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1.  Effects of hyperbaric oxygen on intestinal mucosa apoptosis caused by ischemia-reperfusion injury in rats 
Hyperbaric oxygen (HBO) is an effective adjuvant therapy for ischemia- reperfusion (I/R) injury of the brain, small intestine and testis in addition to crushing injury. Studies have shown that HBO increases the activity of villi of the ileum 30 minutes after I/R injury. The present study aimed to observe the effect of HBO on apoptosis of epithelial cells in the small intestine during different periods of I/R and to elucidate the potential mechanisms.
Rats were subjected to 60-minute ischemia by clamping the superior mesenteric artery and 60-minute reperfusion by removal of clamping. The rats were randomly divided into four groups: I/R group, HBO precondition or HBO treatment before ischemia (HBO-P), HBO treatment during ischemia period (HBO-I), and HBO treatment during reperfusion (HBO-R). After 60-minute reperfusion, samples of the small intestine were prepared to measure the level of ATP by using the colorimetric method and immunochemical expression of caspase-3. The levels of TNF-α in intestinal tissue were measured using the enzyme-linked immunosorbent assay method (Elisa).
TNF-α levels were significantly lower in the HBO-I group than in the HBO-P (P<0.05), HBO-R and I/R groups; there was no significant difference between the HBO-R and I/R groups (P>0.05). The expression of caspas-3 was significantly lower in the HBO-I group than in the HBO-P group (P<0.05); it was also significantly lower in the HBO-P group than in the I/R and HBO-R groups (P<0.05). ATP level was significantly lower in the HBO-I group than in the HBO-P group (P<0.05), and also it was significantly lower in the HBO-P group than in the I/R and HBO-R groups (P<0.05).
There is an association between HBO, small intestinal I/R injury, and mucosa apoptosis. HBO maintains ATP and aerobic metabolism, inhibites TNF-α production, and thus prevents intestinal mucosa from apoptosis. Best results can be obtained when HBO is administered to patients in the period of ischemia, and no side effects are produced when HBO is given during the period of reperfusion.
PMCID: PMC4129796  PMID: 25215052
Hyperbaric oxygen; Ischemia-reperfusion injury; Apoptosis
2.  Intravesical instillation of pentosan polysulfate encapsulated in a liposome nanocarrier for interstitial cystitis 
We determined the effect of intravesical instillation of pentosan polysulfate encapsulated in liposomes for refractory interstitial cystitis patients. This was an open label uncontrolled study. Subjects were recruited from a private urology practice. Inclusion criteria included patients who met NIDDK criteria for Interstitial Cystitis (IC) and who were responding poorly to conventional treatments. Exclusion criteria included evidence of a urinary tract infection, bladder cancer, or other forms of chronic cystitis. Patients received 400 mg of Pentosan Polysulfate (PP) encapsulated into liposomes as an intravesical instillation performed every 2 weeks for 3 months. Baseline and post treatment outcome measures were obtained that included the O’Leary-Sant Interstitial Cystitis Symptom and Problem Questionnaire and the Pelvic Pain and Urgency/Frequency Patient symptom Scale tests. A total of 37 instillations were used and no adverse events occurred. Clinically significant decreases in symptom scores greater than 50% were seen in virtually all outcome measures at 3 month follow up. All subjects reported remarkable subjective improvement in pain symptoms marked by decreased use of narcotics and increased enjoyment of daily activities. No patients developed systemic symptoms or poor tolerance of the instillations. Intravesical Pentosan Polysulfate encapsulated into liposomes can significantly decrease frequency, urgency, pain and improve quality of life for two months after deployment. Additional studies are needed to determine cellular effects of glycosaminoglycan restoration, ideal doses, dosing intervals, safety and cost-effectiveness of this therapy.
PMCID: PMC4219302  PMID: 25374916
Interstitial cystitis; pentosan polysulfate; liposome; glycosaminoglycan; urothelium; nanospheres
3.  Hyperbaric oxygen therapy for late radiation tissue injury in gynecologic malignancies 
Current Oncology  2011;18(5):220-227.
Late radiation tissue injury is a serious complication of radiotherapy for patients with gynecologic malignancies. Strategies for managing pain and other clinical features have limited efficacy; however, hyperbaric oxygen therapy (HBO2) may be an effective option for some patients.
In a systematic review of the literature, the Ovid medline, embase, Cochrane Library, National Guidelines Clearinghouse, and Canadian Medical Association Infobase databases were searched to June 2009 for clinical practice guidelines, systematic reviews, randomized controlled trials, or other relevant evidence. Studies that did not evaluate soft tissue necrosis, cystitis, proctitis, bone necrosis, and other complications were excluded.
Two randomized trials, eleven nonrandomized studies, and five supporting documents comprise the evidence base. In addition, information on the harms and safety of treatment with HBO2 were reported in three additional sources. There is modest direct evidence and emerging indirect evidence that the use of HBO2 is broadly effective for late radiation tissue injury of the pelvis in women treated for gynecologic malignancies.
Based on the evidence and expert consensus opinion, HBO2 is likely effective for late radiation tissue injury of the pelvis, with demonstrated efficacy specifically for radiation damage to the anus and rectum;the main indication for HBO2 therapy in gynecologic oncology is in the management of otherwise refractory chronic radiation injury;HBO2 may provide symptomatic benefit in certain clinical settings (for example, cystitis, soft-tissue necrosis, and osteonecrosis); andHBO2 may reduce the complications of gynecologic surgery in patients undergoing surgical removal of necrosis.
PMCID: PMC3185899  PMID: 21980249
Hyperbaric oxygen therapy; HBO2; late radiation tissue injury; lrti; radiotherapy; gynecologic cancers; adverse effects; cancer pain; clinical practice guideline; systematic review
4.  Oxybiotest project: microorganisms under pressure. Hyperbaric oxygen (HBO) and simple pressure interaction on selected bacteria 
Medical Gas Research  2012;2:24.
HyperBaric Oxygen (HBO) therapy involves exposure to pure oxygen in a pressurized room, and it is an already well-established treatment for various conditions, including those originated by serious infections. Starting from the observation of an increased number of patients who were accessing our HBO units for diseases supported from concomitant multidrug-resistant microorganisms, as well as considering the evident clinical benefit and laboratory final outcome of those patients at the end of the treatment, aim of our study was to measure, or better define at least, if there was any interaction between a hyperbaric environment and some selected microorganisms and if those positive results were due to the increased oxygen partial pressure (pO2) value or just to the increased pressure, regardless of the fraction of inspired oxygen (FiO2) applied (21÷100%).
Design and methods
We applied various increased pO2 values in a hyperbaric environment. Our study design was tailored in four steps to answer four specific questions, ordered in a progressive process: OxyBioTest (OBT)-1,2,3, and 4. Specifically, we chose to investigate possible changes in the Minimum Inhibitory Concentration (MIC) and in the Minimum Bactericidal Concentration (MBC) of multi-resistant microorganisms after a single session of hyperbaric therapy.
OBT-1 and OBT-2 provide a semi-quantitative confirmation of the bacterio-cidal and cytostatic effects of HBO. HBO is cidal only if the total exposure pressure is elevated, and cidal or cytostatic effect are not always dependent on the pO2 applied.
OBT-4 has shown the adjuvant effect of HBO and antimicrobial drug against some selected bacteria.
We seem allowed to hypothesize that only in case of a good approach to a lesion, permitting smaller bacterial loads thanks to surgical debridement and/or eventual antibiotic therapy for example, You can observe the clear effectiveness of the HyperBaric Oxygen (HBO) exposure as a valid adjuvant therapy, even when that lesion is substained from multidrug-resistant micro-organisms. On the contrary when the bacterial load is very high we observe an unchanged situation or a just a slightly diminishing in the number of cfu/ml.
Even if confined in this ‘in vitro’ environment and in a single treatment, just knowing the microorganism strain responsible of the lesion we seem allowed to both weight the possible related effectiveness using HBO Therapy (HBOT) and derive the best pO2 to treat the case. A further possible development of the study highlights a comparison between Acinetobacter baumannii (ACBA) and Pseudomonas aeruginosa (PSAE), and Escherichia coli (ESCO) and Klebsiella pneumoniae (KLPN).
PMCID: PMC3517458  PMID: 22963601
Hyperbaric; Oxygen; Microorganism; Bacteria
5.  Hyperbaric Oxygen Treatment Induces a Two-Phase Antinociceptive Response of Unusually Long Duration in Mice 
Hyperbaric oxygen (HBO2) therapy is approved by the FDA for limited clinical indications but is reported to produce pain relief in several chronic pain conditions. However, there have been no studies to explain this apparent analgesic effect of HBO2. Research conducted in our laboratory demonstrates that four daily 60-min HBO2 treatments at 3.5 ATA induced an unparalleled antinociceptive response that consists of 1) an early phase that lasted at least six hours after the HBO2 treatment before dissipating; and 2) a late phase that emerged about 18 hours after the early phase and lasted for up to three weeks. The early phase was sensitive to antagonism by acutely intracerebroventricular (i.c.v.)-administered opioid antagonist naltrexone and the nitric oxide synthase (NOS)-inhibitor L-NAME. The late phase was inhibited by treatment with i.c.v. naltrexone or L-NAME during the four HBO2 treatments but was not antagonized by either naltrexone or L-NAME following acute pretreatment two weeks after HBO2 treatment. These experimental results implicate a novel mechanism that is activated by HBO2, resulting in an antinociceptive response of unusually long duration that is of potential interest in the clinical management of pain.
Hyperbaric oxygen treatment of mice can induce a two-phase antinociceptive response of unusually long duration. Nitric oxide and opioid receptors appear to initiate or mediate both phases of the antinociceptive response. Further elucidation of the underlying mechanism may potentially identify molecular targets that cause long-lasting activation of endogenous analgesic systems.
PMCID: PMC2910818  PMID: 20418186
Hyperbaric oxygen; antinociception; nitric oxide; opioid receptors; mice
6.  Effects of hyperbaric oxygen on aggressive periodontitis and subgingival anaerobes in Chinese patients 
To investigate the effects of hyperbaric oxygen (HBO2) on aggressive periodontitis (AgP), and subgingival obligate anaerobes in Chinese patients.
Materials and Methods:
Sixty cases of Chinese patients with AgP were randomly divided into two groups –the HBO2 group (30 cases) and the control group (30 cases). Study teeth were divided into four groups –: the HBO2 therapy, the HBO2 + scaling scaling group, the scaling group and the control group. Subgingival anaerobic organisms were measured with anaerobic culture, and number of obligate anaerobes and facultative anaerobes and Bacteroides melaninogenicus was counted. Comparisons of changes in the clinical indices, and subgingival anaerobes were made between the groups.
Highly significant differences in gingival index (GI), probing depth (PD), attachment loss (AL), and Plaque index (PLI), and tooth odontoseisis (TO) were seen in the HBO2, the HBO2 + scaling and the scaling groups when compared with the control group (P<0.01). The number of subgingival anaerobes as well as the types of obligate anaerobes and facultative anaerobes and the number of Bacteroides melaninogenicus were reduced markedly in these three treatment groups. Highly statistical differences in clinical indices, subgingival anaerobe number and types of obligate anaerobes and facultative anaerobes and Bacteroides melaninogenicus were found when comparisons were made between the HBO2 + scaling and the HBO2 groups, as well as between the HBO2 + scaling and the scaling groups. Clinical follow-ups indicated that the GI, PD, AL, TO, PLI and subgingival anaerobes number of the three therapeutic groups were reduced more severely than the control group.
HBO2 had good therapeutic effects on Chinese patients with AgP. HBO2 therapy combined with scaling and root planing was the most beneficial in the treatment of AgP. The therapeutic effect of HBO2 on AgP is most likely through inhibition of the growth of subgingival anaerobes. Clinical follow-ups suggest that the effect could last more than 2 years.
PMCID: PMC3590714  PMID: 23493978
Aggressive periodontitis; Chinese; hyperbaric oxygen; subgingival anaerobes
7.  Influence of Adjuvant Hyperbaric Oxygen Therapy on Short-term Complications During Surgical Reconstruction of Upper and Lower Extremity War Injuries: Retrospective Cohort Study 
Croatian medical journal  2008;49(2):224-232.
To determine the effects of hyperbaric oxygen (HBO) therapy on short-term complications of complex war wounds to the upper and lower extremities in patients who were and those who were not treated according to North Atlantic Treaty Organization (NATO) emergency war surgery recommendations.
We retrospectively analyzed data of 388 male patients undergoing reconstructive surgery for Gustilo type III A, B, and C war wounds to the extremities at the Department of Reconstructive Surgery, Split University Hospital Center, between 1991 and 1995. The occurrence of main wound complications (deep infection, osteomyelitis, skin grafts lyses, and flap necrosis) during hospitalization and time from wounding to granulation formation were analyzed with respect to the use of HBO therapy as a risk factor. Odds ratio (OR) with 95% confidence intervals (CI) was calculated for the occurrence of wound complications with respect to HBO therapy and adjusted for NATO surgical strategy by logistic regression.
Of 388 patients, 310 (80%) were initially treated according to the NATO surgical strategy and 99 (25%) received HBO therapy. Deep soft-tissue infection developed in 196 (68%) patients who did not receive HBO therapy and in 35 (35%) who received it (P<0.001). Osteomyelitis developed in 214 (74%) patients who did not receive HBO therapy and in 62 (63%) who received it (P = 0.030). Skin graft lysis occurred in 151 (52%) patients who did not receive HBO therapy and in 23 (23%) who received it (P<0.001, χ2 test). Flap necrosis occurred in 147 (51%) patients who did not receive HBO therapy and in 15 (15%) who received it (P<0.001). Median time to granulation formation was 9 (5-57) days in patients who received HBO therapy, and 12 (1-12) days in those who did not (P<0.001, Mann-Whitney test). These results were consistent over the groups of patients stratified according to the wound severity and remained unaltered after the adjustment for NATO surgical strategy. The effect of HBO therapy was greater in non-NATO than in NATO treated patients in case of deep soft-tissue infection (OR, 10.7 vs OR, 3.8; P = 0.031 for interaction).
HBO therapy reduced the frequency of wound complications in patients with Gustilo type III wounds and shortened the time to granulation formation. HBO therapy was more effective in non-NATO than in NATO treated patients for the prevention of deep soft-tissue infection but not flap necrosis.
PMCID: PMC2359875  PMID: 18461678
8.  Therapeutic effect of hyperbaric oxygen in psoriasis vulgaris: two case reports and a review of the literature 
Psoriasis is an inflammatory and immunological cutaneous disease. The high morbidity in patients with psoriasis results from severe clinical manifestations and/or adverse effects of treatment. The Undersea and Hyperbaric Medical Society and Federal Medicare and Medicaid Services have approved the use of hyperbaric oxygen (HBO2) for more than 15 indications, including wound healing, infections and late effects of radiation, which are largely unresponsive to conventional treatments. Accumulated data show that HBO2 has anti-inflammatory effects and other positive influences on the immune system, making it a rational treatment in the management of psoriasis plaques and arthritis.
Case presentation
We present the cases of two patients with long histories of psoriasis vulgarus who exhibited marked improvement with use of HBO2. The first patient was 40 years old and had pustular psoriasis and psoriatic arthritis. He was treated with six sessions of HBO2 (at 2.8 atmospheres of pressure for 60 minutes), which successfully controlled his symptoms. At the 18-month post-treatment follow up, the patient exhibited complete remission of psoriasis and marked improvement in psoriatic arthritis without medication. The second patient was 55 years old with extensive psoriatic lesions, and exhibited marked improvement within 15 sessions of HBO2. No adverse effects of HBO2 were identified.
HBO2 may possess potential therapeutic efficacy in the management of psoriasis. We outline the pathogenesis of psoriasis and the selective anti-inflammatory and immunosuppressive effects of HBO2. We hope that this will provide a basis for elucidating the mechanisms of action and consequently pave the way for further controlled studies.
PMCID: PMC2737769  PMID: 19830133
9.  Involvement of brain opioid receptors in the anti-allodynic effect of hyperbaric oxygen in rats with sciatic nerve crush-induced neuropathic pain 
Brain research  2013;1537:10.1016/j.brainres.2013.08.050.
Earlier research has demonstrated that hyperbaric oxygen (HBO2) can produce an antinociceptive effect in models of acute pain. Recent studies have revealed that HBO2 can produce pain relief in animal models of chronic pain as well. The purpose of the present investigation was to ascertain whether HBO2 treatment might suppress allodynia in rats with neuropathic pain and whether this effect might be blocked by the opioid antagonist naltrexone (NTX). Male Sprague Dawley rats were subjected to a sciatic nerve crush under anesthesia and mechanical thresholds were assessed using an electronic von Frey anesthesiometer. The time course of the HBO2-induced anti-allodynic effect in different treatment groups was plotted, and the area-under-the-curve (AUC) was determined for each group. Seven days after the nerve crush procedure, rats were treated with HBO2 at 3.5 atmospheres absolute (ATA) for 60 min and exhibited an anti-allodynic effect, compared to nerve crush-only control rats. Twenty-four hours before HBO2 treatment, another group of rats was implanted with Alzet® osmotic minipumps that continuously released NTX into the lateral cerebral ventricle for 7 days. These NTX-infused, HBO2-treated rats exhibited an allodynic response comparable to that exhibited by rats receiving nerve crush only. Analysis of the AUC data showed that HBO2 significantly reduced the nerve crush-induced allodynia; this anti-allodynic effect of HBO2 was reversed by NTX. These results implicate opioid receptors in the pain relief induced by HBO2.
PMCID: PMC3827781  PMID: 23998986
Hyperbaric oxygen; anti-allodynia; naltrexone; opioid receptors; neuropathic pain; sciatic nerve crush; rat
10.  Interstitial Cystitis in Persistent Posthysterectomy Chronic Pelvic Pain 
Hysterectomies may be performed unnecessarily in women with chronic pelvic pain if the diagnosis of interstitial cystitis is not considered. The objectives of this study were to investigate the prevalence of interstitial cystitis in patients with posthysterectomy chronic pelvic pain and to evaluate the efficacy of various therapies for interstitial cystitis.
A study was performed of 111 patients with chronic pelvic pain whose pain persisted after hysterectomy. Patients were screened with the Pelvic Pain and Urgency/Frequency symptom scale, and underwent Potassium Sensitivity Testing. Patients were treated with dietary changes alone or in combination with cystoscopic hydrodistention or oral pentosan polysulfate, or both of these, for 3 to 6 months.
Of the 111 patients enrolled, 79% (n=88) were diagnosed with bladder dysfunction consistent with interstitial cystitis. For patients treated with dietary modification alone (n=33), the mean score on the Pelvic Pain and Urgency/Frequency questionnaire improved 15.4%, from 13.18 at baseline to 11.15 at follow-up. For patients treated with pentosan polysulfate or cystoscopic hydrodistention, or both, plus diet changes (n=78), Pelvic Pain and Urgency/Frequency scores improved 34.2%, from 15.01 to 9.87.
In this study, nonsurgical treatment for interstitial cystitis resulted in a marked improvement in symptoms that had not improved with surgery. Without determining the origin of bladder pain, gynecologists should not proceed to hysterectomy in patients with chronic pelvic pain.
PMCID: PMC3016837  PMID: 15554275
Chronic pelvic pain; Posthysterectomy pain; Bladder-origin pain; Interstitial cystitis; Potassium Sensitivity Test; Pelvic Pain and Urgency/Frequency questionnaire
11.  Early Identification of Interstitial Cystitis May Avoid Unnecessary Hysterectomy 
Interstitial cystitis is a clinical syndrome characterized by symptoms of pelvic pain, urinary urgency and frequency, and nocturia. It can be difficult to accurately identify interstitial cystitis because the symptoms overlap many other common gynecologic and urologic conditions. Patients with undiagnosed interstitial cystitis may undergo unnecessary procedures, including hysterectomy.
A PubMed literature search for articles dating back to 1990 was conducted on the topics of interstitial cystitis and hysterectomy. Further references were identified by cross-referencing the bibliographies in articles of interest.
The literature review found that hysterectomy is performed more often in patients with undiagnosed interstitial cystitis than in patients with a confirmed diagnosis. Interstitial cystitis often coexists with conditions like endometriosis, for which hysterectomy is indicated. Many patients subsequently diagnosed with interstitial cystitis continue to experience persistent pelvic pain despite having had a hysterectomy for chronic pelvic pain. Careful history and physical examination can identify the majority of interstitial cystitis cases.
Interstitial cystitis should be considered prior to hysterectomy in women who present with pelvic pain or who experience pelvic pain after a hysterectomy. If interstitial cystitis is diagnosed, appropriate therapy may eliminate the need for hysterectomy.
PMCID: PMC3015962  PMID: 19793476
Interstitial cystitis; Hysterectomy; Pelvic pain; Pentosan polysulfate sodium
12.  Effects of hyperbaric oxygen on pain-related behaviours and nitric oxide synthase expression in a rat model of neuropathic pain 
Neuropathic pain is complex, and a satisfactory therapeutic method of treatment has yet to be developed; therefore, finding a new and effective therapeutic method is an important issue in the field of neuropathic pain.
To determine the effects of hyperbaric oxygen (HBO) on pain-related behaviours and nitric oxide synthase (NOS) expression in a rat model of neuropathic pain.
Forty male Sprague Dawley rats were randomly divided into five groups (eight rats per group) including control, sham operation, sciatic nerve with chronic constriction injury (CCI), HBO pretreatment (pre-HBO) and HBO post-treatment (post-HBO) groups. Pain-related behaviours and NOS expression in the spinal cord were compared among the five groups.
Compared with the CCI group, the mechanical withdrawal threshold was significantly increased and thermal withdrawal latency was significantly extended in the pre-HBO and post-HBO groups (all P<0.05). After CCI, expression of spinal neuronal NOS and inducible NOS were increased. Expression of spinal neuronal NOS and inducible NOS were significantly decreased in the pre-HBO and post-HBO groups compared with the CCI group (all P<0.05). Spinal eNOS expression changed very little.
HBO has been used as an effective and noninvasive method for the treatment of spinal cord injuries and high-altitude sickness, and in immunosuppression and stem-cell research; however, it has yet to be applied to the treatment of neuropathic pain. The present study indicated that HBO effectively increased mechanical withdrawal threshold and thermal withdrawal latency, demonstrating that HBO has therapeutic effects on neuropathic pain.
HBO inhibits pain in rats with CCI through the regulation of spinal NOS expression.
PMCID: PMC3673931  PMID: 23748254
Hyperbaric oxygen; Neuropathic pain; Nitric oxide synthase
13.  Hyperbaric oxygen therapy as an adjunctive treatment for sternal infection and osteomyelitis after sternotomy and cardiothoracic surgery 
A retrospective study to evaluate the effect of hyperbaric oxygen (HBO2) therapy on sternal infection and osteomyelitis following median sternotomy.
Materials and methods
A retrospective analysis of patients who received sternotomy and cardiothoracic surgery which developed sternal infection and osteomyelitis between 2002 and 2009. Twelve patients who received debridement and antibiotic treatment were selected, and six of them received additional HBO2 therapy. Demographic, clinical characteristics and outcome were compared between patients with and without HBO2 therapy.
HBO2 therapy did not cause any treatment-related complication in patients receiving this additional treatment. Comparisons of the data between two study groups revealed that the length of stay in ICU (8.7 ± 2.7 days vs. 48.8 ± 10.5 days, p < 0.05), duration of invasive (4 ± 1.5 days vs. 34.8 ± 8.3 days, p < 0.05) and non-invasive (4 ± 1.9 days vs. 22.3 ± 6.2 days, p < 0.05) positive pressure ventilation were all significantly lower in patients with additional HBO2 therapy, as compared to patients without HBO2 therapy. Hospital mortality was also significantly lower in patients who received HBO2 therapy (0 case vs. 3 cases, p < 0.05), as compared to patients without the HBO2 therapy.
In addition to primary treatment with debridement and antibiotic use, HBO2 therapy may be used as an adjunctive and safe treatment to improve clinical outcomes in patients with sternal infection and osteomyelitis after sternotomy and cardiothoracic surgery.
PMCID: PMC3215992  PMID: 22004802
hyperbaric oxygen; sternal infection; osteomyelitis; sternotomy; Cardiothoracic surgery
14.  Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34+ cells in a murine model of umbilical cord blood transplantation 
Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six-to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34+ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received two hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34+ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood , and spleen (p=0.0293) retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34+ cell infusion significantly improves engraftment.
PMCID: PMC4075130  PMID: 23953010
Umbilical cord blood; CD34+; engraftment; hyperbaric oxygen
15.  Hyperbaric Hyperoxia Accelerates Fracture Healing in Mice 
PLoS ONE  2013;8(8):e72603.
Increased oxygen tension influences bone metabolism. This study comprised two main experiments: one aimed to determine the bone mineral apposition and bone formation rates in vivo under hyperbaric hyperoxia (HBO), and the other aimed to evaluate the effects of exposure to HBO on fracture healing. In experiment 1, male mice were exposed to HBO [90 min/day at 90% O2 at 2 atmospheres absolute (ATA) for 5 days]. In experiment 2, an open femur fracture model was created in mice, followed by exposure to HBO 5 times/week (90 min/day at 90% O2 at 2 ATA) for 6 weeks after surgery. In experiment 1, HBO treatment significantly increased the mineral apposition and bone formation rates in the lumbar vertebra and femur and type 1 collagen alpha 1 and alkaline phosphatase mRNA expression in the lumbar vertebra. In experiment 2, at 2 weeks after fracture, the fracture callus was significantly larger in the HBO group than in the non-HBO group. Furthermore, at 4 and 6 weeks after fracture, radiographic findings showed accelerated fracture healing in the HBO group. At 6 weeks after fracture, femur stiffness and maximum load were significantly higher in the HBO group than in the non-HBO group. Urinary 8-hydroxy-2′-deoxyguanosine and plasma calcium concentrations were not significantly different between groups. These results suggest that exposure to HBO enhances bone anabolism and accelerates fracture healing without causing oxidative DNA damage or disruption of plasma calcium homeostasis.
PMCID: PMC3743787  PMID: 23967323
16.  Hyperbaric Oxygen Exposures at 3 and 4 Atmospheres Absolute Pressure for Experimental Gas Gangrene: Succinate Protection Against Oxygen Toxicity 
The concurrent effect of succinate administration to protect against oxygen toxicity and of hyperbaric oxygen (HBO) exposures to treat model gas gangrene in mice was tested to determine whether succinate would interfere with the therapeutic efficacy of HBO. HBO (seven 90-min exposures) at 3 atmospheres absolute pressure (ATA) had been shown to reduce significantly the mortality of mice injected with Clostridium perfringens suspended in 10 μg of Adrenalin. When succinate was tested with this system, mortality of HBO-exposed infected animals was again significantly reduced (79% control mortality versus 17% HBO-exposed mortality), indicating that succinate does not interfere with the action of HBO. Exposures to 4 ATA of O2 were evaluated in the same model clostridial infection with succinate used to prevent oxygen toxicity. Five 30-min exposures at 4 ATA reduced the mortality of infected animals (62% control versus 6% HBO-exposed mortality). Intraperitoneal succinate injections (10 mmoles/kg) were given 20 to 25 min prior to four of the seven 3-ATA exposures and before three of the five 4-ATA exposures. The intermittent succinate injections gave significant protection against the development of oxygen toxicity in infected and noninfected mice at both O2 pressures. These studies support the potential clinical use of succinate or other oxygen-protective agents (i) to shorten HBO exposure times by using higher pressures to deliver the necessary O2 dose, (ii) to increase the O2 dose for difficult clinical situations by using maximal exposures at 4 ATA or more prolonged exposures at 2 to 3 ATA, and (iii) to continue HBO exposures in patients who require treatment but develop symptoms of oxygen toxicity.
PMCID: PMC444324  PMID: 4670508
17.  Synergistic Inhibitory Effect of Hyperbaric Oxygen Combined with Sorafenib on Hepatoma Cells 
PLoS ONE  2014;9(6):e100814.
Hypoxia is a common phenomenon in solid tumors, associated with chemotherapy and radiotherapy resistance, recurrence and metastasis. Hyperbaric oxygen (HBO) therapy can increase tissue oxygen pressure and content to prevent the resistance, recurrence and metastasis of cancer. Presently, Sorafenib is a first-line drug, targeted for hepatocellular carcinoma (HCC) but effective in only a small portion of patients and can induce hypoxia. The purpose of this study is to investigate the effect of HBO in combination with sorafenib on hepatoma cells.
Hepatoma cell lines (BEL-7402 and SK-Hep1) were treated with HBO at 2 atmosphere absolute pressure for 80 min per day or combined with sorafenib or cisplatin. At different time points, cells were tested for cell growth, colony formation, apoptosis, cell cycle and migration. Finally, miRNA from the hepatoma cells was detected by microRNA array and validated by qRT-PCR.
Although HBO, sorafenib or cisplatin alone could inhibit growth of hepatoma cells, HBO combined with sorafenib or cisplatin resulted in much greater synergistic growth inhibition (cell proliferation and colony formation) in hepatoma cells. Similarly, the synergistic effect of HBO and sorafenib on induction of apoptosis was also observed in hepatoma cells. HBO induced G1 arrest in SK-Hep1 not in BEL-7402 cells, but enhanced cell cycle arrest induced by sorafenib in BEL-7402 treated cells. However, HBO had no obvious effect on the migration of hepatoma cells, and microRNA array analysis showed that hepatoma cells with HBO treatment had significantly different microRNA expression profiles from those with blank control.
We show for the first time that HBO combined with sorafenib results in synergistic growth inhibition and apoptosis in hepatoma cells, suggesting a potential application of HBO combined with sorafenib in HCC patients. Additionally, we also show that HBO significantly altered microRNA expression in hepatoma cells.
PMCID: PMC4067386  PMID: 24956259
18.  Hyperbaric Oxygen Prevents Early Death Caused by Experimental Cerebral Malaria 
PLoS ONE  2008;3(9):e3126.
Cerebral malaria (CM) is a syndrome characterized by neurological signs, seizures and coma. Despite the fact that CM presents similarities with cerebral stroke, few studies have focused on new supportive therapies for the disease. Hyperbaric oxygen (HBO) therapy has been successfully used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis.
Methodology/Principal Findings
C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were exposed to daily doses of HBO (100% O2, 3.0 ATA, 1–2 h per day) in conditions well-tolerated by humans and animals, before or after parasite establishment. Cumulative survival analyses demonstrated that HBO therapy protected 50% of PbA-infected mice and delayed CM-specific neurological signs when administrated after patent parasitemia. Pressurized oxygen therapy reduced peripheral parasitemia, expression of TNF-α, IFN-γ and IL-10 mRNA levels and percentage of γδ and αβ CD4+ and CD8+ T lymphocytes sequestered in mice brains, thus resulting in a reduction of blood-brain barrier (BBB) dysfunction and hypothermia.
The data presented here is the first indication that HBO treatment could be used as supportive therapy, perhaps in association with neuroprotective drugs, to prevent CM clinical outcomes, including death.
PMCID: PMC2518956  PMID: 18769544
19.  Long Course Hyperbaric Oxygen Stimulates Neurogenesis and Attenuates Inflammation after Ischemic Stroke 
Mediators of Inflammation  2013;2013:512978.
Several studies have provided evidence with regard to the neuroprotection benefits of hyperbaric oxygen (HBO) therapy in cases of stroke, and HBO also promotes bone marrow stem cells (BMSCs) proliferation and mobilization. This study investigates the influence of HBO therapy on the migration of BMSCs, neurogenesis, gliosis, and inflammation after stroke. Rats that sustained transient middle cerebral artery occlusion (MCAO) were treated with HBO three weeks or two days. The results were examined using a behavior test (modified neurological severity score, mNSS) and immunostaining to evaluate the effects of HBO therapy on migration of BMSCs, neurogenesis, and gliosis, and expression of neurotrophic factors was also evaluated. There was a lower mNSS score in the three-week HBO group when compared with the two-day HBO group. Mobilization of BMSCs to an ischemic area was more improved in long course HBO treatments, suggesting the duration of therapy is crucial for promoting the homing of BMSCs to ischemic brain by HBO therapies. HBO also can stimulate expression of trophic factors and improve neurogenesis and gliosis. These effects may help in neuronal repair after ischemic stroke, and increasing the course of HBO therapy might enhance therapeutic effects on ischemic stroke.
PMCID: PMC3595722  PMID: 23533308
20.  Comparison of an Interstitial Cystitis/Bladder Pain Syndrome Clinical Cohort With Symptomatic Community Women From the RAND Interstitial Cystitis Epidemiology Study 
The Journal of urology  2011;187(2):508-512.
The RAND Interstitial Cystitis Epidemiology survey estimated that 2.7% to 6.5% of United States women have urinary symptoms consistent with a diagnosis of interstitial cystitis/bladder pain syndrome. We describe the demographic and clinical characteristics of the symptomatic community based RAND Interstitial Cystitis Epidemiology cohort, and compare them with those of a clinically based interstitial cystitis/bladder pain syndrome cohort.
Materials and Methods
Subjects included 3,397 community women who met the criteria for the RAND Interstitial Cystitis Epidemiology high sensitivity case definition, and 277 women with an interstitial cystitis/bladder pain syndrome diagnosis recruited from specialist practices across the United States (clinical cohort). Questions focused on demographic information, symptom severity, quality of life indicators, concomitant diagnoses and treatment.
Average symptom duration for both groups was approximately 14 years. Women in the clinical cohort reported worse baseline pain and maximum pain, although the absolute differences were small. Mean Interstitial Cystitis Symptom Index scores were approximately 11 for both groups, but mean Interstitial Cystitis Problem Index scores were 9.9 and 13.2 for the clinical cohort and the RAND Interstitial Cystitis Epidemiology cohort, respectively (p <0.001). The RAND Interstitial Cystitis Epidemiology subjects were more likely to be uninsured.
The RAND Interstitial Cystitis Epidemiology community cohort was remarkably similar to an interstitial cystitis/bladder pain syndrome clinical cohort with respect to demographics, symptoms and quality of life measures. In contrast to other chronic pain conditions for which clinical cohorts typically report worse symptoms and functional status than population based samples, our data suggest that many measures of symptom severity and functional impact are similar, and sometimes worse, in the RAND Interstitial Cystitis Epidemiology cohort. These findings suggest that interstitial cystitis/bladder pain syndrome is significantly burdensome, and likely to be underdiagnosed and undertreated in the United States.
PMCID: PMC3894739  PMID: 22177158
cystitis; interstitial; epidemiology; prevalence; questionnaires
21.  Bladder Pain Syndrome Treated with Triple Therapy with Gabapentin, Amitriptyline, and a Nonsteroidal Anti-Inflammatory Drug 
Bladder pain syndrome is a chronic disease that manifests as bladder pain, frequency, nocturia, and urgency. Gabapentin, amitriptyline, and nonsteroidal anti-inflammatory drugs are efficacious treatments for bladder pain syndrome. Here, we assessed the effect of triple therapy with these drugs in women with bladder pain syndrome.
Between May 2007 and May 2010, we conducted a prospective nonrandomized study on 74 patients with bladder pain syndrome. Of these patients, 38 (11 men and 27 women; mean age, 55.9 years; range, 25 to 77 years; mean follow-up, 12.6 months) were administered the interstitial cystitis (IC) symptom scales (O'Leary-Sant Symptom Index) and visual analog scale (VAS) 1, 3, and 6 months after treatment to assess the efficacy of triple therapy.
The pretreatment O'Leary-Sant IC symptom score was 11.7, and the post-treatment scores were 4.4, 3.8, and 4.0 at 1, 3, and 6 months, respectively; the pretreatment problem index score was 10.5, and the post-treatment scores were 3.7, 2.7, and 2.9 at 1, 3, and 6 months, respectively. The pretreatment VAS score was 6.7, and the post-treatment scores were 1.8, 1.5, and 1.7 at 1, 3, and 6 months, respectively. The O'Leary-Sant IC symptom index and problem index and VAS scores improved considerably 1 month after treatment (P<0.05). However, the results at 1, 3, and 6 months after treatment were not significantly different (P>0.05).
Triple therapy was sufficiently effective in patients with bladder pain syndrome and caused no significant adverse effects. However, large-scale studies should be performed to verify our findings.
PMCID: PMC3021818  PMID: 21253338
Bladder pain syndrome; Interstitial cystitis; Visual analog scale
22.  Effect of Hyperbaric Oxygen Therapy on whole blood cyanide concentrations in carbon monoxide intoxicated patients from fire accidents 
Hydrogen cyanide (HCN) and carbon monoxide (CO) may be important components of smoke from fire accidents. Accordingly, patients admitted to hospital from fire accidents may have been exposed to both HCN and CO. Cyanide (CN) intoxication results in cytotoxic hypoxia leading to organ dysfunction and possibly death. While several reports support the use of hyperbaric oxygen therapy (HBO) for the treatment of severe CO poisoning, limited data exist on the effect of HBO during CN poisoning. HBO increases the elimination rate of CO haemoglobin in proportion to the increased oxygen partial pressure and animal experiments have shown that in rats exposed to CN intoxication, HBO can increase the concentration of CN in whole blood.
The purpose of the present study was to determine whole blood CN concentrations in fire victims before and after HBO treatment.
Materials and methods
The patients included were those admitted to the hospital because of CO intoxication, either as fire victims with smoke inhalation injuries or from other exposures to CO. In thirty-seven of these patients we measured CN concentrations in blood samples, using a Conway/microdiffusion technique, before and after HBO. The blood samples consisted of the remaining 2 mL from the arterial blood gas analysis. CN concentration in blood from fire victims was compared to 12 patients from non-fire accidents but otherwise also exposed to CO intoxication.
The mean WB-CN concentration before patients received HBO did not differ significantly between the two groups of patients (p = 0.42). The difference between WB-CN before and after HBO did not differ significantly between the two groups of patients (p = 0.7). Lactate in plasma before and after did not differ significantly between the two groups of patients. Twelve of the 25 fire patients and one of the non-fire patients had been given a dose of hydroxycobalamin before HBO.
Discussion and Conclusion
CN concentrations in blood from patients admitted to hospital with CO intoxication and smoke inhalation exposure did not differ significantly from controls. Accordingly, we were not able to detect any changes in CN concentrations in blood after treatment with HBO.
Trial Registration identifier: NCT00280579
PMCID: PMC2894003  PMID: 20550698
23.  Hyperbaric oxygen therapy (HBOT) in case of hemorrhagic cystitis after radiotherapy 
We present the effect of hyperbaric oxygen therapy (HBOT) after radiotherapy for cancer in the pelvic cavity resulting in hematuria. Increasing the pressure of oxygen (PO2) in ischemic tissues favors the formation of new blood vessels and increases the secretion of collagen.
Material and methods
We evaluated 10 patients who were treated with HBOT from October 2006 to December 2010 due to persistent radiation damage to the lining of the bladder leading to recurrent hematuria. The study group was comprised of seven men and three women. In the case of cervical and endometrial cancers, 30 Gy of brachytherapy with 45-50 Gy of teleradiotherapy were used. In prostate cancer (PCa), we applied 50 Gy of teleradiotherapy with an additional dose of 20-24 Gy, and in the case of bladder cancer (BCa), 50 Gy of teleradiotherapy was applied with an additional dose of 16 Gy. HBOT consisted of 60 HBO2 treatments, in which patients were administered 100% oxygen at a pressure of 2.5 atm.
The group effect of total or partial resolution was observed in six patients. In one case, treatment was discontinued due to an increase in hematuria and the consequent suspicion of bladder tumor recurrence. While in and additional three cases, the treatment did not produce the desired result.
Treatment of hemorrhagic cystitis is a difficult therapeutic challenge. One possible method is the implementation of HBOT. In very difficult cases, HBO2 treatment appears to be effective in giving more than half of patients a chance of getting better.
PMCID: PMC3921805  PMID: 24578962
bladder cancer; hematuria; hemorrhagic cystitis; hyperbaric oxygen therapy; radiotherapy
24.  Ozone Therapy and Hyperbaric Oxygen Treatment in Lung Injury in Septic Rats 
Various therapeutic protocols were used for the management of sepsis including hyperbaric oxygen (HBO) therapy. It has been shown that ozone therapy (OT) reduced inflammation in several entities and exhibits some similarity with HBO in regard to mechanisms of action. We designed a study to evaluate the efficacy of OT in an experimental rat model of sepsis to compare with HBO. Male Wistar rats were divided into sham, sepsis+cefepime, sepsis+cefepime+HBO, and sepsis+cefepime+OT groups. Sepsis was induced by an intraperitoneal injection of Escherichia coli; HBO was administered twice daily; OT was set as intraperitoneal injections once a day. The treatments were continued for 5 days after the induction of sepsis. At the end of experiment, the lung tissues and blood samples were harvested for biochemical and histological analysis. Myeloperoxidase activities and oxidative stress parameters, and serum proinflammatory cytokine levels, IL-1β and TNF-α, were found to be ameliorated by the adjuvant use of HBO and OT in the lung tissue when compared with the antibiotherapy only group. Histologic evaluation of the lung tissue samples confirmed the biochemical outcome. Our data presented that both HBO and OT reduced inflammation and injury in the septic rats' lungs; a greater benefit was obtained for OT. The current study demonstrated that the administration of OT as well as HBO as adjuvant therapy may support antibiotherapy in protecting the lung against septic injury. HBO and OT reduced tissue oxidative stress, regulated the systemic inflammatory response, and abated cellular infiltration to the lung demonstrated by findings of MPO activity and histopathologic examination. These findings indicated that OT tended to be more effective than HBO, in particular regarding serum IL-1β, lung GSH-Px and histologic outcome.
PMCID: PMC3020392  PMID: 21234269
Sepsis; Escherichia coli; HBO; Ozone; Oxidant stress; Antioxidant.
25.  Combined intravesical sodium hyaluronate/chondroitin sulfate therapy for interstitial cystitis/bladder pain syndrome: a prospective study 
Therapeutic Advances in Urology  2013;5(4):175-179.
The aim of this study was to verify the efficacy and safety of intravesical treatment combining sodium hyaluronate (HA) and chondroitin sulfate (CS) in patients with interstitial cystitis/bladder pain syndrome (IC/BPS).
Between February 2010 and May 2011, 20 consecutive women with IC/BPS were treated with intravesical instillations containing sodium HA (1.6%; 800 mg/50 ml) and sodium CS (2%; 1 g/50 ml) weekly for the first month, biweekly for the second month, and then monthly for at least 3 months. Before and after treatment, all patients filled in the Interstitial Cystitis Symptom Index and Problem Index (ICSI/ICPI), the Patient Health Questionnaire 9 and the Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF). Treatment efficacy was assessed by comparing the pre- and post-treatment mean scores of the three questionnaires using Student’s t test (p value <0.05 was considered significant).
Statistically significant mean decreases in ICSI (from 13.0 to 9.3; p = 0.0003), ICPI (from 11.35 to 8.85; p = 0.0078) and PUF (from 20.0 to 15.75; p = 0.0007) questionnaire scores were seen. No cases of side effects or complications were observed. The mean follow up was 5 months.
Despite the limitations of this study, the outcomes confirmed the role of combination therapy with HA and CS as a safe and effective option for the treatment of IC/BPS. Further randomized controlled studies with a higher number of patients and a longer follow-up period are needed to confirm these results.
PMCID: PMC3721440  PMID: 23904856
chondroitin sulfate; hyaluronic acid; interstitial cystitis; intravesical administration; painful bladder syndrome

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