/articles/srep02084.
[17] Cassandra A. Godman, Rashmi Joshi, Charles Giardina, George Perdrizet, Lawrence E. Hightower, “Hyperbaric oxygen treatment induces antioxidant gene expression,” Annals of the New York Academy of Sciences, 1197, 178-183, 2010, http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2009.05393.x/abstract.
[18] Jeysen Zivan Yogaratnam, Gerard Laden, Levant Guvendik, Mike Cowen, Alex Cale, Steve Griffin, “Can hyperbaric oxygen be used as adjunctive heart failure therapy through the induction of endogenous heat shock proteins?” Advances in Therapy, 24(1), 106-118, 2007, https://oxfordrecoverycenter.com/wp-content/uploads/2017/02/Can-Hyperbaric-Oxygen-Be-Used-as-Adjunctive-Heart-Failure-Therapy-Through-the-Induction-of-Endogenous-Heat-Shock-Proteins.pdf.
[19] Stephen R. Thom, Veena M. Bhopale, Omaida C. Velazquez, Lee J. Goldstein, Lynne H. Thom, Donald G. Buerk, “Stem cell mobilization by hyperbaric oxygen,” American Journal of Physiology – Heart and Circulatory Physiology, 290(4), H1378-1386, 2006, http://ajpheart.physiology.org/content/290/4/H1378.long.
[20] Claudio Franceschi, Judith Campisi, “Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases,” The Journals of Gerontology Series A, Biological Sciences and Medical Sciences, 69(Suppl. 1), S4-9, 2014, https://academic.oup.com/biomedgerontology/article-lookup/doi/10.1093/gerona/glu057.
[21] Joaquin Jordan, Tomas Segura, David Brea, Maria F. Galindo, Jose Castillo, “Inflammation as therapeutic objective in stroke,” Current Pharmaceutical Design, 14, 3549-3564, 2008, http://www.eurekaselect.com/68189/article.
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