Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects.

(1) Background: Cancer is one of the leading causes of mortality worldwide. Radiotherapy and chemotherapy attempt to kill tumor cells by different mechanisms mediated by an intracellular increase of free radicals. However, free radicals can also increase in healthy cells and lead to oxidative stress, resulting in further damage to healthy tissues. Approaches to prevent or treat many of these side effects are limited. Ozone therapy can induce a controlled oxidative stress able to stimulate an adaptive antioxidant response in healthy tissue. This review describes the studies using ozone therapy to prevent and/or treat chemotherapy-induced toxicity, and how its effect is linked to a modification of free radicals and antioxidants. (2) Methods: This review encompasses a total of 13 peer-reviewed original articles (most of them with assessment of oxidative stress parameters) and some related works. It is mainly focused on four drugs: Cisplatin, Methotrexate, Doxorubicin, and Bleomycin. (3) Results: In experimental models and the few existing clinical studies, modulation of free radicals and antioxidants by ozone therapy was associated with decreased chemotherapy-induced toxicity. (4) Conclusions: The potential role of ozone therapy in the management of chemotherapy-induced toxicity merits further research. Randomized controlled trials are ongoing.

Pulsed Ultrasounds Reduce Pain and Disability, Increasing Rib Fracture Healing, in a Randomized Controlled Trial.

INTRODUCTION: Rib fractures are an important health issue worldwide, with significant, pain, morbidity, and disability for which only symptomatic treatment exists. OBJECTIVES: Based on our previous experimental model, the objective of the current study was to assess for the first time whether pulsed ultrasound (PUS) application could have beneficial effects on humans. METHODS: Prospective, double-blinded, randomized, controlled trial of 51 patients. Four were excluded, and 47 were randomized into the control group (N = 23) or PUS group (N = 24). The control group received a PUS procedure without emission, and the PUS group received 1 Mhz, 0.5 W/cm2 for 1 min/cm2. Pain level, bone callus healing rate, physical and work activity, pain medication intake, and adverse events were blindly evaluated at baseline and one, three, and six months. RESULTS: There were no significant differences at baseline between groups. PUS treatment significantly decreased pain by month 1 (P = 0.004), month 3 (P = 0.005), and month 6 (P = 0.025), significantly accelerated callus healing by month 1 (P = 0.013) and month 3 (P < 0.001), accelerated return to physical activity by month 3 (P = 0.036) and work activity (P = 0.001) by month 1, and considerably reduced pain medication intake by month 1 (P = 0.057) and month 3 (P = 0.017). No related adverse events were found in the PUS group. CONCLUSIONS: This study is the first evidence that PUS treatment is capable of improving rib fracture outcome, significantly accelerating bone callus healing, and decreasing pain, time off due to both physical activity and convalescence period, and pain medication intake. It is a safe, efficient, and low-cost therapy that may become a new treatment for patients with stable rib fractures.

Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted?

INTRODUCTION: This article provides an overview of the potential use of ozone as an adjuvant during cancer treatment. METHODS: We summarize the findings of the most relevant publications focused on this goal, and we include our related clinical experience. RESULTS: Over several decades, prestigious journals have published in vitro studies on the capacity of ozone to induce direct damage on tumor cells and, as well, to enhance the effects of radiotherapy and chemotherapy. Indirect effects have been demonstrated in animal models: immune modulation by ozone alone and sensitizing effect of radiotherapy by concurrent ozone administration. The effects of ozone in modifying hemoglobin dissociation curve, 2,3-diphosphoglycerate levels, locoregional blood flow, and tumor hypoxia provide additional support for potential beneficial effects during cancer treatment. Unfortunately, only a few clinical studies are available. Finally, we describe some works and our experience supporting the potential role of local ozone therapy in treating delayed healing after tumor resection, to avoid delays in commencing radiotherapy and chemotherapy. CONCLUSIONS: In vitro and animal studies, as well as isolated clinical reports, suggest the potential role of ozone as an adjuvant during radiotherapy and/or chemotherapy. However, further research, such as randomized clinical trials, is required to demonstrate its potential usefulness as an adjuvant therapeutic tool.

Airway transplantation of adipose stem cells protects against bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis. Adipose-derived stem cells (ADSC) have demonstrated regenerative properties in several tissues. The hypothesis of this study was that airway transplantation of ADSC could protect against bleomycin (BLM)-induced pulmonary fibrosis (PF). Fifty-eight lungs from 29 male Sprague-Dawley rats were analyzed. Animals were randomly divided into five groups: a) control (n=3); b) sham (n=6); c) BLM (n=6); d) BLM+ADSC-2d (n=6); and e) BLM+ADSC-14d (n=8). Animals received 500 µL saline (sham), 2.5 UI/kg BLM in 500 µL saline (BLM), and 2×106 ADSC in 100 µL saline intratracheally at 2 (BLM+ADSC-2d) and 14 days (BLM+ADSC-14d) after BLM. Animals were sacrificed at 28 days. Blinded Ashcroft score was used to determine pulmonary fibrosis extent on histology. Hsp27, Vegf, Nfkß, IL-1, IL-6, Col4, and Tgfß1 mRNA gene expression were determined using real-time quantitative-PCR. Ashcroft index was: control=0; sham=0.37±0.07; BLM=6.55±0.34 vs sham (P=0.006). BLM vs BLM+ADSC-2d=4.63±0.38 (P=0.005) and BLM+ADSC-14d=3.77±0.46 (P=0.005). BLM vs sham significantly increased Hsp27 (P=0.018), Nfkß (P=0.009), Col4 (P=0.004), Tgfß1 (P=0.006) and decreased IL-1 (P=0.006). BLM+ADSC-2d vs BLM significantly decreased Hsp27 (P=0.009) and increased Vegf (P=0.006), Nfkß (P=0.009). BLM+ADSC-14d vs BLM significantly decreased Hsp27 (P=0.028), IL-6 (P=0.013), Col4 (P=0.002), and increased Nfkß (P=0.040) and Tgfß1 (P=0.002). Airway transplantation of ADSC significantly decreased the fibrosis rate in both early and established pulmonary fibrosis, modulating the expression of Hsp27, Vegfa, Nfkß, IL-6, Col4, and Tgfß1. From a translational perspective, this technique could become a new adjuvant treatment for patients with IPF.

Ozone Therapy Protects Against Rejection in a Lung Transplantation Model: A New Treatment?

BACKGROUND: No satisfactory treatment exists for chronic rejection (CR) after lung transplantation (LT). Our objective was to assess whether ozone (O3) treatment could ameliorate CR. METHODS: Male Sprague-Dawley inbred rats (n = 36) were randomly assigned into four groups: (1) control (n = 6), (2) sham (n = 6), (3) LT (n = 12), and (4) O3-LT (n = 12). Animals underwent left LT. O3 was rectally administered daily for 2 weeks before LT (from 20 to 50 µg) and 3 times/wk (50 µg/dose) up to 3 months. CR; acute rejection; and Hspb27, Prdx, Epas1, Gpx3, Vegfa, Sftpa1, Sftpb, Plvap, Klf2, Cldn5, Thbd, Dsip, Fmo2, and Sepp1 mRNA gene expression were determined. RESULTS: Severe CR was observed in all animals of LT group, but none of the O3-LT animals showed signs of CR, just a mild acute rejection was observed in 1 animal. A significant decrease of Hspb27, Prdx, Epas1, Gpx3, Vegfa, Sftpa1, Sftpb, Plvap, Klf2, Cldn5, Thbd, Dsip, and Fmo2 gene expression in the O3-LT group was observed CONCLUSIONS: O3 therapy significantly delayed the onset of CR regulating the expression of genes involved in its pathogenesis. No known immunosuppressive therapy has been capable of achieving similar results. From a translational point of view, O3 therapy could become a new adjuvant treatment for CR in patients undergoing LT.

Oncological resection of lung cancer invading the aortic arch In full thickness using a non-fenestrated endograft.

T4 lung cancer invading the full thickness of the aortic arch was completely removed in a 78-year-old lady using a non-fenestrated endograft closing the left subclavian artery origin without performing surgical revascularization. Left thoracotomy and upper lobectomy with resection of superior segment of the lower lobe and full thickness of the infiltrated aorta was performed without covering the aortic defect. The margins of the specimen were free of tumor. The patient survived 32 months. J. Surg. Oncol. 2016;114:412-415. © 2016 Wiley Periodicals, Inc.

Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients.

Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n = 12) previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83%) patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52-119). Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p < 0.001) and the number of endoscopy treatments from 37 to 4 (p = 0.032). Hemoglobin levels changed from 11.1 (7-14) g/dL to 13 (10-15) g/dL, before and after ozone therapy, respectively (p = 0.008). Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

Spinal cord stimulation as adjuvant during chemotherapy and reirradiation treatment of recurrent high-grade gliomas.

AIMS: Relapsed high-grade gliomas (HGGs) have poor prognoses and there is no standard treatment. HGGs have ischemia/hypoxia associated and, as such, drugs and oxygen have low access, with increased resistance to chemotherapy and radiotherapy. Tumor hypoxia modification can improve outcomes and overall survival in some patients with these tumors. In previous works, we have described that cervical spinal cord stimulation can modify tumor microenvironment in HGG by increasing tumor blood flow, oxygenation, and metabolism. The aim of this current, preliminary, nonrandomized, study was to assess the clinical effect of spinal cord stimulation during brain reirradiation and chemotherapy deployed for the treatment of recurrent HGG; the hypothesis being that an improvement in oxygenated blood supply would facilitate enhanced delivery of the scheduled therapy. MATERIALS AND METHODS: Seven patients had spinal cord stimulation applied during the scheduled reirradiation and chemotherapy for the treatment of recurrent HGG (6 anaplastic gliomas and 1 glioblastoma). Median dose of previous irradiation was 60 Gy (range = 56-72 Gy) and median dose of reirradiation was 46 Gy (range = 40-46 Gy). Primary end point of the study was overall survival (OS) following confirmation of HGG relapse. RESULTS: From the time of diagnosis of last tumor relapse before reirradiation, median OS was 39 months (95% CI = 0-93) for the overall study group: 39 months (95% CI = 9-69) for those with anaplastic gliomas and 16 months for the patient with glioblastoma. Posttreatment, doses of corticosteroids was significantly decreased (P = .026) and performance status significantly improved (P = .046). CONCLUSIONS: Spinal cord stimulation during reirradiation and chemotherapy is feasible and well tolerated. In our study, spinal cord stimulation was associated with clinical improvement and longer survival than previously reported in recurrent anaplastic gliomas. Spinal cord stimulation as adjuvant during chemotherapy and reirradiation in relapsed HGGs merits further research.

Stem cells protect the bronchial stump in rat, increasing Sox6, Col2a1, and Agc1 expression.

BACKGROUND: Post-pneumonectomy bronchopleural fistulas (BPFs) are associated with high morbidity and mortality. Currently, since the management of BPFs is difficult to assess, the best therapeutic approach is prevention. Our objective was to evaluate the effects of adipose-derived stem cells (ASCs) on the healing of the bronchial stump in an experimental animal model. METHODS: Left pneumonectomy was performed in 37 Sprague-Dawley rats. Animals were randomly assigned to a control group (n = 13), an ASC group (n = 12), and an ASC plus Tissucol(®) group (ASCT) (n = 12). The ASCs and ASCTs were locally administered at the bronchial stump after surgical pneumonectomy. Animals were killed at 10 and 20 days. We analyzed histological changes and changes in the expression of relevant genes involved in wound repair in the bronchial stump. RESULTS: Two control animals, one animal from the ASC group, and one from the ASCT group died from early BPF. All the remaining animals had an adequate postoperative outcome. ASCs and ASCTs significantly decreased the necrosis and ulcerations of the bronchial stump at 10 and 20 days. ASCs significantly decreased mRNA expression of Igf1 at 10 days and Igf1, Tgfb1, Vegfa, and Col2a1 at 20 days, whereas there was increased expression of Agc1 and Col2a1 at 10 days and Sox6 at 20 days. CONCLUSIONS: Our findings indicate that local ASCs protected the bronchial stump after pneumonectomy and induced local changes in gene expression related to their protective action. These results could lead to a potential new therapeutic modality for the prevention of BPF.

Autologous platelet-poor plasma decreases the bronchial stump necrosis in rat.

BACKGROUND: Necrosis of the bronchial stump is a very important trigger for bronchopleural fistula. The administration of local autologous platelet-poor plasma (PPP) could protect the bronchial stump. MATERIALS AND METHODS: Left pneumonectomy was performed in 25 Sprague-Dawley rats. Animals were randomly assigned to a control group (n=13) and PPP group (n=12). PPP was locally administered on the bronchial stump after pneumonectomy. We analyzed histologic changes in the bronchial stump and messenger RNA expression changes of genes involved in wound repair at 10 and 20 d. RESULTS: Local PPP treatment produced a mass of fibrous tissue surrounding the bronchial stump and significantly decreased the presence of necrosis at 20 d. PPP increased the expression of insulin like growth factor 1 at 10 d although it did not reach statistical significance. CONCLUSIONS: Our findings indicate that local PPP treatment of the bronchial stump after pneumonectomy decreased necrosis and could have a protective effect on the bronchial stump.

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model.

BACKGROUND: Chronic rejection (CR) is the main reason for the limited survival rates among lung transplant (LT) recipients. There remains no effective treatment for CR. The aim of this study was to identify new molecular mechanisms involved in CR by using DNA microarray analysis. METHODS: We performed 10 left LTs using the microsurgical cuff technique in inbred Sprague-Dawley rats. Lung isograft samples were obtained 3 months after surgery. We analyzed histologic, apoptotic and gene expression changes by DNA microarray and quantitative PCR analysis. RESULTS: Histologic analyses confirmed signs of CR in all lungs and positive labeling for apoptotic and anti-apoptotic markers. A total of 702 genes were regulated in the CR lungs: 317 genes were upregulated and 385 were downregulated. Significant changes for about 30 biologic processes, including regulation of the cytoskeleton, and 15 signaling pathways, such as adherens junctions, were observed. We found significantly increased mRNA expression of the Cldn5, Epas1, Tgfb1, Vegf, Selp1, Hsp27 and Igf1 genes. CONCLUSIONS: This is the first experimental study performed in an orthotopic model of LT using DNA microarray analysis. The individual genes, biologic process and pathways identified may represent novel targets that could be manipulated and contribute to the development of treatments capable of providing protection from CR.

Severe compensatory hyperhidrosis following thoracic sympathectomy successfully treated with low doses of botulinum toxin A.

Compensatory hyperhidrosis is an adverse effect of thoracic sympathectomy that can be debilitating, which is why an efficient treatment is demanded. Botulinum toxin is an emerging treatment, not well known yet. We report two cases of compensatory hyperhidrosis following thoracic sympathectomy which were both treated with low doses of botulinum toxin A. The patients, a male and a female, noted a high level of satisfaction with the abolishment of sweating that was maintained up to 10 months. We consider that low doses of botulinum toxin A is a well tolerated, safe and effective treatment for compensatory hyperhidrosis and should be offered as an alternative treatment.

Estradiol worsens the syndrome of ischemia-reperfusion injury in an experimental lung transplantation model.

Ischemia-reperfusion injury (IRI) is a common complication after lung transplantation. There is evidence that reactive oxygen species are involved in its pathogenesis. We designed an experimental study to evaluate whether the administration of antioxidants to lung transplantation recipients protects against IRI and early acute rejection (AR). Twenty-five rats received left lung transplants after 6 h of ischemia. Fifty minutes before the reperfusion, groups of five rats received a single dose of desferrioxamine (20 mg/kg), estradiol (25 mg/kg), or melatonin (10 mg/kg). The animals were killed 48 h after surgery and the postoperative outcome, IRI, and AR were evaluated. The frequency of severe injury and of moderate-to-severe edema was higher in animals treated with estradiol than in the control group (P = 0.022 and P = 0.026, respectively). No significant changes in the degree of IRI or AR were observed in the groups treated with desferrioxamine or melatonin. In our study, treatment with the antioxidants melatonin or desferrioxamine before reperfusion had no effects on IRI damage or on AR frequency or severity. However, treatment with estradiol resulted in a worse postoperative outcome and in severe edema. Therefore, despite the antioxidant capacity of estradiol, it is recommended that an evaluation of these adverse effects of estradiol in human lung transplant recipients be performed.

Pobreza y economía social: análisis de una encuesta (ENNIV 1997) / Poverty and social economy: survey annalysis (ENNIV 1997)

Contiene: Visión global, pobreza y desarrollo social; La pobreza vista desde distintos ángulos; Movilidad social y oportunidad demográfica: Perú: 1994-1997; Ajuste económico, desigualdad y movilidad; La educación y la probabilidad de ser pobre en el Perú de hoy; Los retornos a la educación y a la experiencia en el Perú 1985-97; La demanda por servicios de salud de la mujer rural en el Perú; El aseguramiento público en salud: factores que intervienen en la elección de proveedor; La mujer peruana y la brecha salarial; Determinantes de las decisiones de trabajo en tareas no agropecuarias dentro de la finca en el Perú