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Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare peripheral neurological disorder that manifests with increased sensitivity to pressure. In people with this disorder, the peripheral nerves are unusually sensitive to pressure. Minor trauma or compression causing paralysis in the extremities is a hallmark of this disorder. Ensuring there is no pressure on the extremities is recommended as a preventive measure. We describe for the first time, postoperative vocal cord paralysis in a patient with HNPP due to left recurrent laryngeal nerve palsy. Anesthesiologists and surgeons should be aware of this possible complication in patients with HNPP.
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Artrogripose , Neuropatia Hereditária Motora e Sensorial , Paralisia das Pregas Vocais , Humanos , Paralisia das Pregas Vocais/etiologia , Anestesiologistas , ConscientizaçãoRESUMO
BACKGROUND: Vascular malformations are composed of morphologically abnormal vascular tissue, and when located in the head and neck region, they can make it difficult to secure the airway during general anesthesia. CASE PRESENTATION: A 28-year-old pregnant woman with vascular malformations in the pharynx was scheduled to undergo a cesarean section, for which spinal anesthesia was initially chosen. However, after magnetic resonance imaging results revealed the presence of multiple vascular malformations in the lumbar multifidus muscles, spinal anesthesia was considered to be of high risk. Thus, the patient was subjected to general anesthesia tracheal intubation under sedation, and the course of the surgery was without complications. CONCLUSIONS: Because the pathophysiology and clinical sequelae of vascular malformations may be involved in complications, thorough presurgical evaluation of the patient's physical condition and careful anesthesia planning should be done.
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A peripheral nerve block may be used to improve patient tolerance of awake intubation. During an awake intubation, the glossopharyngeal, superior laryngeal, and recurrent laryngeal nerves can mediate discomfort, pain, cough, glottic closure, and gag reflexes. We describe the use of ultrasound-guided superior laryngeal, recurrent laryngeal, and glossopharyngeal nerve blocks to facilitate awake intubation in a patient predicted to have a difficult airway. The glossopharyngeal nerve block was performed via the parapharyngeal space approach targeting the distal glossopharyngeal nerve. This procedure resulted in an uneventful awake intubation.
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Nervo Glossofaríngeo , Laringe , Humanos , Intubação Intratraqueal , Tosse , Ultrassonografia de IntervençãoRESUMO
Airway ultrasound allows for precise airway evaluation, particularly for assessing the difficult airway and the potential for front of neck access. Many studies have shown that identification of the cricothyroid membrane by airway ultrasound is more accurate than digital palpation. However, no reports to date have provided clinical evidence that ultrasound identification of the cricothyroid membrane increases the success rate of cricothyroidotomy. This is a narrative review which describes patients with difficult airways for whom airway ultrasound may have been useful for clinical decision making. The role of airway ultrasound for the evaluation of difficult airways is summarized and an approach to the use of ultrasound for airway management is proposed. The goal of this review is to present practical applications of airway ultrasound for patients predicted to have a difficult airway and who undergo cricothyroidotomy.
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BACKGROUND: Difficult peripheral venous access, especially in obese people, is challenging for novices. We conducted a randomized cross-over study to examine whether near-infrared venous imaging or ultrasound guidance is more useful for novice operators to obtain difficult peripheral venous access. METHODS: Medical students were recruited as participants. After receiving basic training using commercial simulators, participants were randomly assigned to obtain simulated venous access using a difficult venous access simulator with near-infrared venous imaging or ultrasound guidance in a randomized cross-over design. A difficult venous access simulator was newly developed with deep and narrow vessels to simulate an obese patient. The primary outcome measure of the study was the first-time success rate (%), and the secondary outcome measures included procedure time (seconds) and the number of 3 consecutive successful attempts, to represent proficiency with the procedure. Pearson chi-square test, the Wilcoxon signed-rank test, and generalized estimating equations were used for statistical analysis. RESULTS: Forty-one medical students with no experience performing peripheral venous access were enrolled in this study. The rate of successful first attempts did not differ between the 2 groups (70% for near-infrared; 65% for ultrasound guidance; P = .64). The duration of the procedure for the first attempt was significantly shorter using near-infrared imaging (median: 14; interquartile range: 12-19) compared to ultrasound guidance (median 46; interquartile range: 26-52; P = .007). The number of attempts until 3 consecutive successes was not significantly different comparing the 2 approaches (near-infrared: 3 (3, 7.25), ultrasound guidance: 3 (3, 6.25), P = .63). CONCLUSION: There was no difference in success rate of first-time attempts or acquiring proficiency for the 2 methods. However, duration of the first attempt was significantly shorter with near-infrared imaging than with ultrasound guidance. Near-infrared imaging may require less training than ultrasound guidance. Near-infrared venous imaging may be useful for novices to obtain difficult peripheral venous access in obese patients.
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Cateterismo Periférico , Ultrassonografia de Intervenção , Humanos , Estudos Cross-Over , Ultrassonografia de Intervenção/métodos , Veias/diagnóstico por imagem , Ultrassonografia , Obesidade , Cateterismo Periférico/métodosRESUMO
BACKGROUND: Diagnosis of perioperative anaphylaxis is difficult because of its non-specific and variable signs and symptoms. Therapeutic agents used to treat anaphylaxis and anaesthesiologist responses also vary depending on the case, which might affect outcomes; however, only a few studies have focused on these factors. METHODS: This prospective study of perioperative anaphylaxis, a part of the Japanese Epidemiologic Study for Perioperative Anaphylaxis, investigated the clinical signs, its severity, therapeutic drugs, epinephrine administration, and anaesthesiologist responses in cases of perioperative anaphylaxis to assess trends and variability. Shock index was used to assess severity of cardiovascular collapse. RESULTS: In 43 patients analysed in this study, cardiovascular signs (88.4%) were the most frequent, followed by skin (81.4%) and respiratory signs (60.5%). The presence of signs increased during the clinical course. The median time from the first signs to diagnosis of anaphylaxis was 10 (5.0-17.8) min. The rates of epinephrine use were 30.2% (unused), 48.8% (i.v.), and 20.9% (i.m.). The median time from diagnosis of anaphylaxis to epinephrine administration was 7 (inter-quartile range: 1.5-8.0) min. Antihistamines and corticosteroids were each used in 69.8% of cases. The worst shock index was higher in patients who received i.v. epinephrine (2.77 [0.90] mean [standard deviation]) than in both no epinephrine use cases (1.35 [0.41]) and i.m. epinephrine cases (1.89 [0.77] (P<0.001]). CONCLUSIONS: The clinical signs and treatments of perioperative anaphylaxis are variable, and the choice regarding epinephrine administration is based on symptom severity. CLINICAL TRIAL REGISTRATION: UMIN000035350.
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Anafilaxia , Anestesia , Humanos , Corticosteroides/uso terapêutico , Anafilaxia/diagnóstico , Anafilaxia/tratamento farmacológico , Anafilaxia/epidemiologia , População do Leste Asiático , Epinefrina/uso terapêutico , Estudos Prospectivos , Anestesia/efeitos adversosRESUMO
BACKGROUND: We developed a novel photoacoustic needle, which emits ultrasound produced by the photoacoustic effect. This study focused on the most common "pitfall" associated with placement during ultrasound-guided vascular access, which is misidentification of the needle tip. METHODS: The study was conducted as a prospective cohort study using a questionnaire. The authors intentionally created two successful and one failed ultrasound-guided central venous catheterization videos using the photoacoustic needle on a simulator. Each of these three videos was then split into two movies for viewing, one with standard ultrasound images only and the second including the images from the photoacoustic needle, for a total of six movies. RESULTS: Participants who were 18 anesthesiologists, 12 residents, and 10 medical students, watched each of the six movies and completed a survey whether the puncture was successful or not. In the results, there was a significant difference in the percentage of correct answers whether the movie depicted successful or failed puncture with and without the photoacoustic ultrasound (p = 0.0001). CONCLUSION: The novel photoacoustic needle improved the ability to identify the needle tip on recorded videos. It may have efficacy to prevent serious mechanical complication during the ultrasound-guided vascular access in clinical practice.
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We have implemented several preventive measures to reduce central line-associated bloodstream infection (CLABSI) in the general intensive care unit (ICU) of a university hospital in Japan. Here, we analyzed the factors associated with CLABSI in patients with central venous catheter (CVC) insertions and evaluated the effects of our implemented preventive measures. From July 2013 to June 2018, data was collected from the medical records of 1472 patients with 1635 CVC insertions, including age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, duration of ICU stay, duration of catheter insertion, insertion site, and mechanical ventilation status. During weekly conferences, a surveillance team comprising intensive care and infection control doctors and nurses determined the patients' CLABSI status. The analyzed factors were compared between CLABSI and central line patients without bloodstream infection. Multivariate analysis revealed three factors associated with CLABSI. Adjusted odds ratios with 95% confidence intervals were as follows: duration of ICU stay, 1.032 (1.019-1.044); duration of catheter insertion, 1.041 (1.015-1.066); and APACHE II score, 1.051 (1.000-1.105). The prominent risk factors were associated with the severity of the initial condition and exacerbation of the clinical condition of the patients during their stays in the ICU. Further strategies to reduce CLABSI must be developed.
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Bacteriemia , Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Cateteres Venosos Centrais , Sepse , Humanos , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Relacionadas a Cateter/etiologia , Cateterismo Venoso Central/efeitos adversos , Incidência , Cateteres Venosos Centrais/efeitos adversos , Unidades de Terapia Intensiva , Fatores de Risco , Sepse/complicações , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Bacteriemia/prevenção & controleRESUMO
Acquired hemophilia A is a rare condition caused by autoantibodies against endogenous coagulation factor VIII, which results in spontaneous bleeding. Workup of a patient with difficult hemostasis after removing and placing a central venous catheter led to the diagnosis of acquired hemophilia A. A 64-year-old man was transferred with an intramuscular right thigh mass. Initial biopsy at an outside facility showed degenerated muscle and coagula and he was transferred for incisional biopsy and definitive treatment. The patient had difficult venous access, and a right internal jugular venous catheter was placed. The catheter insertion site showed slow continuous bleeding. Achieving adequate hemostasis after removing the catheter was difficult, and a hematoma formed after the placement of an infraclavicular axillary venous catheter under ultrasound guidance. Coagulation studies revealed a prolonged activated partial thromboplastin time at 96 seconds. The patient was then diagnosed with acquired hemophilia A by enzyme-linked immunosorbent assay using anti-factor VIII antibodies. Even if ultrasound-guided central venous catheterization is performed carefully, bleeding may occur in some patients, suggesting the possibility of coagulopathy. Decision-making for performing central venous catheterization requires extensive knowledge of coagulopathies to understand the causes of bleeding complications.
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Burn injury remains a significant public health issue worldwide. Metabolic derangements are a major complication of burn injury and negatively affect the clinical outcomes of severely burned patients. These metabolic aberrations include muscle wasting, hypermetabolism, hyperglycemia, hyperlactatemia, insulin resistance, and mitochondrial dysfunction. However, little is known about the impact of burn injury on the metabolome profile in skeletal muscle. We have previously shown that farnesyltransferase inhibitor (FTI) reverses burn injury-induced insulin resistance, mitochondrial dysfunction, and the Warburg effect in mouse skeletal muscle. To evaluate metabolome composition, targeted quantitative analysis was performed using capillary electrophoresis mass spectrometry in mouse skeletal muscle. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and hierarchical cluster analysis demonstrated that burn injury induced a global change in metabolome composition. FTI treatment almost completely prevented burn injury-induced alterations in metabolite levels. Pathway analysis revealed that the pathways most affected by burn injury were purine, glutathione, ß-alanine, glycine, serine, and threonine metabolism. Burn injury induced a suppressed oxidized to reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio as well as oxidative stress and adenosine triphosphate (ATP) depletion, all of which were reversed by FTI. Moreover, our data raise the possibility that burn injury may lead to increased glutaminolysis and reductive carboxylation in mouse skeletal muscle.
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Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its reduced form (ubiquinol) functions as an antioxidant. Little is known as to whether oral CoQ10 supplementation effectively increases intracellular CoQ10 levels in humans. To study the bioavailability of CoQ10 supplementation, we conducted a randomized, double-blind, placebo-controlled study of reduced CoQ10 (ubiquinol-10) (1800 mg/day, t.i.d.) in burn patients at a single, tertiary-care hospital. Baseline plasma CoQ10 levels were significantly lower in burn patients than in healthy volunteers, although plasma CoQ10/cholesterol ratio did not differ between the groups. CoQ10 supplementation increased plasma concentrations of total and reduced CoQ10 and total CoQ10 content in peripheral blood mononuclear cells (PBMCs) in burn patients compared with the placebo group. CoQ10 supplementation did not significantly change circulating levels of mitochondrial DNA, inflammatory markers (e.g., interleukins, TNF-α, IFN-γ), or Sequential Organ Failure Assessment (SOFA) scores compared with the placebo group. This study showed that a relatively high dose of reduced CoQ10 supplementation increased the intracellular CoQ10 content in PBMCs as well as plasma concentrations in burn patients.
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We developed a novel technology using the photoacoustic effect that improve needle tip visibility. We evaluated whether this technology improves needle tip visibility when performing a deep peripheral nerve block in a cadaver model. A photoacoustic needle was developed using a conventional echogenic needle with an intraluminal optical fiber. A pulsed laser sends light from a source through the fiber, which is converted to ultrasound at the needle tip using the photoacoustic effect. A nerve block expert performed deep nerve blocks using the photoacoustic needle and the ultrasound views recorded, with or without photoacoustic ultrasound at the needle tip. Needle tip visibility was evaluated by questionnaire (Likert scale 1: very poor, 5: very good) completed by anesthesiologists evaluating recorded images. The score was presented as median [first quartile, third quartile]. Statistical analysis was performed using the Wilcoxon matched-pairs signed rank test. The scores of needle tip visibility with photoacoustic ultrasound from the needle tip (4.3 [4.0, 4.5]) was significantly higher than that without photoacoustic ultrasound (3.5 [3.2, 3.8]) (p < 0.01). Ultrasound emitted at the needle tip using the photoacoustic effect improves needle tip visibility during deep peripheral nerve blocks.Clinical trial number University Hospital Medical Information Network Center Clinical Trials Registration System (UMIN000036974).
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Anestesia por Condução/métodos , Bloqueio Nervoso/métodos , Nervos Periféricos/diagnóstico por imagem , Técnicas Fotoacústicas/métodos , Humanos , Agulhas , Ultrassonografia/métodosRESUMO
Sepsis remains a leading cause of mortality in critically ill patients and is characterized by multi-organ dysfunction. Mitochondrial damage has been proposed to be involved in the pathophysiology of sepsis. In addition to metabolic impairments resulting from mitochondrial dysfunction, mitochondrial DNA (mtDNA) causes systemic inflammation as a damage-associated molecular pattern when it is released to the circulation. Metabolic derangements in skeletal muscle are a major complication of sepsis and negatively affects clinical outcomes of septic patients. However, limited knowledge is available about sepsis-induced mitochondrial damage in skeletal muscle. Here, we show that sepsis induced profound abnormalities in cristae structure, rupture of the inner and outer membranes and enlargement of the mitochondria in mouse skeletal muscle in a time-dependent manner, which was associated with increased plasma mtDNA levels. Farnesyltransferase inhibitor, FTI-277, prevented sepsis-induced morphological aberrations of the mitochondria, and blocked the increased plasma mtDNA levels along with improved survival. These results indicate that protein farnesylation plays a role in sepsis-induced damage of the mitochondria in mouse skeletal muscle. Our findings suggest that mitochondrial disintegrity in skeletal muscle may contribute to elevated circulating mtDNA levels in sepsis.
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DNA Mitocondrial/sangue , Farnesiltranstransferase/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Sepse/tratamento farmacológico , Animais , Masculino , Metionina/análogos & derivados , Metionina/farmacologia , Camundongos , Mitocôndrias/patologia , Músculo Esquelético/patologia , Sepse/sangue , Sepse/patologia , Fatores de TempoRESUMO
BACKGROUND: Cricothyroidotomy is the final strategy in the "cannot intubate, cannot oxygenate" scenario, but half of needle cricothyroidotomy attempts result in failure. The most frequent complication in needle cricothyroidotomy is posterior tracheal wall injury. We hypothesized that needle length is related to posterior wall injury and compared needle cricothyroidotomy with a commercial kit to a modified shorter needle to evaluate success and posterior wall injury rates. METHODS: The commercial kit has a needle stopper to prevent posterior wall injury, with a penetrating length of 25âmm. We made long stopper to shorten the length by 5âmm (net 20âmm penetrating length). Residents were recruited, received a lecture about cricothyroidotomy and practiced needle cricothyroidotomy using the commercial kit on a simulator. They then performed cricothyroidotomy using the commercial kit or the shorter needle on an ex-vivo porcine larynx covered with artificial skin. An intra-tracheal endoscope recorded the procedure. The video was evaluated for success/failure or posterior wall injury by independent evaluators. Larynxes with a distance from the outer surface to the inner lumen exceeding 13âmm were excluded. The distance in each larynx was measured by dissection after the study. Success and posterior wall injury rates were analyzed using Fisher exact test (Pâ<â.05 was statistically significant). RESULTS: Forty-seven residents participated in the study. Data for two residents were excluded. There was no statistically significant difference in success rate between the commercial kit (100%, 45/45) and the shorter needle (91%, 41/45, Pâ=â.12). Failure was defined if the needle tip did not reach the lumen in four trials. Cannulated but complicated by posterior wall injury occurred in 33% (15/45) with the commercial kit and 5% (2/43) with the shorter needle (Pâ<â.01). CONCLUSION: During needle cricothyroidotomy, force is needed for the needle to penetrate the cricothyroid ligament. The advancing needle sometimes cannot be stopped after penetrating the cricothyroid ligament. These data suggest that needle length is associated with posterior wall injury.
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Cartilagem Cricoide/cirurgia , Agulhas/efeitos adversos , Traqueia/lesões , Animais , Estudos Cross-Over , Modelos Animais de Doenças , Desenho de Equipamento/métodos , Desenho de Equipamento/normas , Agulhas/tendências , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/fisiopatologia , Suínos/lesões , EnsinoRESUMO
BACKGROUND: A high-fidelity task simulator for cricothyroidotomy was created using data from a 3-dimensional (3D) computed tomography scan using a 3D printer. We hypothesized that this high-fidelity cricothyroidotomy simulator results in increased proficiency for needle cricothyroidotomy compared with conventional simulators. METHODS: Cricothyroidotomy-naive residents were recruited and randomly assigned to 2 groups, including simulation training with a conventional simulator (GroupâC) and with a high-fidelity simulator (Group 3D). After simulation training, participants performed cricothyroidotomy using an ex vivo porcine larynx fitted with an endoscope to record the procedure. The primary outcomes were success rate and procedure time. The secondary outcome was a subjective measure of the similarity of the simulator to the porcine larynx. RESULTS: Fifty-two residents participated in the study (GroupâC: nâ=â27, Group 3D: nâ=â25). There was no significant difference in the success rate or procedure time between the 2 groups (success rate: Pâ=â.24, procedure time: Pâ=â.34). There was no significant difference in the similarity of the simulators to the porcine larynx (Pâ=â.81). CONCLUSION: We developed a high-fidelity simulator for cricothyroidotomy from 3D computed tomography data using a 3D printer. This anatomically high-fidelity simulator did not have any advantages compared with conventional dry simulators.
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Anestesiologia/educação , Treinamento com Simulação de Alta Fidelidade/métodos , Internato e Residência/métodos , Músculos Laríngeos/cirurgia , Traqueotomia/educação , Manuseio das Vias Aéreas/métodos , Simulação por Computador , Avaliação Educacional/métodos , Humanos , Japão , Modelos Anatômicos , Materiais de Ensino/normasRESUMO
Mitochondrial dysfunction is associated with metabolic alterations in various disease states, including major trauma (e.g., burn injury). Metabolic derangements, including muscle insulin resistance and hyperlactatemia, are a clinically significant complication of major trauma. Coenzyme Q10 (CoQ10) is an essential cofactor for mitochondrial electron transport, and its reduced form acts as a lipophilic antioxidant. Here, we report that burn injury induces impaired muscle insulin signaling, hyperlactatemia, mitochondrial dysfunction (as indicated by suppressed mitochondrial oxygen consumption rates), morphological alterations of the mitochondria (e. g., enlargement, and loss of cristae structure), mitochondrial oxidative stress, and disruption of mitochondrial integrity (as reflected by increased mitochondrial DNA levels in the cytosol and circulation). All of these alterations were significantly alleviated by CoQ10 treatment compared with vehicle alone. These findings indicate that CoQ10 treatment is efficacious in protecting against mitochondrial dysfunction and insulin resistance in skeletal muscle of burned mice. Our data highlight CoQ10 as a potential new strategy to prevent mitochondrial damage and metabolic dysfunction in burn patients.
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Queimaduras/metabolismo , Insulina/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Transdução de Sinais , Ubiquinona/análogos & derivados , Animais , Masculino , Camundongos , Ubiquinona/metabolismoRESUMO
RATIONALE: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an immune-mediated syndrome caused by the production of antibodies against NMDA receptors. As NMDA receptors are important targets of many anesthetic drugs, the perioperative management of patients with anti-NMDA receptor encephalitis is challenging for anesthesiologists. PATIENT CONCERNS: A 31-year-old woman presented with akinesia and aphasia, which worsened despite steroid therapy. DIAGNOSIS: Anti-NMDA receptor encephalitis associated with ovarian teratoma. INTERVENTIONS: Laparoscopic ovarian cystectomy was performed under total intravenous anesthesia (TIVA) with peripheral nerve block (PNB). OUTCOMES: The patient recovered without postoperative complications or any adverse events after surgery. LESSONS: Ideal anesthesia for a patient with anti-NMDA receptor encephalitis is still under discussion. We decided to perform TIVA with PNB because the effect of propofol on NMDA receptors is considered less than that of volatile anesthetics; moreover, PNB may reduce the amount of propofol and opioids required for anesthesia. To conclude, TIVA with PNB may be the most appropriate method for anesthesia in a patient with anti-NMDA receptor encephalitis undergoing ovarian cystectomy.
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Analgésicos Opioides , Anestesia Intravenosa/métodos , Encefalite Antirreceptor de N-Metil-D-Aspartato , Bloqueio Nervoso/métodos , Neoplasias Ovarianas , Ovariectomia , Complicações Pós-Operatórias/prevenção & controle , Propofol , Receptores de N-Metil-D-Aspartato/imunologia , Teratoma , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/efeitos adversos , Encefalite Antirreceptor de N-Metil-D-Aspartato/etiologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Anticorpos/sangue , Feminino , Humanos , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Ovariectomia/efeitos adversos , Ovariectomia/métodos , Propofol/administração & dosagem , Propofol/efeitos adversos , Teratoma/complicações , Teratoma/patologia , Teratoma/cirurgia , Resultado do TratamentoRESUMO
Highly active antiretroviral therapy (HAART) has successfully reduced the mortality rate of patients with human immune deficiency virus (HIV) and HIV protease inhibitors (HIV PIs) are key components of HAART. Complications of HAART, particularly those associated with HIV PIs including lipodystrophy and metabolic disturbance, have emerged as an important public health issue. No specific treatment is available to prevent and/or treat HIV PI-associated lipodystrophy and metabolic syndrome. The present study demonstrated that a relatively low-dose of farnesyltransferase inhibitor (FTI), tipifarnib (3 mg/kg/day, subcutaneous injection) and lonafarnib (5 mg/kg/day, subcutaneous injection), prevented the onset of lipodystrophy and metabolic syndrome induced by the combination of two HIV PIs, lopinavir (50 mg/kg/day, intraperitoneal injection) and ritonavir (12.5 mg/kg/day, intraperitoneal injection), in mice. Consistent with previous studies, treatment with lopinavir/ritonavir for 2 weeks decreased body weight, adipose tissue mass, levels of plasma adiponectin and leptin, and increased plasma levels of triglycerides, total cholesterol and insulin. Tipifarnib and lonafarnb prevented or ameliorated all of these alterations in the HIV PI-treated mice. These data identify FTIs as a novel potential strategy to prevent or treat HIV PI-associated lipodystrophy and metabolic syndrome in HIV-infected patients on HAART.
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Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.