Next Article in Journal
The ED-PLANN Score: A Simple Risk Stratification Tool for Out-of-Hospital Cardiac Arrests Derived from Emergency Departments in Korea
Next Article in Special Issue
Special Issue “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment”
Previous Article in Journal
Continuous Renal Replacement Therapy in the Critically Ill Patient: From Garage Technology to Artificial Intelligence
Previous Article in Special Issue
The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 11
Issue 1
10.3390/jcm11010173
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Brief Report

Male vs. Female Differences in Responding to Oxygen–Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

by
Salvatore Chirumbolo
1,*,
Luigi Valdenassi
2,
Marianno Franzini
2,
Sergio Pandolfi
2,3,
Giovanni Ricevuti
2,4 and
Umberto Tirelli
5
1
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
2
Italian Society of Oxygen Ozone Therapy (SIOOT), University of Pavia, 27100 Pavia, Italy
3
Villa Mafalda Clinics, Via Monte delle Gioie 5 Rome, 00199 Roma, Italy
4
School of Pharmacy, Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
5
Tirelli Medical Group, 33170 Pordenone, Italy
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2022, 11(1), 173; https://doi.org/10.3390/jcm11010173
Submission received: 23 November 2021 / Revised: 23 December 2021 / Accepted: 27 December 2021 / Published: 29 December 2021
(This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)
Browse Figure
Review Reports Versions Notes

Abstract

:
(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a syndrome that has fatigue as its major symptom. Evidence suggests that ozone is able to relieve ME/CFS-related fatigue in affected patients. (2) Objective: To evaluate whether differences exist between males and females in ozone therapy outputs in ME/CFS. (3) Methods: In total, 200 patients previously diagnosed with ME/CFS (mean age 33 ± 13 SD years) underwent treatment with oxygen–ozone autohemotherapy (O2-O3-AHT). Fatigue was investigated via an FSS 7-scoring questionnaire before and following 1 month after treatment. (4) Results: The Mann-Whitney test (MW test) assessed the significance of this difference (H = 13.8041, p = 0.0002), and female patients showed better outcomes than males. This difference was particularly striking in the youngest age cohort (14–29 years), and a KW test resulted in H = 7.1609, p = 0.007 for the Δ = 28.3% (males = 3.8, females = 5.3). (5) Conclusions: When treated with O2-O3-AHT, females respond better than males.

1. The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Challenge

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex pathology, and was recently reviewed in [1]. ME/CFS must be considered a serious and long-term syndrome, which is characterized by fatigue and debilitating muscular–skeletal pain, conditions that affect many fundamental aspects of people’s social habits [2,3,4]. Fatigue is a major symptom in ME/CFS and its treatment is accounted for in many forerunners in Italy [5,6,7,8,9,10,11,12,13,14,15,16]. Tirelli et al. performed a study with 82 CFS patients living in northern Italy, showing that early symptoms occur between 24 and 40 years and that ME/CFS is primarily (3:1) observed in female subjects [15]. However, ME/CFS diagnosis is particularly burdensome, as patients with fatigue and other clinical signs are more often misdiagnosed with other chronic illnesses [17,18]; this is despite official diagnostic criteria for ME/CFS from the Centers for Disease Control and Prevention, the so-called IOM 2015 Diagnostic Criteria, having been updated in the CDC’s 1994 guidelines, which can be consulted elsewhere [19]. Fatigue is the leading symptom of ME/CFS, alongside other physical symptoms, such as headaches, tender lymph nodes, sore throat, poor sleep, poor concentration, reduced attention or memory, post-exertional malaise, muscular–skeletal pain and polyarthralgia, [20,21,22,23]. The diagnosis of ME/CFS therefore almost entirely based on fatigue-related symptoms [24,25].
The burdensome task to achieve a proper and sound diagnosis affects the therapeutic approach [26], despite some commendable attempts [5,7,11]; however, ME/CFS remains a considerable concern for clinics. Promising attempts in treating ME/CFS fatigue with oxygen–ozone autohemotherapy (O2-O3-AHT) were successfully performed by our group and others [27,28,29]. O2-O3-AHT may affect many complex issues in terms of immunity, most of which characterize the pathogenetic mechanisms causing ME/CFS [30,31]. Interestingly, ME/CFS might also have an oxidative stress causative pathogenesis [32,33]. This evidence, linked to the increasing awareness that ozone is able to regulate inflammation by targeting the oxidative stress signaling [32], thus suggesting several encouraging pieces of evidence for ME/CFS diagnoses [27], compelled us to treat fatigue in patients with O2-O3-AHT and investigate whether therapy outputs showed differences between male and female patients.

2. Materials and Methods

2.1. Patient Recruitment

In total, 224 outpatients (mean age from the clinical centers of Pordenone and Gorle (Bergamo) were enrolled, having met the eligibility criteria agreed for the present study. Male mean age was 32.04 ± 18.45 SD and female mean age was 29.65 ± 11.54 SD (p = 0.354, in a Wilcoxon test). Of these patients, 200 entered the study; 19 escaped the study design because they referred to other therapy centers and were excluded. Five were formally accepted but never started for family and private reasons. Mean age was 33.08 ± 13.50 SD years [CI95 = 31.20–34.97], and median age was 33.14 years, comprising 69 men (34.5%) and 131 women. All patients were made aware of the therapy protocol and the use of the data for research purposes, according the recommendations of the Declaration of Helsinki.

2.2. Inclusion and Exclusion Criteria

Inclusion criteria were represented by outpatients referred to our clinical healthcare who were previously diagnosed with ME/CFS [23,34] and suffering from fatigue. These patients accepted and signed the informed consent for therapy and allowed for their data to be shared for research purposes. Exclusion criteria were represented by patients without ME/CFS, with other chronic and inflammation diseases, such as tumors or other immunological disorders and those who had taken pharmaceutical drugs in the previous 72 h; other exclusion criteria were those with chronic inflammatory and immune ailments such as autoimmunity, cancer or chronic inflammatory illness and pregnancy.

2.3. Sample Size

Sample size was calculated to achieve an error range of about 10%. Referring to a population proportion of 51%, forecast data resulted in a 13.86% error with 50 patients, whereas there was an error of 9.80% (<10%) with 103 patients; therefore, 200 patients were within the minimal sample size with p < 0.001. The Cohen d statistics for the two independent groups, i.e., before O2-O3-AHT and following O2-O3-AHT, were successfully implemented (p = 0.004323 or Hedges’ g value). Moreover, Glass’ delta was p = 0.012444 (p < 0.02).

2.4. Patient Evaluation of Fatigue Symptomatology

An anamnestic interview and complete visitation of about 20–30 min were performed. Fatigue was the major symptom evaluated in the study as it was able to highlight patients’ overall clinical status in the most sound and reliable manner; this is due to its optimal performance features, stability over time and scant possibility of being overshadowed by other minor symptoms. Each patient was asked to respond to a 7-point scoring system, the Fatigue Severity Scale (FSS), before undergoing therapy and one month following therapy [35,36]. Results were collected as scores and statistically evaluated.

2.5. Patients’ Treatment with Oxygen–Ozone Autohemotherapy (O2-O3-AHT)

Patients underwent no fewer than two weekly sessions of major oxygen–ozone autohemotherapy, according to the protocol previously assessed by the Italian Society of Oxygen–Ozone Therapy (SIOOT) [27]. Briefly speaking, each patient underwent a treatment option requiring an ozone generator, compressed oxygen as a medical grade, a venipuncture syringe and a certified bag with an intravenous cannula for ozone therapy via autohemotherapy. A maximal volume of 200 mL of blood was usually withdrawn from each patient and collected in a CE-certified SANO3 bag, with automatic gentle mixing then immediately treated with 45 μg/mL of an O3 mixture in O2 (Multioxygen Medical 95 CPS, Gorle, Italy). This was finally reintroduced into the circulatory blood directly and within a few minutes [27,37]. Patients were followed up after 30 days following the second O2-O3-AHT session, and were asked to complete the FSS questionnaire, as previously agreed.

2.6. Statistics

Data were collected and expressed as mean ± standard deviation, for quantitative values. Sample size was evaluated by assessing data and forecasting evaluations with Cohen d statistics and a Glass’ delta. Statistical inference, if any, was evaluated following non-parametric tests. Scores were evaluated by a Mann–Whitney test for two independent groups, with p < 0.05. Data were elaborated with SPSS v 24 software and Stata software for graphs.

3. Results

Figure 1 shows the difference (DELTA) in FSS score between female patients and male patients undergoing O2-O3-AHT. The average score was 5.14 ± 1.18 SD for females (CI95 = 4.865–5.4209) and 4.03 ± 1.80 SD for males (CI95 = 3.606–4.450) (mode: 6 and 5, respectively, median 5.5 and 5.0, respectively). The Mann–Whitney (MW) test assessed the significance at p < 0.05 of this difference (p = 0.0001), and female patients showed a better outcome than males. This difference was particularly striking in the youngest age cohort (14–29 years), as the MW test resulted in a p = 0.006 for the Δ = 28.3% (males = 3.8, females = 5.3). By arranging age groups into three clusters, i.e., 14–29 years, 30–49 years and ≥50, no difference in FSS score was reported for either females or males. Due to it having the highest heterogeneity in FSS response, the male group (see Figure 1), i.e., the MW test in the male age clusters, lacked statistical significance (p = 0.76). The O2-O3-AHT works optimally in an independent way with respect to elderly subjects of those of different ages.

4. Discussion

Our results suggest that O2-O3-AHT is able to relieve fatigue in almost half of the whole cohort of ME/CFS patients. Female patients showed a higher ability, particularly during youth (14–29 years), to respond to O2-O3-AHT than males. Age clusters did not significantly affect the influence of O2-O3-AHT on both sexes. Thus far, no sound explanation can be attained to explain why female patients show better outcomes with O2-O3-AHT. This fact might be explained by the different endocrine endowment in males compared to females, at least in terms of ER receptors and their effect on T cell activation and NK cell functional activity [11]. The modulation of immunity may be a sound solution to counter ME/CFS fatigue, and ozone may be a possible approach [5,6,27]. We are therefore unable to fully elucidate how ozone can restore wellness in patients suffering from ME/CFS-related fatigue [27]. Cell biology should suggest that, in ME/CFS mitochondria, activity is greatly disturbed, generating an impairment in fundamental mitochondria-related activities, such as ROS signaling [38], leading to inflammation disorders [39,40]. During ME/CFS, an increase in CD4+CD25+Foxp3+ T regulatory (Treg) cells occurs [41], a circumstance that may be modulated by ozone [42]. ME/CFS pathogenesis involves the impairment of Th17 cells. The CCR6+ Th17 cells in ME/CFS secrete less IL-17 with respect to healthy subjects; moreover, their cell frequency in blood is lower and ozone can restore their numbers [43,44]. The immune micro-environment in ME/CFS is therefore fundamental for proper therapy [9,10,11]. Furthermore, 4-hydroxynonenal (4-HNE) induces the thioredoxin reductase 1 via Nrf2 signaling, and then increases the level of Tregs [45,46]. The ability of ozone to modulate immunity and inflammation via the Nrf2 system is particularly well noted [32]. Ozone may regulate nitric oxide (NO) and eNOS [32]. That said, ME/CFS patients should have normal NO alongside normal IL-6 levels, both before and after physical exercise upon fatigue symptoms, but should also show high levels of F2-isoprostanes, i.e., oxidative stress biomarkers, which are probably quenched by the activity of ozone on the Nrf2/Keap1/ARE system [47,48,49].
The ability of O2-O3-AHT to elicit a greater response in females than males may involve ER-beta signaling on T reg biology [50], and may signal the possible involvement of Nrf2 signaling, as elicited by O2-O3-AHT. This represents another issue that should be investigated in future studies [51,52].

5. Conclusions

Patients suffering from ME/CFS fatigue and being treated with O2-O3-AHT experience rapid relief of their symptoms. Female subjects are able to respond to O2-O3-AHT and reduce fatigue symptoms better than males. Further insights are needed to elucidate the mechanism by which these differences occur.

Author Contributions

Conceptualization, U.T. and S.C.; methodology, U.T., M.F., L.V. and S.C.; software, S.C.; validation, U.T., G.R. and S.C.; formal analysis, S.C. and S.P.; investigation, U.T. and M.F.; resources, U.T., M.F. and L.V.; data curation, S.C. and S.P.; writing—original draft preparation, S.C.; writing—review and editing, U.T., S.C. and S.P.; visualization, U.T.; supervision, U.T., M.F., L.V., S.P., G.R. and S.C.; project administration, U.T.; funding acquisition, M.F. and L.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by SIOOT, Gorle (BG).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Tirelli Clinical Group (code TIR18APR).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study. All subjects were outpatients of our healthcare institution, and made their own decisions and were aware of the purpose of undergoing treatment with oxygen–ozone, which is not an experimental therapy. Therefore, patients were simply asked to agree and sign a consent form to use their data for research purposes. All subjects gave their informed consent for optional inclusion in the research before they participated in the study, which was conducted in accordance with the Declaration of Helsinki.

Data Availability Statement

Data repository can be requested to the Prof Umberto Tirelli, at your disposal and to Prof M Franzini at SIOOT (Bergamo).

Acknowledgments

A special thank to all the caregivers and health personnel involved in the management of the study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Deumer, U.S.; Varesi, A.; Floris, V.; Savioli, G.; Mantovani, E.; López-Carrasco, P.; Rosati, G.M.; Prasad, S.; Ricevuti, G. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview. J. Clin. Med. 2021, 10, 4786. [Google Scholar] [CrossRef]
  2. Barhorst, E.E.; Boruch, A.E.; Cook, D.B.; Lindheimer, J.B. Pain-related post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A systematic review and three-level meta-analysis. Pain Med. 2021, pnab308. [Google Scholar] [CrossRef]
  3. Noor, N.; Urits, I.; Degueure, A.; Rando, L.; Kata, V.; Cornett, E.M.; Kaye, A.D.; Imani, F.; Narimani-Zamanabadi, M.; Varrassi, G.; et al. A Comprehensive Update of the Current Understanding of Chronic Fatigue Syndrome. Anesth. Pain Med. 2021, 11, e113629. [Google Scholar] [CrossRef] [PubMed]
  4. Lim, E.J.; Son, C.G. Prevalence of Chronic Fatigue Syndrome (CFS) in Korea and Japan: A Meta-Analysis. J. Clin. Med. 2021, 10, 3204. [Google Scholar] [CrossRef] [PubMed]
  5. Tirelli, U.; Lleshi, A.; Berretta, M.; Spina, M.; Talamini, R.; Giacalone, A. Treatment of 741 Italian patients with chronic fatigue syndrome. Eur. Rev. Med. Pharmacol. Sci. 2013, 17, 2847–2852. [Google Scholar] [PubMed]
  6. Tirelli, U.; Cirrito, C.; Pavanello, M.; Del Pup, L.; Lleshi, A.; Berretta, M. Oxygen-ozone therapy as support and palliative therapy in 50 cancer patients with fatigue—A short report. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 8030–8033. [Google Scholar]
  7. Arpino, C.; Carrieri, M.P.; Valesini, G.; Pizzigallo, E.; Rovere, P.; Tirelli, U.; Conti, F.; Dialmi, P.; Barberio, A.; Rusconi, N.; et al. Idiopathic chronic fatigue and chronic fatigue syndrome: A comparison of two case-definitions. Ann. Ist. Super. Sanita 1999, 35, 435–441. [Google Scholar] [PubMed]
  8. Tirelli, U.; Chierichetti, F.; Tavio, M.; Simonelli, C.; Bianchin, G.; Zanco, P.; Ferlin, G. Brain positron emission tomography (PET) in chronic fatigue syndrome: Preliminary data. Am. J. Med. 1998, 105, 54S–58S. [Google Scholar] [CrossRef]
  9. Montoya, J.G.; Holmes, T.H.; Anderson, J.N.; Maecker, H.T.; Rosenberg-Hasson, Y.; Valencia, I.J.; Chu, L.; Younger, J.W.; Tato, C.M.; Davis, M.M. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc. Natl. Acad. Sci. USA 2017, 114, E7150–E7158. [Google Scholar] [CrossRef] [Green Version]
  10. Tirelli, U.; Marotta, G.; Improta, S.; Pinto, A. Immunological abnormalities in patients with chronic fatigue syndrome. Scand. J. Immunol. 1994, 40, 601–608. [Google Scholar] [CrossRef]
  11. Tirelli, V.; Pinto, A.; Marotta, G.; Crovato, M.; Quaia, M.; De Paoli, P.; Galligioni, E.; Santini, G. Clinical and immunologic study of 205 patients with chronic fatigue syndrome: A case series from Italy. Arch. Intern. Med. 1993, 153, 116–120. [Google Scholar] [CrossRef]
  12. Estévez-López, F.; Mudie, K.; Wang-Steverding, X.; Bakken, I.J.; Ivanovs, A.; Castro-Marrero, J.; Nacul, L.; Alegre, J.; Zalewski, P.; Słomko, J.; et al. Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology. J. Clin. Med. 2020, 9, 1557. [Google Scholar] [CrossRef]
  13. Vincent, A.; Brimmer, D.J.; Whipple, M.O.; Jones, J.F.; Boneva, R.; Lahr, B.D.; Maloney, E.; St Sauver, J.L.; Reeves, W.C. Prevalence, incidence, and classification of chronic fatigue syndrome in Olmsted County, Minnesota, as estimated using the Rochester Epidemiology Project. Mayo Clin. Proc. 2012, 87, 1145–1152. [Google Scholar] [CrossRef]
  14. Lim, E.J.; Ahn, Y.C.; Jang, E.S.; Lee, S.W.; Lee, S.H.; Son, C.G. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J. Transl. Med. 2020, 18, 100. [Google Scholar] [CrossRef] [PubMed]
  15. Capelli, E.; Lorusso, L.; Ghitti, M.; Venturini, L.; Cusa, C.; Ricevuti, G. Chronic fatigue syndrome: Features of a population of patients from northern Italy. Int. J. Immunopathol. Pharmacol. 2015, 28, 53–59. [Google Scholar] [CrossRef]
  16. Spazzapan, S.; Bearz, A.; Tirelli, U. Fatigue in cancer patients receiving chemotherapy. An analysis of published studies. Ann. Oncol. 2004, 15, 1576. [Google Scholar] [PubMed]
  17. Solomon, L.; Reeves, W.C. Factors influencing the diagnosis of chronic fatigue syndrome. Arch. Intern. Med. 2004, 164, 2241–2245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Brenna, E.; Araja, D.; Pheby, D.F.H. Comparative Survey of People with ME/CFS in Italy, Latvia, and the UK: A Report on Behalf of the Socioeconomics Working Group of the European ME/CFS Research Network (EUROMENE). Medicina 2021, 57, 300. [Google Scholar] [CrossRef]
  19. Kennedy, G.; Abbot, N.C.; Spence, V.; Underwood, C.; Belch, J.J. The specificity of the CDC-1994 criteria for chronic fatigue syndrome: Comparison of health status in three groups of patients who fulfill the criteria. Ann. Epidemiol. 2004, 14, 95–100. [Google Scholar] [CrossRef]
  20. Kuratsune, H. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve 2018, 70, 11–18. [Google Scholar]
  21. Carruthers, B.M.; van de Sande, M.I.; De Meirleir, K.L.; Klimas, N.G.; Broderick, G.; Mitchell, T.; Staines, D.; Powles, A.C.; Speight, N.; Vallings, R.; et al. Myalgic encephalomyelitis: International Consensus Criteria. J. Intern. Med. 2011, 270, 327–338. [Google Scholar] [CrossRef] [Green Version]
  22. Bruun Wyller, V.; Bjørneklett, A.; Brubakk, O.; Festvåg, L.; Follestad, I.; Malt, U.; Malterud, K.; Nyland, H.; Rambøl, H.; Stubhaug, B.; et al. Diagnosis and Treatment of Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME); Report from Norwegian Knowledge Centre for the Health Services (NOKC) No. 09-2006; Knowledge Centre for the Health Services at The Norwegian Institute of Public Health (NIPH): Oslo, Norway, 2006.
  23. Chew-Graham, C.; Dowrick, C.; Wearden, A.; Richardson, V.; Peters, S. Making the diagnosis of Chronic Fatigue Syndrome/Myalgic Encephalitis in primary care: A qualitative study. BMC Fam. Pract. 2010, 11, 16. [Google Scholar] [CrossRef] [Green Version]
  24. Son, C.G. Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”. Integr. Med. Res. 2019, 8, 89–91. [Google Scholar] [CrossRef] [PubMed]
  25. Nelsen, D.A., Jr. Differential diagnosis for chronic fatigue syndrome. Am. Fam. Physician 2003, 67, 252, author reply 252. [Google Scholar]
  26. Craig, T.; Kakumanu, S. Chronic fatigue syndrome: Evaluation and treatment. Am. Fam. Physician 2002, 65, 1083–1089. [Google Scholar] [PubMed]
  27. Tirelli, U.; Cirrito, C.; Pavanello, M. Ozone therapy is an effective therapy in chronic fatigue syndrome: Result of an Italian study in 65 patients. Ozon Ther. 2018, 3, 27–30. [Google Scholar] [CrossRef]
  28. Morelli, L.; Bramani, S.C.; Morelli, F.C. Oxygen-ozone therapy in meningoencephalitis and chronic fatigue syndrome. Treatment in the field of competitive sports: Case report. Ozone Ther. 2019, 4, 20–23. [Google Scholar] [CrossRef]
  29. Borrelli, E.; Bocci, V. A novel therapeutic option for Chronic Fatigue Syndrome and Fibromyalgia. Rivista Ital. Ossig-Ozonoterap. 2002, 1, 149–153. [Google Scholar]
  30. Viebahn-Haensler, R.; León Fernández, O.S. Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases. Int. J. Mol. Sci. 2021, 22, 7890. [Google Scholar] [CrossRef]
  31. Bjørklund, G.; Dadar, M.; Pivina, L.; Doşa, M.D.; Semenova, Y.; Maes, M. Environmental, Neuro-immune, and Neuro-oxidative Stress Interactions in Chronic Fatigue Syndrome. Mol. Neurobiol. 2020, 57, 4598–4607. [Google Scholar] [CrossRef]
  32. Chirumbolo, S.; Valdenassi, L.; Simonetti, V.; Bertossi, D.; Ricevuti, G.; Franzini, M.; Pandolfi, S. Insights on the mechanisms of action of ozone in the medical therapy against COVID-19. Int. Immunopharmacol. 2021, 96, 107777. [Google Scholar] [CrossRef]
  33. Paul, B.D.; Lemle, M.D.; Komaroff, A.L.; Snyder, S.H. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc. Natl. Acad. Sci. USA 2021, 118, e2024358118. [Google Scholar] [CrossRef] [PubMed]
  34. Baker, R.; Shaw, E.J. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): Summary of NICE guidance. BMJ 2007, 335, 446–448. [Google Scholar] [CrossRef] [Green Version]
  35. Neuberger, G.B. Measures of fatigue Arthritis and Rheumatisms. Arthr. Care Res. 2003, 48, S175–S183. [Google Scholar] [CrossRef]
  36. Tirelli, U.; Franzini, M.; Valdenassi, L.; Pisconti, S.; Taibi, R.; Torrisi, C.; Pandolfi, S.; Chirumbolo, S. Fatigue in post-acute sequelae of SARS-CoV2 (PASC) treated with oxygen-ozone autohemotherapy-Preliminary results on 100 patients. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 5871–5875. [Google Scholar] [PubMed]
  37. Lvis, A.M.; Ekta, J.S. Ozone therapy: A clinical review. J. Nat. Sci. Biol. Med. 2011, 2, 66–70. [Google Scholar]
  38. Anderson, G.; Maes, M. Mitochondria and immunity in chronic fatigue syndrome. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2020, 103, 109976. [Google Scholar] [CrossRef]
  39. Maes, M.; Twisk, F.N.; Kubera, M.; Ringel, K. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J. Affect. Disord. 2012, 136, 933–939. [Google Scholar] [CrossRef] [PubMed]
  40. Maes, M.; Twisk, F.N.; Ringel, K. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: Inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother. Psychosom. 2012, 81, 286–295. [Google Scholar] [CrossRef]
  41. Brenu, E.W.; Huth, T.K.; Hardcastle, S.L.; Fuller, K.; Kaur, M.; Johnston, S.; Ramos, S.B.; Staines, D.R.; Marshall-Gradisnik, S.M. Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. Int. Immunol. 2014, 26, 233–242. [Google Scholar] [CrossRef] [PubMed]
  42. Wei, M.; Tu, L.; Liang, Y.H.; Liu, J.; Gong, Y.J.; Zhang, J.H.; Zhang, Y.H. Effects of ozone exposure on percentage of CD4(+)CD25(high)Foxp(3+) regulatory T cells and mRNA expression of Foxp3 in asthmatic rats. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2013, 31, 693–696. [Google Scholar]
  43. Broderick, G.; Fuite, J.; Kreitz, A.; Vernon, S.D.; Klimas, N.; Fletcher, M.A. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav. Immun. 2010, 24, 1209–1217. [Google Scholar] [CrossRef] [Green Version]
  44. Izadi, M.; Tahmasebi, S.; Pustokhina, I.; Yumashev, A.V.; Lakzaei, T.; Alvanegh, A.G.; Roshangar, L.; Dadashpour, M.; Yousefi, M.; Ahmadi, M. Changes in Th17 cells frequency and function after ozone therapy used to treat multiple sclerosis patients. Mult. Scler. Relat. Disord. 2020, 46, 102466. [Google Scholar] [CrossRef] [PubMed]
  45. Chen, Z.H.; Saito, Y.; Yoshida, Y.; Sekine, A.; Noguchi, N.; Niki, E. 4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via activation of Nrf2. J. Biol. Chem. 2005, 280, 41921–41927. [Google Scholar] [CrossRef] [Green Version]
  46. Wang, X.; Dong, H.; Li, Q.; Li, Y.; Hong, A. Thioredoxin induces Tregs to generate an immunotolerant tumor microenvironment in metastatic melanoma. Oncoimmunology 2015, 4, e1027471. [Google Scholar] [CrossRef] [Green Version]
  47. Meeus, M.; Van Eupen, I.; Hondequin, J.; De Hauwere, L.; Kos, D.; Nijs, J. Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: A case-control study. In Vivo 2010, 24, 865–869. [Google Scholar]
  48. Robinson, M.; Gray, S.R.; Watson, M.S.; Kennedy, G.; Hill, A.; Belch, J.J.; Nimmo, M.A. Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand. J. Med. Sci. Sports 2010, 20, 282–290. [Google Scholar] [CrossRef] [PubMed]
  49. Milne, G.L.; Musiek, E.S.; Morrow, J.D. F2-isoprostanes as markers of oxidative stress in vivo: An overview. Biomarkers 2005, 10 (Suppl. S1), S10–S23. [Google Scholar] [CrossRef] [PubMed]
  50. Goodman, W.A.; Bedoyan, S.M.; Havran, H.L.; Richardson, B.; Cameron, M.J.; Pizarro, T.T. Impaired estrogen signaling underlies regulatory T cell loss-of-function in the chronically inflamed intestine. Proc. Natl. Acad. Sci. USA 2020, 117, 17166–17176. [Google Scholar] [CrossRef]
  51. Gräns, H.; Nilsson, M.; Dahlman-Wright, K.; Evengård, B. Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome. J. Clin. Pathol. 2007, 60, 195–198. [Google Scholar] [CrossRef] [Green Version]
  52. Ishii, T.; Warabi, E. Mechanism of Rapid Nuclear Factor-E2-Related Factor 2 (Nrf2) Activation via Membrane-Associated Estrogen Receptors: Roles of NADPH Oxidase 1, Neutral Sphingomyelinase 2 and Epidermal Growth Factor Receptor (EGFR). Antioxidants 2019, 8, 69. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Jcm 11 00173 g001 550
Figure 1. Box plot representation of the FSS differential response between male and female patients with ME/CFS treated with O2-O3-AHT.
Figure 1. Box plot representation of the FSS differential response between male and female patients with ME/CFS treated with O2-O3-AHT.
Jcm 11 00173 g001
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Chirumbolo, S.; Valdenassi, L.; Franzini, M.; Pandolfi, S.; Ricevuti, G.; Tirelli, U. Male vs. Female Differences in Responding to Oxygen–Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J. Clin. Med. 2022, 11, 173. https://doi.org/10.3390/jcm11010173

AMA Style

Chirumbolo S, Valdenassi L, Franzini M, Pandolfi S, Ricevuti G, Tirelli U. Male vs. Female Differences in Responding to Oxygen–Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Journal of Clinical Medicine. 2022; 11(1):173. https://doi.org/10.3390/jcm11010173

Chicago/Turabian Style

Chirumbolo, Salvatore, Luigi Valdenassi, Marianno Franzini, Sergio Pandolfi, Giovanni Ricevuti, and Umberto Tirelli. 2022. "Male vs. Female Differences in Responding to Oxygen–Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)" Journal of Clinical Medicine 11, no. 1: 173. https://doi.org/10.3390/jcm11010173

APA Style

Chirumbolo, S., Valdenassi, L., Franzini, M., Pandolfi, S., Ricevuti, G., & Tirelli, U. (2022). Male vs. Female Differences in Responding to Oxygen–Ozone Autohemotherapy (O2-O3-AHT) in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Journal of Clinical Medicine, 11(1), 173. https://doi.org/10.3390/jcm11010173

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop