Medicine Correspondence Blog

The Medicine Correspondence Blog allows authors to post Letters to the Editors, Reviews, and other editorial writings that are not considered original research.

Friday, February 16, 2018

We have recently read the report of Tang et al[1] in your prestigious Journal and we were really puzzled by the title that reported a severe side effect supposedly induced by Ozone Therapy (OT). It is absolutely necessary to clarify some important points, considering the poor scientific evidence regarding the description of OT and the medical history of the patient.

First of all, the authors should avoid the use of the term "alternative treatment" because OT, just like many other integrative approaches, could never be considered "alternative" to any other therapeutic methods included in the conventional allopathic medicine. Indeed, as reported by us[2,3] and others[4], the use of medical ozone, being absolutely safe[5], is indicated in many conditions with excellent clinical results as a complementary or integrative procedure, associated with other regular therapies. Recent studies[6] reported the discovery of interesting metabolic pathways activated by administration of correct OT doses as recommended by international guidelines[7].

We have also found it imperative to note how scarce and poor the literature reported in the article is. We were really even more astounded reading the case presentation and the discussion, as most of the statements are both unscientific and meaningless, demonstrating little knowledge of the subject matter and lack of responsibility on behalf of the authors.

First, we have no information concerning the method used to inject ozone into the patient. No report or paper may be worthy of being published on the basis of what was stated by the authors on page 3, row 4: "the dose was unknown". How could a side effect of a beta blocker for example be defined without knowing the administered dose? No further comments.

Second, the ozonated Major Auto-Hemotherapy (MAH) technique is one of the safest methods when compared to other therapeutic approaches. In our clinics over the last 30 years, we have administered approximately 50 thousand MAHs to humans without relevant side effects. Only in very few cases mild reactions were observed, like facial redness and tingling. No elevation of serum potassium was ever reported, even when administered to chronic kidney disease (CKD) patients. Thousands of physicians around the world have been performing MAHs since 1960, so one can only wonder how many procedures have been administered so far.

Finally, we were really surprised to notice that the authors confused MAH with "input of red blood cells in vitro". Major Auto-Hemotherapy cannot be defined as a blood transfusion procedure, or even be compared to it since it lacks, by definition and by practical means, the fundamental characteristic of a transfusion: withdrawal, deposit and subsequent re-infusion of heterologous blood from a donor to a receiver. The release of potassium from lysed red blood cells is related to the storage of the blood. However, there is no scientific evidence that could explain a possible increase of serum potassium secondary to re-injection of the autologous ozonated blood according to the standard MAH procedure, including in patients with CKD.

 The authors declare to have no conflicts of interest to disclose.


[1] Tang WJ, Jiang L, Wang Y, et al. Ozone therapy induced sinus arrest in a hypertensive patient with chronic kidney disease. Medicine 2017; 96:50.

[2] Re L, Malcangi G, Martinez-Sanchez G. Medical ozone is now ready for a scientific challenge: current status and future perspectives. Journal of Experimental and Integrative Medicine 2012; 2(3):193-196.

[3] Re L, Rowen R and Travagli V. Ozone Therapy and Its Use in Medicine. Cardiology      2016;134:99–100.

[4] Bocci V, Valacchi G, Rossi R, et al. Studies on the biological effects of ozone: 9. Effects of ozone on human platelets. Platelets 1999; 10: 110 -116.

[5] Jacobs, MT. Investigation into pitfalls and typical complications in ozone-oxygen therapy. Untersuchung uber Zwischenfalle und typische Komplikationen in der Ozon Sauerstoff-Therapie. OzoNachrichten, 1982; 1:5.

 [6] Re L, Martínez-Sánchez G, Bordicchia M, et al.. Is ozone pre-conditioning effect linked to Nrf2/EpRE activation pathway in vivo? A preliminary result. Eur J Pharmacol, 2014; 742: 158–162.

[7] Viebahn-Hänsler R, Fernández OSL and Fahmy Z. Ozone in Medicine: The Low-Dose Ozone Concept - Guidelines and Treatment Strategies. Ozone: Science & Engineering, 2012; 34: 408–424.

Corresponding Authors: Lamberto Re, MDa,*, Jose Baeza Noci, MDb, Maria-Emilia Gadelha Serra, MDc, He Xiaofeng, MDd and Valter Travagli, PharmDe

Friday, February 16, 2018

We congratulate Pu and colleagues for their successful study1. Along with the developing technology, alternative treatment methods have started to be used in thoracic aortic pathologies. The conventional method for treating thoracic aortic pathologies is open surgery involving interposition grafting2. However, even though this method is commonly practiced, it is still associated with high surgical morbidity and mortality, especially in the patients with several comorbidities2-4. As a result, technologies were developed to address the problems of open surgery, and surgeons currently tend to prefer alternative, less invasive treatment options 2,3.  Currently, the leading alternative is a hybrid treatment involving the use of both open surgery and endovascular methods in the same or different sessions. In this case, two discussion topics arise. The first is that when should we perform the endovascular process? In the same session or in a different session?  Generally, since hybrid operation rooms are not common, the endovascular process is performed at different sessions. Hybrid procedure has disadvantages such as prolonged operation time, more blood loss, contrast agent use when performed in the same session with open surgery 6,7. However, it is also true that a single session anesthesia procedure gathers round a psychological protective effect on the patient, and gives the chance of open surgical intervention in case of a complication that may develop during endovascular intervention. The second topic is related to an another situation, especially when the hybrid intervention is to be performed in the same session. In this technique endovascular intervention can be performed in two methods. The first method is antegrade approach that using an extra graft or placing directly from the ascending aorta. The second method is retrograde procedure that the endovascular intervention through the femoral or iliac artery. Performing this procedure by antegrade route provides such advantages as avoiding complications likely to develop in the iliofemoral artery used as the site of access during the procedure and ensuring sufficient length in order for the endograft carrier systems to reach the attachment sites 5,6. Moreover, presence of shorter carrier systems in the antegrade approach will cause delivery of less rotational power, thus providing maximum precision in the placement of the graft. Another advantage is that antegrade approach permits manual manipulations of the endograft in order to fit it to a desired position in the aortic arch, thanks to the open sternum 1,2. Apart from that, there appears to be a risk of entering the false lumen in the femoral or iliac arteries upon using the retrograde route especially in dissection cases. We believe that learning about the authors' views on this subject will add value to their study.


1) Pu XB, Chen SJ, Chen M, Feng Y.Two-stage hybrid treatment strategy for an adult patient with aortic arch coarctation, poststenotic aneurysm, and hypoplastic left subclavian artery: A case report. Medicine (Baltimore). 2017 Dec;96(48):e8618.

2) Yilik L, Gokalp O, Yurekli İ, Bayrak S, Gunes T, Karakas N, Ozsoyler I, Gurbuz A. Hybrid repair of aortic arch aneurysms in same session. Thorac Cardiovasc Surg. 2012; 60(8):501-507.

3) Yilik L, Gunes T, Ozsoyler I, Gurbuz A. Hybrid approaches to repair of aortic pathologies. Turkiye Klinikleri J Cardiovasc Surg-Special Topics 2009;2(1):64-75.

4) Antoniou GA, Mireskandari M, Bicknell CD, Cheshire NJ, Gibbs RG, Hamady M et al. Hybrid repair of the aortic arch in patients with extensive aortic disease. Eur J Vasc Endovasc Surg. 2010 Dec;40(6):715-21.

5) Chan YC, Cheng SW, Ting AC, Ho P. Supra-aortic hybrid endovascular procedures for complex thoracic aortic disease: Single center early to midterm results J Vasc Surg 2008;48:571-9.

6) Riessenman PJ, Tamaddon HS, Farber MA. Surgical bypass procedures to facilitate endovascular repair of aortic arch patology. J Cardiovacs Surg 2008;49:461-9.

Corresponding Author: Hasan INER, M.D.

Adiyaman Education and Research Hospital,

Department of Cardiovascular Surgery,

02000, Adiyaman, Turkey​


Thursday, January 25, 2018

We read with interest the article by Lv et al. about a 48yo Han Chinese female with CPEO plus ptosis, cataract, cerebellar atrophy, and cerebral atrophy due to one mutation each in the 12S-rRNA and the 16S-rRNA respectively [1]. We have the following comments and concerns.

The main shortcoming of the report is that the patient had two different mtDNA mutations but it is neither discussed to which degree either of the two contributed to the phenotype or if both were pathogenic. Pathogenicity of the mutations is particularly questionable since the mutations did not segregate with the phenotype within the family, since no heteroplasmy rates were provided, since no biochemical investigations of the muscle homogenate had been carried out, since no single fiber studies were conducted, and since no cybrid studies had been undertaken [2fimerrf]. Given the weak evidence for the two variants to have been pathogenic, mutations in other mtDNA located genes or in nuclear gens should have been excluded.

Missing in this study is the heteroplasmy rate of either variants. It could have been determined in mtDNA from hair follicles, buccal mucosa, skin fibroblasts, blood lymphocytes, muscle, or urinary epithelial cells. Heteroplasmy rates are of paramount importance to assess the pathogenicity of either variants and to assess the degree of genotype phenotype correlation [3poulton]. Heteroplasmy rate may vary between tissues and may explain the phenotypic heterogeneity within a family.

We also disagree with the classification of the phenotype as "CPEO plus". Patients with a mitochondrial disorder (MID) frequently manifest as a multisystem disease, either already at onset of the disease or during the further course of the disease. Additionally, the phenotypic heterogeneity with and between families is broad for most of the mitochondrial mutations. Thus, most of the unsharply defined specific mitochondrial syndromes, tagged with one of the >50 acronyms, can present with variable plus or minus variants and may overlap considerably. For this reason it is more convenient to talk about mitochondrial multiorgan disorder syndromes (MIMODS) [4fimimodscore] and to precisely describe their highly variable phenotype.

A further shortcoming is that the patient was not sufficiently and prospectively investigated for multisystem disease. Recording of an ECG is not sufficient to exclude or confirm cardiac involvement in the MID. It is essential that MID patients undergo clinical cardiologic investigations, echocardiography and long-term ECG recordings [5wahbi15]. Since MID patients frequently present with thyroid dysfunction, diabetes, hypocorticism, hypogonadism, or hypopituitarism, such endocrine abnormalities need to be excluded or confirmed. How was subclinical or mildly manifesting gastrointestinal, renal, dermal, hematological, or pulmonary involvement excluded? Not even the height of the patient is reported.

A strong limitation of the study is that neither the mother nor the children of the index case were sufficiently investigated with regard to transmission and segregation of the mutations. .

Overall, this interesting case report could be more meaningful, if the pathogenicity of either variants would have been more strongly confirmed, if heteroplasmy rates of either variants would have been provided, if the patient would have been prospectively investigated for involvement of organs other than the brain and the eyes, and if first degree relative would have been genetically tested.


Corresponding author:

 Josef Finsterer, MD, PhD [1], Sinda Zarrouk-Mahjoub, PhD [2]

 [1] Krankenanstalt Rudolfstiftung, Vienna, Austria

[2] University of Tunis El Manar and Genomics Platform, Pasteur Institute of Tunis, Tunisia


Finsterer J, MD, PhD

Postfach 20

1180 Vienna

Austria, Europe




1 Lv ZY, Xu XM, Cao XF, Wang Q, Sun DF, Tian WJ, Yang Y, Wang YZ, Hao YL. Mitochondrial mutations in 12S rRNA and 16S rRNA presenting as chronic progressive external ophthalmoplegia (CPEO) plus: A case report. Medicine (Baltimore) 2017 Dec;96(48):e8869. doi: 10.1097/MD.0000000000008869.


2 Finsterer J, Zarrouk-Mahjoub S, Shoffner JM. MERRF Classification: Implications for Diagnosis, and Clinical Trials. Pediatr Neurol 2018;(in press)


3 Poulton J, Finsterer J, Yu-Wai-Man P. Genetic Counselling for Maternally Inherited Mitochondrial Disorders. Mol Diagn Ther 2017;21:419-429.


4 Finsterer J, Zarrouk-Mahjoub S. Mitochondrial multiorgan disorder syndrome score generated from definite mitochondrial disorders. Neuropsychiatr Dis Treat 2017;13:2569-2579.


5 Wahbi K, Bougouin W, Béhin A, Stojkovic T, Bécane HM, Jardel C, Berber N, Mochel F, Lombès A, Eymard B, Duboc D, Laforêt P. Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. Eur Heart J 2015;36:2886-93. ​

Tuesday, January 16, 2018

Dear Sirs

We read with interest the article published by De Miguel-Díez J et al. (1) Reporting on a recent decrease of ventilator-associated pneumonia (VAP) rates in patients admitted to hospitals of the Public Healthcare System in Spain from 2010 to 2014. According to De Miguel-Díez, VAP incidence rates decreased significantly from 41.7 cases/100,000 inhabitants in 2010 to 40.5 in 2014. The authors found no difference in VAP rates in mechanically ventilated patients, however, with percentages ranging from 3.93% of ventilated patients in 2010 to 3.97% in 2014. These results are based on the retrospective analysis of the Spanish National Discharge Database (SNHDD), which includes patient discharge diagnoses and procedures. In their discussion, De Miguel-Díaz et al speculate about the causes which might have led to the reduction in Spanish National VAP rates.

In Spain, most patients needing prolonged mechanical ventilation are admitted to intensive care units (ICU). Since 2009 these ICUs apply the recommendations of National Projects aiming at the reduction of invasive device-associated infections. The Projects are endorsed by the Ministry of Health and the Regional Departments of Health. The scientific lead is of the Projects the Spanish Society of Critical Care (Sociedad de Medicina Intensiva, Crítica y Unidades Coronarias (SEMICYUC) and the Spanish Society of Critical Care Nurses (Sociedad Española de Enfermería Intensiva y Unidades Coronarias (SEEIUC). Project "Neumonía Zero" started in 2011, with the main objective to reduce VAP rates in critically ill patients.  Objectives, recommendations and performance indicators have previously been published (2), as well as the final results of its implementation (3). Project "Neumonía Zero" was a prospective study and the diagnosis of VAP was established by intensivists experts in the management of patients with severe infection, according to previously established standardized criteria, trained in specific workshops. Since 2012, the results of the intervention have been presented at national and international meetings (4,5) and mentioned in the Spanish press and media, both general and specialized in healthcare. Over the course of the implementation phase of the Project (2011-2012), the 181 participating ICUs, approximately 80% of Spanish ICUs, the adjusted ventilator-associated pneumonia incidence density rate decreased from 9.83 (95% CI, 8.42–11.48) per 1,000 ventilator days in the baseline period to 4.34 (95% CI, 3.22–5.84) after 19–21 months of participation. The impact of "Neumonía Zero" has persisted beyond its implementation phase, according to publications of the European Centre for Disease Prevention and Control (ECDC) (6) (Healthcare-associated infections acquired in intensive care units – Annual Epidemiological Report 2016 [2014 data]), where the incidence density for Spain in 2014 is 6.3 VAP episodes per 1000 days of mechanical ventilation.

In conclusion, the reduction of VAP in the critically ill in Spain is well documented and attributable to adherence to recommendations contained in the bundle of "Neumonía Zero" as endorsed by the Working Group for Infectious Disease and Sepsis of SEMICYUC (7).  Observance of the preventive measures and its results is an achievement of the attending healthcare personnel and their continuous commitment to quality improvement should be acknowledged.




Francisco Álvarez Lerma, Servicio de Medicina Intensiva. Hospital del Mar. Barcelona

José Garnacho Montero, Servicio de Medicina Intensiva. Hospital Virgen de la Macarena. Sevilla.

Miguel Sánchez García, Servicio de Medicina Intensiva. Hospital Clinico San Carlos. Madrid.



  1. De Miguel-Diez J, Lopéz de Andres A, Hernández-Barrera V et al. Decreasing incidence and mortality among hospitaled patients suffering a ventilator-associated pneumonia. Medicine 2017, 96: 30(e7625)
  2. Alvarez –Lerma F, Sánchez García M, Lorente L, et al. Guidelines for the preventiion of ventilator-associated pneumonia and their implementation. The Spanich "Zero-VAP" bundle. Med Intensiva. 2014; 38(4):226-36
  3. Álvarez-Lerma F, Palomar-Martínez M, Sánchez-García M, et al. Prevention of Ventilator-Associated Pneumonia: The Multimodal Approach of the Spanish ICU "Pneumonia Zero" Program. Crit Care Med. 2017 Oct 11. doi: 10.1097/CCM.0000000000002736. [Epub ahead of print]
  4. Álvarez-Lerma F,  Palomar M. Olaechea, P. et ál. Why the rates of mechanical ventilation-related pneumonia have decreased in Spain?. European Society of Intensive Care Medicine. 25th Annual Congress. Lisbon, Portugal. October 13-17, 2012. INTENSIVE CARE MEDICINE, 38, 1, S129-S129
  5. Álvarez Lerma F, Álvarez J, Añón JM, et al. Informe final del Proyecto Neumonía Zero.X Congreso Panamericano de Medicina Crítica y Terapia intensiva. Madrid. Junio 2014. Med Intensiva 38 (Especial Congreso): S2
  6. European Centre for Disease Prevention and Control (ECDC). Healthcare-associated infections acquired in intensive care units - Annual Epidemiological Report 2016 [2014 data. Disponible en (última entrada 4 de noviembre 2017)
  7. Hernández-Tejedor APeñuelas O, Sirgo Rodríguez G, et al. Recommendations of the Working Groups from the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) for the management of adult critically ill patients. Med Intensiva. 2017 ; 41:285-305​

Thursday, January 11, 2018

         We commend Meng et al.[1] for introducing a new hemostatic technique for total placenta previa (PP) with the placenta covering the previous cesarean scar: the lower uterine segment was sutured by "multifaceted spiral suture" from the intrauterine side, with the uterus preserved in all 33 patients. We have some concerns.

          Firstly, the study population was unclear. Whereas they treated 180 patients with PP with the placenta covering the previous cesarean scar, they performed this procedure in 33 patients. They state, "There were only 33 patients accorded with the aforesaid requirements because 147 patients underwent other supplementary hemostatic methods". The "aforesaid" requirements were "2 imaging evidence of total PP" or "its confirmation by magnetic resonance imaging". Distinction between 33 vs. 147 patients can be interpreted in two ways: i) "total" PP was (n=33) or was not (n=147) confirmed, or ii) this suture (n=33) or other hemostatic procedure (n=147) was performed on attending doctors' choice.  

         Secondly, Meng et al. employed this spiral suture to "all" 33 patients "routinely", meaning that they employed it "prophylactically" at least in some patients. Almost all patients (30/33) had one previous cesarean section. A reported incidence for PP patients with one previous cesarean suffering abnormally invasive placenta (AIP; accreta, increta, percreta) was 11 %.[2] In Meng et al.' series, the incidence of AIP or suspected AIP was 73% (24/33), showing a much higher incidence. Putting this aside, we sometimes encounter a PP patient in whom the placenta is removed easily and there is no bleeding from the placental separation site. Even in this occasion, we "prophylactically" employ Bakri intrauterine hemostatic balloon.[3] We wonder whether "suturing" this non-bleeding lower segment is really necessary. We are concerned that "prophylactic" suture ligation (to no bleeding site) may tear the weak lower segment, causing bleeding.

         Thirdly, in percreta, the placental removal is difficult and its forcible removal usually destroys the uterine wall. Thus, no "room" remains for suture ligation: uterine reconstruction and not suture ligation is required. Spiral suture may achieve hemostasis to accreta (narrow meaning) or lesser degree of increta; however, we wonder how we handle percreta by spiral suture. What we really wish to know is how to handle "percreta".

         Lastly, AIP can be confirmed only after hysterectomy. Meng et al. stated that the villi attaching to the myometrium was considered as AIP. However, the forcible placental removal usually can remove only the surface side of the AIP: as described, in percreta, "total removal" is difficult, and, thus, myometrial attachment cannot be usually confirmed in the "removed" placenta. Since pathological diagnosis of AIP was difficult, the word of "clinically or intra-surgically suspected AIP" may better illustrate the situation of this study population.

         We totally agree with Meng et al.'s claim that "separation of the bladder" may cause some troubles in PP with AIP. This usually causes massive bleeding at the beginning of the surgery.[4] We support their fundamental concept; however, clarification should be made before Meng et al.'s suture may become reproducible to every obstetrician. 


[1] Meng Y, Wu P, Deng D, et al. Multifaceted spiral suture: A hemostatic technique in managing placenta praevia or accrete: A retrospective study.

Medicine (Baltimore). 2017;96:e9101.

[2] Grobman WA, Gersnoviez R, Landon MB, et al. Pregnancy outcomes for women with placenta previa in relation to the number of prior cesarean deliveries. Obstet Gynecol. 2007;110:1249-55.

[3] Matsubara S. Prophylactic use of Bakri balloon for reduction of hemorrhage at cesarean for placenta previa: addition and clarification. Arch Gynecol Obstet. 2017 Jul 26. doi: 10.1007/s00404-017-4475-9. [Epub ahead of print]

[4] Matsubara S, Takahashi H, Baba Y. Handling aberrant vessels located in the posterior bladder wall in surgery for abnormally invasive placenta: a non/less-touch technique. Arch Gynecol Obstet. 2017;296:851-3.

Author Correspondence:

Shigeki Matsubara and Hironori Takahashi

Shigeki Matsubara, MD, PhD

Director and Professor, Department of Obstetrics and Gynecology,

Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan​

E-mail address of coauthor:

Hironori Takahashi: