Correction to: A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo.

The original article [1] contained two minor errors.

A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo.

BACKGROUND: A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis. METHODS: A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n = 181) with bipolar disorder and current depressive symptoms were randomised to 2000 mg/day NAC (n = 59), 2000 mg/day NAC with the combination nutraceutical treatment (CT, n = 61), or placebo (n = 61). The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes. RESULTS: One hundred forty-eight participants had post-randomisation data and were analysed (NAC = 52, CT = 47, Placebo = 49). No between-group differences were found for the rate of change between baseline and 16 weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group. CONCLUSIONS: These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction. TRIAL REGISTRATION: ANZCTR ( ACTRN12612000830897 ).

The chemistry and biological activities of N-acetylcysteine.

BACKGROUND: N-acetylcysteine (NAC) has been in clinical practice for several decades. It has been used as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication, doxorubicin cardiotoxicity, ischemia-reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, heavy metal toxicity and psychiatric disorders. SCOPE OF REVIEW: The mechanisms underlying the therapeutic and clinical applications of NAC are complex and still unclear. The present review is focused on the chemistry of NAC and its interactions and functions at the organ, tissue and cellular levels in an attempt to bridge the gap between its recognized biological activities and chemistry. MAJOR CONCLUSIONS: The antioxidative activity of NAC as of other thiols can be attributed to its fast reactions with OH, NO2, CO3(-) and thiyl radicals as well as to restitution of impaired targets in vital cellular components. NAC reacts relatively slowly with superoxide, hydrogen-peroxide and peroxynitrite, which cast some doubt on the importance of these reactions under physiological conditions. The uniqueness of NAC is most probably due to efficient reduction of disulfide bonds in proteins thus altering their structures and disrupting their ligand bonding, competition with larger reducing molecules in sterically less accessible spaces, and serving as a precursor of cysteine for GSH synthesis. GENERAL SIGNIFICANCE: The outlined reactions only partially explain the diverse biological effects of NAC, and further studies are required for determining its ability to cross the cell membrane and the blood-brain barrier as well as elucidating its reactions with components of cell signaling pathways.

Diagnosis and management of oral leishmaniasis--case series and literature review.

The worldwide prevalence of leishmaniasis is increasing because of ecologic changes and increased medical profession awareness. Furthermore, solitary cases have been recently reported in Western countries. The authors describe the epidemiology, mode of transmission, and diagnosis of leishmaniasis and present 4 oral cases treated with systemic, localized, or combined therapy. The authors suggest that clinicians should maintain a high index of suspicion for atypical, resistant, oral and perioral lesions in individuals with a history of traveling in certain geographic regions. After diagnosis, treatment should be determined jointly by experts from the fields of oral and maxillofacial surgery, oral medicine, and dermatology based on leishmaniasis species and clinical presentation.

The mechanism underlying nitroxyl and nitric oxide formation from hydroxamic acids.

BACKGROUND: The pharmacological effects of hydroxamic acids (RC(O)NHOH, HX) are partially attributed to their ability to serve as HNO and/or NO donors under oxidative stress. Given the development and use of HXs as therapeutic agents, elucidation of the oxidation mechanism is needed for more educated selection of HX-based drugs. METHODS: Acetohydroxamic and glycine-hydroxamic acids were oxidized at pH 7.0 by a continuous flux of radiolytically generated (·)OH or by metmyoglobin and H(2)O(2) reactions system. Gas chromatography and spectroscopic methods were used to monitor the accumulation of N(2)O, N(2), nitrite and hydroxylamine. RESULTS: Oxidation of HXs by (·)OH under anoxia yields N(2)O, but not nitrite, N(2) or hydroxylamine. Upon the addition of H(2)O(2) to solutions containing HX and metmyoglobin, which is instantaneously and continuously converted into compound II, nitrite and, to a lesser extent, N(2)O are accumulated under both anoxia and normoxia. CONCLUSIONS: Oxidation of HXs under anoxia by a continuous flux of (·)OH, which solely oxidizes the hydroxamate moiety to RC(O)NHO(·), forms HNO. This observation implies that bimolecular decomposition of RC(O)NHO(·) competes efficiently with unimolecular decomposition processes such as internal disproportionation, hydrolysis or homolysis. Oxidation by metmyoglobin/H(2)O(2) involves relatively mild oxidants (compounds I and II). Compound I reacts with HX forming RC(O)NHO(·) and compound II, which oxidizes HX, RC(O)NHO(·), HNO and NO. The latter reaction is the main source of nitrite. GENERAL SIGNIFICANCE: HXs under oxidative stress release HNO, but can be considered as NO-donors provided that HNO oxidation is more efficient than its reaction with other biological targets.

Gene delivery in salivary glands: from the bench to the clinic.

In vivo gene delivery has long been seen as providing opportunities for the development of novel treatments for disorders refractory to existing therapies. Over the last two decades, salivary glands have proven to be a useful, if somewhat unconventional, target tissue for studying several potential clinical applications of therapeutic gene delivery. Herein, we follow the progress, address some problems and assess the outlook for clinical applications of salivary gland gene delivery. Our experience with these tissues provides a roadmap for the process of moving an idea from the laboratory bench to patients.

On the distinction between nitroxyl and nitric oxide using nitronyl nitroxides.

A better understanding of the origins of NO and HNO and their activities and biological functions requires accurate methods for their detection and quantification. The unique reaction of NO with nitronyl nitroxides such as 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (C-PTIO), which yields the corresponding imino nitroxides, is widely used for NO detection (mainly by electron paramagnetic resonance spectroscopy) and for modulation of NO-induced physiological functions. The present study demonstrates that HNO readily reacts with nitronyl nitroxides, leading to the formation of the respective imino nitroxides and hydroxylamines via a complex mechanism. Through the use of the HNO donor Angeli's salt (AS) with metmyoglobin as a competing agent, the rate constant for C-PTIO reduction by HNO has been determined to be (1.4 +/- 0.2) x 10(5) M(-1) s(-1) at pH 7.0. This reaction yields the corresponding nitronyl hydroxylamine C-PTIO-H and NO, which is trapped by C-PTIO to form (*)NO(2) and the corresponding imino nitroxide, C-PTI. (*)NO(2) oxidizes the nitronyl and imino nitroxides to their respective oxoammonium cations, which decay mainly via comproportionation with the nitronyl and imino hydroxylamines. When [AS] > [C-PTIO], the reduction of C-PTI by HNO proceeds, eventually converting C-PTIO to the corresponding imino hydroxylamine, C-PTI-H. Similar results were obtained for 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO). It is concluded that nitronyl nitroxide is readily reduced by HNO to nitronyl hydroxylamine and is eventually converted into imino nitroxide and imino hydroxylamine. The yield of the imino hydroxylamine increases at the expense of the imino nitroxide as the ratio [AS](0)/[nitronyl nitroxide](0) is increased. Since the reaction of NO with nitronyl nitroxide yields only the corresponding imino nitroxide, nitronyl nitroxide can discriminate NO from HNO only when present at a concentration much lower than the total production of HNO.

Sorting behavior of a transgenic erythropoietin-growth hormone fusion protein in murine salivary glands.

Salivary glands are useful gene transfer target sites for the production of therapeutic proteins, and can secrete proteins into both saliva and the bloodstream. The mechanisms involved in this differential protein sorting are not well understood, although it is believed, at least in part, to be based on the amino acid sequence of the encoded protein. We hypothesized that a transgenic protein, human erythropoietin (hEpo), normally sorted from murine salivary glands into the bloodstream, could be redirected into saliva by fusing it with human growth hormone (hGH). After transfection, the hEpo-hGH fusion protein was expressed and glycosylated in both HEK 293 and A5 cells. When packaged in an adenovirus serotype 5 vector and delivered to murine submandibular cells in vivo via retroductal cannulation, the hEpo-hGH fusion protein was also expressed, albeit at approximately 26% of the levels of hEpo expression. Importantly, in multiple experiments with different cohorts of mice, the hEpo-hGH fusion protein was sorted more frequently into saliva, versus the bloodstream, than was the hEpo protein (p < 0.001). These studies show it is possible to redirect the secretion of a transgenic constitutive pathway protein from salivary gland cells after gene transfer in vivo, a finding that may facilitate developing novel treatments for certain upper gastrointestinal tract disorders.

Sorting of growth hormone-erythropoietin fusion proteins in rat salivary glands.

Neuroendocrine and exocrine cells secrete proteins in either a constitutive manner or via the regulated secretory pathway (RSP), but the specific sorting mechanisms involved are not fully understood. After gene transfer to rat salivary glands, the transgenic model proteins human growth hormone (hGH) and erythropoietin (hEpo) are secreted primarily into saliva (RSP; exocrine) and serum (constitutive; endocrine), respectively. We hypothesized that fusion of hGH at either the C-terminus or the N-terminus of hEpo would re-direct hEpo from the bloodstream into saliva. We constructed and expressed two fusion proteins, hEpo-hGH and hGH-hEpo, using serotype 5-adenoviral vectors, and delivered them to rat submandibular glands in vivo via retroductal cannulation. Both the hEpo-hGH and hGH-hEpo fusion proteins, but not hEpo alone, were secreted primarily into saliva (p<0.0001 and p=0.0083, respectively). These in vivo studies demonstrate for the first time that hGH, in an N- as well as C-terminal position, influences the secretion of a constitutive pathway protein.

The effect of a nitroxide antioxidant on ischemia-reperfusion injury in the rat in vivo hind limb model.

Microsurgical procedures such as free tissue transfer or replantations of amputated digits involve an obligatory ischemic period leading to regional tissue oedema, rhabdomyolysis, systemic acidosis, hypercalcemia and multiple organ dysfunction syndrome reflecting ischemia-reperfusion (I/R) injury. Since nitroxide stable radicals act as antioxidants their potential protective effects were tested. Anaesthetized Sabra rats were subjected to regional ischemia of the hind limb for 2 h using a tourniquet. Upon reperfusion rats were injected with 4-OH-2,2,6,6-tetramethylpiperidine-1-oxyl (TPL). Systemic I/R-induced damage was assessed by sampling blood for differential count, lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) serum levels. Regional injury was evaluated by analysing excised muscle samples for oedema (tissue water content) and inflammatory infiltrate (number of cell nuclei in histomorphometric analysis). I/R-induced changes of biomarkers reflecting systemic damage peaked about 8 h following the start of reperfusion and fully disappeared as the biomarkers relaxed to their pre-ischemic values after 24 h. TPL facilitated the recovery of some of these parameters and partially affected release of cellular CPK and LDH. The parameters of I/R-induced regional tissue injury did not demonstrate any recovery and were not inhibited by TPL.

Type 2 diabetes has minimal effect on osseointegration of titanium implants in Psammomys obesus.

OBJECTIVES: Dental implants are routinely used with high success rates in generally healthy individuals. In contrast, their use in patients with uncontrolled diabetes mellitus (DM) remains controversial as altered bone healing around implants has been reported. The majority of reports addressing the issue of osseointegration of implants in animals were performed in beta-cell cytotoxic-induced Type I diabetes. In this study, we assessed the osseointegration of implants in Gerbil Psammomys obesus, a model of nutritionally induced Type 2 DM. MATERIALS AND METHODS: Titanium implants were inserted into the tibial medullary space of 140 male diabetic and control animals. One, 2, 4, and 8 weeks after implantation the tibias were removed for histomorphometric evaluation, which included trabecular bone volumes (TBV) and osseointegration. RESULTS: Two weeks following implantation, diabetic animals had slightly less mature bone when compared with control animals. This distinction was not present 4 weeks after implantation. Interestingly, no correlation was found between ossetointegration or TBV and glucose and insulin levels. Furthermore, no difference in osseointegration and TBV values was seen between the groups. The heterogeneity of serum glucose and insulin levels in this model and the possible role of insulin in bone metabolism are discussed. CONCLUSIONS: No significant difference in osseointegration and TBV was seen between diabetic and control P. obesus, a model of nutritionally induced Type 2 DM.

The effect of informed consent on stress levels associated with extraction of impacted mandibular third molars.

PURPOSE: To evaluate the effect of informed consent on stress levels associated with removal of impacted mandibular third molars. PATIENTS AND METHODS: A total of 60 patients scheduled for extraction of impacted mandibular third molars participated in this study. The patients were unaware of the study's objectives. Data from 20 patients established the baseline levels of electrodermal activity (EDA). The remaining 40 patients were randomly assigned into 2 equal groups receiving either a detailed document of informed consent, disclosing the possible risks involved with the surgery, or a simplified version. Pulse, blood pressure, and EDA were monitored before, during, and after completion of the consent document. RESULTS: Changes in EDA, but not in blood pressure, were measured on completion of either version of the consent document. A greater increase in EDA was associated with the detailed version of the consent document (P = .004). A similar concomitant increase (although nonsignificant) in pulse values was monitored on completion of both versions. CONCLUSIONS: Completion of overdisclosed document of informed consent is associated with changes in physiological parameters. The results suggest that overdetailed listing and disclosure before extraction of impacted mandibular third molars can increase patient stress.

Salivary gland gene therapy.

Salivary glands have proven to be unusual but valuable target sites for multiple clinical gene transfer applications. Access to salivary glands for gene transfer is easy. Multiple studies in animal models have yielded proofs of concept for novel treatments for damaged salivary glands following therapeutic irraditation, in Sjögren's syndrome, and for gene therapeutics systemically by way of the blood-stream and locally in the oral cavity and upper gastrointestinal tract.

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression.

OBJECTIVE: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. METHODS: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. RESULTS: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. CONCLUSION: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

Factors influencing nitroxide reduction and cytotoxicity in vitro.

Nitroxides have been shown to be effective antioxidants, radiation protectors, and redox-active probes for functional electron paramagnetic resonance (EPR) imaging. More recently, the nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidinyl-N-oxyl (Tempol) has been shown to exert differential cytotoxicity to tumor compared with normal cell counterparts. Nitroxides are readily reduced in tissues to their respective hydroxylamines, which exhibit less cytotoxicity in vitro and do not provide radiation protection or an EPR-detectable signal for imaging. In order to better understand factors that influence nitroxide reduction, the rate of reduction of Tempol in mouse and human cell lines and in primary cultures of tumor cells was measured using EPR spectroscopy. Additionally, the cytotoxicity of high concentrations of Tempol and the hydroxylamine of Tempol (Tempol-H) was evaluated in wild-type and glucose-6-phosphate dehydrogenase (G6PD)-deficient Chinese hamster ovary cells. The results show that in general Tempol was reduced at a faster rate when cells were under hypoxic compared with aerobic conditions. Neither depletion of intracellular glutathione nor treatment of cells with sodium cyanide influenced Tempol reduction rates. G6PD-deficient cells were found to reduce Tempol at a significantly slower rate than wild-type cells. Likewise, Tempol-induced cytotoxicity was markedly less for G6PD-deficient cells compared with wild-type cells. Tempol-H exhibited no cytotoxicity to either cell type. Tempol-mediated cytotoxicity was enhanced by glutathione depletion and inhibition of 6-phosphogluconate dehydrogenase in wild-type cells, but was unaltered in G6PD-deficient cells. Collectively, the results indicate that while the bioreduction of Tempol can be influenced by a number of factors, the hexose monophosphate shunt appears to be involved in both nitroxide reduction as well as cytotoxicity induced by high levels of exposure to Tempol.

Suberoylanilide hydroxamic acid radiosensitizes tumor hypoxic cells in vitro through the oxidation of nitroxyl to nitric oxide.

The pharmacological effects of hydroxamic acids are partially attributed to their ability to serve as HNO and/or NO donors under oxidative stress. Previously, it was concluded that oxidation of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) by the metmyoglobin/H2O2 reaction system releases NO, which was based on spin trapping of NO and accumulation of nitrite. Reinvestigation of this system demonstrates the accumulation of N2O, which is a marker of HNO formation, at similar rates under normoxia and anoxia. In addition, the yields of nitrite that accumulated in the absence and the presence of O2 did not differ, implying that the source of nitrite is other than autoxidation of NO. In this system metmyoglobin is instantaneously and continuously converted into compound II, leading to one-electron oxidation of SAHA to its respective transient nitroxide radical. Studies using pulse radiolysis show that one-electron oxidation of SAHA (pKa=9.56 ± 0.04) yields the respective nitroxide radical (pKa=9.1 ± 0.2), which under all experimental conditions decomposes bimolecularly to yield HNO. The proposed mechanism suggests that compound I oxidizes SAHA to the respective nitroxide radical, which decomposes bimolecularly in competition with its oxidation by compound II to form HNO. Compound II also oxidizes HNO to NO and NO to nitrite. Given that NO, but not HNO, is an efficient hypoxic cell radiosensitizer, we hypothesized that under an oxidizing environment SAHA might act as a NO donor and radiosensitize hypoxic cells. Preincubation of A549 and HT29 cells with 2.5 µM SAHA for 24h resulted in a sensitizer enhancement ratio at 0.01 survival levels (SER0.01) of 1.33 and 1.59, respectively. Preincubation of A549 cells with oxidized SAHA had hardly any effect and, with 2mM valproic acid, which lacks the hydroxamate group, resulted in SER0.01=1.17. Preincubation of HT29 cells with SAHA and Tempol, which readily oxidizes HNO to NO, enhanced the radiosensitizing effect of SAHA. Pretreatment with SAHA blocked A549 cells at the G1 stage of the cell cycle and upregulated γ-H2AX after irradiation. Overall, we conclude that SAHA enhances tumor radioresponse by multiple mechanisms that might also involve its ability to serve as a NO donor under oxidizing environments.

Pro-oxidative synergic bactericidal effect of NO: kinetics and inhibition by nitroxides.

NO plays diverse roles in physiological and pathological processes, occasionally resulting in opposing effects, particularly in cells subjected to oxidative stress. NO mostly protects eukaryotes against oxidative injury, but was demonstrated to kill prokaryotes synergistically with H2O2. This could be a promising therapeutic avenue. However, recent conflicting findings were reported describing dramatic protective activity of NO. The previous studies of NO effects on prokaryotes applied a transient oxidative stress while arbitrarily checking the residual bacterial viability after 30 or 60min and ignoring the process kinetics. If NO-induced synergy and the oxidative stress are time-dependent, the elucidation of the cell killing kinetics is essential, particularly for survival curves exhibiting a "shoulder" sometimes reflecting sublethal damage as in the linear-quadratic survival models. We studied the kinetics of NO synergic effects on H2O2-induced killing of microbial pathogens. A synergic pro-oxidative activity toward gram-negative and gram-positive cells is demonstrated even at sub-µM/min flux of NO. For certain strains, the synergic effect progressively increased with the duration of cell exposure, and the linear-quadratic survival model best fit the observed survival data. In contrast to the failure of SOD to affect the bactericidal process, nitroxide SOD mimics abrogated the pro-oxidative synergy of NO/H2O2. These cell-permeative antioxidants, which hardly react with diamagnetic species and react neither with NO nor with H2O2, can detoxify redox-active transition metals and catalytically remove intracellular superoxide and nitrogen-derived reactive species such as (•)NO2 or peroxynitrite. The possible mechanism underlying the bactericidal NO synergy under oxidative stress and the potential therapeutic gain are discussed.

Oxidative & nitrosative stress in depression: why so much stress?

Many studies support a crucial role for oxidative & nitrosative stress (O&NS) in the pathophysiology of unipolar and bipolar depression. These disorders are characterized inter alia by lowered antioxidant defenses, including: lower levels of zinc, coenzyme Q10, vitamin E and glutathione; increased lipid peroxidation; damage to proteins, DNA and mitochondria; secondary autoimmune responses directed against redox modified nitrosylated proteins and oxidative specific epitopes. This review examines and details a model through which a complex series of environmental factors and biological pathways contribute to increased redox signaling and consequently increased O&NS in mood disorders. This multi-step process highlights the potential for future interventions that encompass a diverse range of environmental and molecular targets in the treatment of depression.

The use of cyclic nitroxide radicals as HNO scavengers.

Reduction of cyclic stable nitroxides (RNO) by HNO to the respective hydroxylamines (RNO-H) has been demonstrated using EPR spectrometry. HNO shows low reactivity toward piperidine, pyrrolidine and nitronyl nitroxides with rate constants below 1.4 × 10(5)M(-1)s(-1) at pH 7.0, despite the high driving force for these reactions. The rate constants can be predicted assuming that the reactions take place via a concerted proton-electron transfer pathway and significantly low self-exchange rate constants for HNO/NO and RNO-H/RNO. NO does not react with piperidine and pyrrolidine nitroxides, but does add to HNO forming the highly oxidizing and moderately reducing hyponitrite radicals. In this work, the radicals are produced by pulse radiolysis and the rate constants of their reactions with 2,2,6,6,-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and 3-carbamoyl-PROXYL have been determined at pH 6.8 to be (2.4 ± 0.2)× 10(6), (9.8 ± 0.2)× 10(5), (5.9 ± 0.5)× 10(5)M(-1)s(-1), respectively. This low reactivity implies that NO competes efficiently with these nitroxides for the hyponitrite radical. The ability of TEMPOL and 2-(4-carboxyphenyl)-4,4,5,5,-tetramethyl-imidazoline-1-oxyl-3-oxide (C-PTIO) to oxidize HNO and their different reactivity toward NO are used to quantify HNO formed via acetohydroxamic acid oxidation. The extent of TEMPOL or C-PTIO reduction was similar to the yield of HNO formed upon oxidation by ()OH under anoxia, but not by the metmyoglobin and H(2)O(2) reaction system where both nitroxides catalytically facilitate H(2)O(2) depletion and nitrite accumulation. In this system the conversion of C-PTIO into 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl (C-PTI) is a minor reaction, which does not provide any mechanistic insight.

A novel dental implant system with an internal port for endoscopic closed sinus augmentation: a feasibility study in pigs.

PURPOSE: This study describes the use of an innovative dynamic implant valve approach (DIVA) for dental implant placement and sinus augmentation procedures. MATERIALS AND METHODS: The DIVA implant system was tested in vitro for leakage and mechanical fatigue. A closed sinus elevation procedure with a gel-type bone substitute was performed using the DIVA implant in a swine model (n = 6). Implants were placed and evaluated radiographically and histologically. RESULTS: Elevation of the maxillary sinus membrane and augmentation were performed in a simple, minimally invasive fashion. Histologic analyses demonstrated complete sealing of the DIVA implant and excellent osseointegration. CONCLUSION: The DIVA can be used as a simplified viable option for dental implantation and augmentation procedures. Hermetic sealing of this implant system, which features an inner screw, renders it safe.