Surgical landmarks of the glossopharyngeal nerve

Damage to the glossopharyngeal nerve can occur as a result of various Head and Neck surgeries. Associated with this damage are assorted side effects, such as dysphagia, xerostomia, and loss of taste. This study serves to create probabilistic maps of the glossopharyngeal nerve using quantitative data, and to identify different landmarks in order to locate the nerve. Eleven cadaveric heads were bilaterally dissected to expose and measure the glossopharyngeal nerve. The mastoid process is a more reliable marker for the location of the glossopharyngeal nerve as it stretches through the lateral neck. Additionally, distance landmark measurements from the nerve leaving the jugular foramen to it entering the pharyngeal space are offered. Furthermore, statistical probability equations for nerve location have been created. Measurements and models created by this study will aid in pre-operative identification of glossopharyngeal nerve landmarks that will lead to an increase in quality of life in Head and Neck surgery patients

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Coenzyme Q10 Alleviates Chronic Nucleoside Reverse Transcriptase Inhibitor-Induced Premature Endothelial Senescence.

Human immunodeficiency virus (HIV)-infected patients undergoing antiretroviral therapy are afforded an increased lifespan but also exhibit an elevated incidence of cardiovascular disease. HIV therapy uses a combination drug approach, and nucleoside reverse transcriptase inhibitors (NRTI) are a backbone of this therapy. Endothelial dysfunction is an initiating event in cardiovascular disease etiology, and in our prior studies, NRTIs induced an endothelial dysfunction that was dependent upon mitochondrial oxidative stress. Moreover, short-term NRTI administration induced a mitophagy-associated endothelial toxicity and increased reactive oxygen species (ROS) production that was rescued by coenzyme Q10 (Q10) or overexpression of a mitochondrial antioxidant enzyme. Thus, our objective was to examine mitochondrial toxicity in endothelial cells after chronic NRTI treatment and evaluate Q10 as a potential adjunct therapy for preventing NRTI-induced mitochondrial toxicity. Human aortic endothelial cells (HAEC) were exposed to chronic NRTI treatment, with or without Q10. ROS production, cell proliferation rate, levels of senescence, and mitochondrial bioenergetic function were determined. Chronic NRTI increased ROS production but decreased population doubling. In addition, NRTI increased the accumulation of ß-galactosidase, indicative of an accelerated rate of senescence. Moreover, ATP-linked respiration was diminished. Co-treatment with Q10 delayed the onset of NRTI-induced senescence, decreased ROS production and rescued the cells' mitochondrial respiration rate. Thus, our findings may suggest antioxidant enrichment approaches for reducing the cardiovascular side effects of NRTI therapy.

Overexpression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD) provides protection against AZT- or 3TC-induced endothelial dysfunction.

Nucleoside reverse transcriptase inhibitors (NRTIs) are considered the backbone of current combination therapies for HIV. These therapies have significantly decreased mortality and morbidity in HIV-infected patients, but some are associated with cardiovascular complications, including endothelial dysfunction, an early marker for atherosclerosis. Our prior studies demonstrated that co-treatment of cells with an antioxidant therapy reversed NRTI-induced endothelial injury. Thus, as a proof of concept that mitochondrially-targeted antioxidants may be useful in preventing NRTI toxicity, in the current study, mice overexpressing a mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), were compared with wild-type (WT) mice. Mice were treated chronically with either zidovudine (AZT), lamivudine (3TC), or tenofovir (TDF) to determine whether overexpression of MnSOD protected them from endothelial dysfunction. Endothelial function was assessed using vessel reactivity experiments on thoracic aortas as well as measures of endothelium derived factors nitric oxide (NO), endothelin-1 (ET-1), and prostacyclin. Oxidative stress was evaluated as levels of plasma 8-isoprostane. Alterations in vessel reactivity, NO, and ET-1 in WT mice treated with AZT or 3TC were noted. Overexpression of MnSOD offered protection from decreases in vessel reactivity and increases in ET-1. These findings indicate that mitochondrial oxidative stress induced by AZT or 3TC plays a major role in mediating NRTI-induced endothelial dysfunction, and suggest that the use of targeted antioxidants administered in conjunction with NRTIs may attenuate these effects.

Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.

Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTIs of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial cytotoxicity, in some cases, cells were cotreated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6h, NRTIs increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/NADH ratio. Moreover, nitric oxide levels were decreased, whereas endothelin-1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTIs only, markers for mitochondrial toxicity returned to baseline levels by 18-24h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and Nix, respectively, we observed autophagy of mitochondria at 8-10h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTI-induced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction.

The role of glucocorticoids in the immediate vs. delayed effects of acute ethanol exposure on cytokine production in a binge drinking model.

BACKGROUND: Acute ethanol administration just prior to a stimulus, such as the viral mimic poly I:C, results in decreased proinflammatory cytokine production. Studies have indicated that this suppression is not primarily mediated by glucocorticoids (corticosterone in mice) released in the ethanol-induced stress response. Fewer studies have been done on the effects of acute ethanol administration 12 or more hours prior to a stimulus. The purpose of this study was to determine the role of corticosterone on these effects. Also, since gender differences occur in immune responses, separate experiments were performed using male and female mice. METHODS: Mice were treated with ethanol 15 min or 12h before stimulation by poly I:C to demonstrate immunosuppressive effects of ethanol on cytokine production. A glucocorticoid synthesis inhibitor was used to manipulate corticosterone levels. RESULTS: Short-term and persistent effects of acute ethanol exposure on corticosterone and cytokine levels were nearly identical in males and females. Blocking glucocorticoid synthesis altered the inhibition of some cytokines, particularly IL-6, in females, but not in males. CONCLUSION: These results indicate that the short-term effects of acute ethanol on poly I:C-induced cytokine production are not primarily mediated by corticosterone in male or female mice. In female mice, however, corticosterone does appear to mediate the persistent effects of acute ethanol administration on poly I:C- induced IL-6 levels. Since many IL-6 related disorders are gender associated, further research into the bidirectional effects of the HPG and HPA axes on alterations in cytokine production mediated by ethanol is warranted.

Innate immunity and inflammation in sepsis: mechanisms of suppressed host resistance in mice treated with ethanol in a binge-drinking model.

Sepsis is a major cause of mortality worldwide. Acute or chonic ethanol exposure typically suppresses innate immunity and inflammation and increases the risk of mortality in patients with sepsis. The study described here was designed to address the mechanism(s) by which acute ethanol exposure alters the course of sepsis. Ethanol administered to mice shortly before Escherichia coli (injected ip to produce sepsis) decreased production of proinflammatory cytokines and chemokines for several hours. Bacteria in the peritoneal cavity decreased over time in control mice and were mostly cleared by 21 h, but in ethanol-treated mice, bacteria increased over time to more than 2 × 10(8) at 21 h. Killing of bacteria in macrophages and neutrophils was apparently compromised by ethanol, as the percentage of these cells that had cleared phagocytosed bacteria increased over time in control mice but not in ethanol-treated mice. The roles of TLR4, MyD88, and myeloperoxidase (MPO) were evaluated using mutant or knockout mice, and these experiments indicated that mice with hyporesponsive TLR4 survived better than those with normal TLR4. Lack of MyD88 or MPO did not significantly alter survival in the presence or absence of ethanol. Ethanol decreased survival in all groups. This indicates that the antimicrobial activities induced though TLR4 are dispensable for survival but contribute to lethality late in the course of sepsis. Thus, the effects of ethanol responsible for lethal outcome in sepsis are not dependent on inhibition of TLR4 signaling, as we and others had previously suspected.

The role of stress mediators in modulation of cytokine production by ethanol.

Acute ethanol exposure in humans and in animal models activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS); the resultant increases in concentration of neuroendocrine mediators contribute to some of the immunosuppressive effects of ethanol. However, the role of these mediators in the ethanol-induced inhibition of inflammatory responses is not clear. This is complicated by the fact that most inflammatory stimuli also activate the HPA axis and SNS, and it has not been determined if ethanol plus an inflammatory stimulus increases these stress responses. Addressing this issue is the major focus of the study described herein. Complementary approaches were used, including quantitative assessment of the stress response in mice treated with polyinosinic-polycytidylic acid (poly I:C, as an inflammatory stimulus) and inhibition of the production or action of key HPA axis and SNS mediators. Treatment of mice with ethanol shortly before treatment with poly I:C yielded a significant increase in the corticosterone response as compared to the response to poly I:C alone, but the increase was small and not likely sufficient to account for the anti-inflammatory effects of ethanol. Inhibition of catecholamine and glucocorticoid production by adrenalectomy, and inhibition of catecholamine action with a sustained release antagonist (nadalol) supported this conclusion and revealed that "excess" stress responses associated with ethanol treatment is not the mechanism of suppression of pro-inflammatory cytokine production, but stress-induced corticosterone does regulate production of several of these cytokines, which has not previously been reported.

Role of corticosterone in immunosuppressive effects of acute ethanol exposure on Toll-like receptor mediated cytokine production.

Acute ethanol (EtOH) exposure causes a stress response in humans, nonhuman primates, and rodents. Previous study results indicate that the suppression of some immunological parameters by EtOH is mediated in part or completely by elevated corticosterone concentrations induced by EtOH. However, initial results suggested that corticosterone is not involved in the modulation of cytokine production by macrophages in response to polyinosinic polycytidylic acid (poly I:C). New studies were conducted to further evaluate the role of corticosterone in EtOH-mediated changes in production of interleukin-6 (IL-6), IL-10, and IL-12 in serum and peritoneal fluid in mice treated with poly I:C or lipopolysaccharide (LPS). Suppression of IL-6, but not IL-12, production by EtOH was found to be mediated by corticosterone. However, poly I:C, LPS, and EtOH all caused similar elevations of corticosterone concentrations; thus, it is not clear if EtOH is required to induce levels or durations of corticosterone needed to mediate the observed effects. The situation with IL-10 was more complicated. Inhibition of corticosterone synthesis with aminoglutethimide prevented the increase in IL-10 production caused by EtOH plus poly I:C as compared to poly I:C only. This indicates that this increase is dependent on corticosterone, but exogenous corticosterone plus poly I:C did not increase IL-10 production. Thus, EtOH and corticosterone are required. However, with LPS inhibition of corticosterone synthesis (using aminoglutethimide) or inhibition of its action (using mifepristone) further increased, or did not affect IL-10 concentrations, suggesting fundamental differences in the signaling pathways leading from poly I:C and LPS to IL-10 production.