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INTRODUCTION: Since its introduction in the mid-1990s the frozen elephant trunk (FET) technique has quickly evolved into an effective hybrid treatment option for patients with various thoracic aortic pathologies, acute and chronic. However, a notable incidence of and risk for distal aortic reinterventions persists after the implementation of the FET device. In this review, the authors analyze the indications and outcomes of thoracic endovascular aortic repair completion following FET. AREAS COVERED: For this review, we looked not only at our own data but also searched PubMed for relevant studies, comments, and current recommendations of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society for Vascular Surgery (ESVS). Additionally, we outline our approach in this 2-stage-treatment plan. EXPERT OPINION: The treatment of acute or chronic aortic pathologies involving the aortic arch frequently requires a 2-stage treatment approach. Sometimes, a tertiary procedure is needed to fix the entire aortic pathology. Thoracic endovascular aortic repair completion following FET requires careful planning to achieve the excellent clinical outcomes that we and numerous other aortic centers have shown. Only a dedicated aortic clinic provides the long-term continuous follow-up required to identify the few patients in need of a tertiary procedure.
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Aorta Torácica , Procedimentos Endovasculares , Humanos , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/métodos , Aorta Torácica/cirurgia , Prótese Vascular , Doenças da Aorta/cirurgia , Correção Endovascular de AneurismaRESUMO
OBJECTIVE: This study examines outcome and durability of physician made bovine pericardial tube grafts in aortic infections in all anatomical locations. METHODS: This was a retrospective and prospective international multicentre study. Peri-operative and long term outcomes of patients undergoing in situ aortic reconstruction for native or graft infections with physician made bovine pericardial tube grafts between January 2008 and December 2020 in four European tertiary referral centres were analysed. The primary endpoint was recurrent aortic infection. Secondary endpoints were persistent infection, aortic re-operation for infection, graft related complications, and death. RESULTS: One hundred and sixty eight patients (77% male, mean age 67 ± 11 years) were identified: 38 (23%) with native and 130 (77%) with aortic graft infection. The thirty day mortality rate was 15% (n = 26) overall, 11% (n = 4), and 17% (n = 22) for native and aortic graft infections, respectively (p = .45). Median follow up was 26 months (interquartile range [IQR] 10, 51). Estimated survival at one, two, three, and five years was 64%, 60%, 57%, and 50%, and significantly better for native (81%, 77%, 77%, and 69%) than for graft infections (58%, 55%, 51%, and 44%; p = .011). Nine patients (5.3%) had persistent infection and 10 patients (6%) had aortic re-infection after a median of 10 months (IQR 5, 22), resulting in an estimated freedom from re-infection at one, two, three, and five years of 94%, 92%, 90%, and 86%. Estimated freedom from graft complications at one, two, three, and five years was 91%, 89%, 87%, and 87%. CONCLUSION: This multicentre study demonstrates low re-infection rates when using physician made bovine pericardial tube grafts, comparable to those of other biological grafts. The rate of graft complications, mainly anastomotic aneurysms and stenoses, was low, while graft degeneration was absent. Physician made bovine pericardial tube grafts are an excellent tool for in situ reconstruction in the setting of native aortic infection or aortic graft infection.
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Bioprótese , Implante de Prótese Vascular , Prótese Vascular , Pericárdio , Infecções Relacionadas à Prótese , Reoperação , Humanos , Masculino , Infecções Relacionadas à Prótese/cirurgia , Infecções Relacionadas à Prótese/mortalidade , Infecções Relacionadas à Prótese/microbiologia , Idoso , Feminino , Prótese Vascular/efeitos adversos , Bovinos , Pericárdio/transplante , Estudos Retrospectivos , Pessoa de Meia-Idade , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Implante de Prótese Vascular/mortalidade , Europa (Continente) , Bioprótese/efeitos adversos , Reoperação/estatística & dados numéricos , Estudos Prospectivos , Animais , Resultado do Tratamento , Recidiva , Desenho de Prótese , Aorta/cirurgia , Fatores de TempoRESUMO
Background and Objectives: The aim of this study was to analyze the influence of mass transfusion on the postoperative outcome and survival in patients presenting with acute Type A aortic dissection. Materials and Methods: Between 2002 and 2020, a total of 505 patients were surgically treated for an acute Type A aortic dissection. Mass transfusion was defined as the peri- and postoperative replacement by transfusion of 10 units. Patient characteristics and outcomes were analyzed and compared between patients with and without mass transfusion. Results: Mass transfusion occurred in 105 patients (20%). The incidences of symptomatic coronary malperfusion (p = 0.017) and tamponade (p = 0.043) were higher in patients with mass transfusion. There was no statistically significant difference in the distal extension of the aortic dissection between the two groups. A valved conduit was significantly more common in patients with mass transfusion (p = 0.007), while the distal aortic repair was similar between the two groups. Cardiopulmonary bypass time (p < 0.001), cross clamp time (p < 0.001) and in-hospital mortality were significantly higher in patients with mass transfusion (p < 0.001), but the survival after discharge (landmark-analysis) showed equal survival between patients with and without mass transfusion (log rank: p = 0.4). Mass transfusion was predictive of in-hospital mortality (OR: 3.308, p < 0.001) but not for survival after discharge (OR: 1.205, p = 0.661). Conclusions: Mass transfusion is necessary in many patients with acute Type A aortic dissection. These patients present sicker and require longer surgery. However, mass transfusion does not influence survival after discharge.
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Dissecção Aórtica , Humanos , Dissecção Aórtica/cirurgia , Procedimentos Cirúrgicos Vasculares , Transfusão de Sangue , Hospitais , Resultado do Tratamento , Estudos Retrospectivos , Doença Aguda , Mortalidade HospitalarRESUMO
BACKGROUND: Our aim was to investigate outcomes and long-term survival in male and female patients after frozen elephant trunk (FET) total arch replacement. METHODS: Between March 2013 and January 2023, 362 patients underwent aortic arch replacement via the FET technique. We compared patient characteristics and intra- and postoperative data between male and female patients. RESULTS: Male patients were significantly younger (p = 0.012) but revealed a higher incidence of coronary artery disease (p = 0.008) and preoperative dialysis (p = 0.017). More male patients presented with type A aortic dissections (p = 0.042) while more female patients had aortic aneurysms (p = 0.025). The aortic root was replaced in significantly more male patients (p = 0.013), resulting in significantly longer cardiopulmonary bypass duration (p < 0.001) and operative times (p < 0.001). There were no statistically significant differences in postoperative outcome parameters including in-hospital mortality (p = 0.346). However, new in-stent thrombus formation was significantly more frequent in female patients (p = 0.002). Age in years (odds ratio (OR): 1.026, p = 0.049), an acute pathology (OR: 1.941, p = 0.031) and preoperative dialyses (OR: 3.499, p = 0.010) were predictive for long-term mortality in our Cox regression model, sex (p = 0.466) was not. There was no statistical difference in overall survival (log rank: p = 0.425). CONCLUSIONS: Female patients are older but reveal fewer cardiovascular risk factors; aneurysms are more common in female than male patients. As female patients undergo concomitant surgical procedures less often, their operative times are shorter. While survival and outcomes were similar, female patients suffered from postoperative new in-stent thrombus formation significantly more often.
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Background and objectives: The treatment of pathologies of the aortic arch is a complex field of cardiovascular surgery that has witnessed enormous progress recently. Such treatment is mainly performed in high-volume centres, and surgeons gain great experience in mastering potential difficulties even under emergency circumstances, thereby ensuring the effective therapy of more complex pathologies with lower complication rates. As the numbers of patients rise, so does the need for well-trained surgeons in aortic arch surgery. But how is it possible to learn surgical procedures in a responsible way that, in addition to surgical techniques, also places particular demands on the overall surgical management such as perfusion strategy and neuro-protection? This is why a good training programme teaching young surgeons without increasing the risk for patients is indispensable. Our intention was to highlight the most challenging aspects of aortic arch surgery teaching and how young surgeons can master them. Materials and Methods: We analysed the literature to find out which methods are most suitable for such teaching goals and what result they reveal when serving as teaching procedures. Results: Several studies were found comparing the surgical outcome of young trainees with that of specialists. It was found that the results were comparable whether the procedure was performed by a specialist or by a trainee assisted by the specialist. Conclusions: We thus came to the conclusion that even for such a complex type of intervention, the responsible training of young surgeons by experienced specialists is possible. However, it requires a clear strategy and team approach to ensure a safe outcome for the patient.
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Aorta Torácica , Cirurgiões , Humanos , Aorta Torácica/cirurgia , Escolaridade , Aprendizagem , IntençãoRESUMO
Thoracic aortic emergencies involving the aortic arch are potentially fatal conditions that require the entire surgical repertoire of conventional surgery, such as complete aortic arch replacement using the frozen-elephant-trunk technique, through hybrid procedures, to full surgical endovascular options with conventional or delivered/fenestrated stent-grafts. An interdisciplinary aortic team should choose the optimal treatment of the pathologies of the aortic arch, considering the morphology of the entire aorta, from the root to beyond the bifurcation, as well as the clinical comorbidities. The treatment goal is a complication-free postoperative result and lasting freedom from aortic reinterventions. Irrespective of the selected therapy method, patients should then be connected to a specialized aortic outpatient clinic. The aim of this review was to provide an overview of pathophysiology and current treatment options in emergencies of the thoracic aorta, also involving the aortic arch. We wanted to summarize the preoperative considerations, intraoperative settings, and strategies, as well the postoperative follow-up.
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Aneurisma da Aorta Torácica , Implante de Prótese Vascular , Humanos , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Prótese Vascular , Emergências , Implante de Prótese Vascular/efeitos adversos , Aorta/cirurgia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/cirurgia , Resultado do Tratamento , Estudos Retrospectivos , StentsRESUMO
BACKGROUND: With increasing life expectancy, there is an increasing proportion of nonagenarians undergoing both elective and emergency surgical procedures. The decision as to whom will benefit from surgical procedures is however difficult to ascertain and still remains a challenge to clinicians. This study is aimed to evaluate the clinical outcomes of colonoscopy in the nonagenarian population, and to determine if the outcomes are acceptable for us to continue to offer such interventions. METHODS: Retrospective study of patients of Dr. G.R (Gastroenterologist) and Dr. W.B (Colorectal Surgeon) between 1 January 2018 and 31 November 2022. All patients who were ≥90 years old and had a colonoscopy was included in the study. Exclusion criteria were patients who were less than 90 years old, had a flexible sigmoidoscopy or colonoscopy as part of their surgical procedure. PRIMARY OUTCOME MEASURES: post-colonoscopy complications and length of stay. SECONDARY OUTCOME MEASURES: reasons for colonoscopy, significant colonoscopy findings, 30-day morbidity and mortality. RESULTS: Sixty patients were included in the study. Median age was 91 (90-100) years old. 33.3% of the patients were males. Seventy percent of the patients were ASA 3. Median length of hospital stay was 1 day. 11.7% of patients were found to have colorectal malignancy. There were no complications after the colonoscopy. There were no 30-day re-admission, morbidity or mortality. CONCLUSION: Colonoscopy can be performed safely in carefully selected nonagenarian patients with acceptable low complication rates.
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Neoplasias Colorretais , Nonagenários , Masculino , Idoso de 80 Anos ou mais , Humanos , Feminino , Estudos Retrospectivos , Procedimentos Cirúrgicos Eletivos/métodos , Tempo de Internação , Colonoscopia/efeitos adversos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/cirurgiaRESUMO
The constant improvement of operative techniques offers the possibility of treating an increasing number of patients with complex acute and chronic thoracic aortic pathologies involving the aortic arch. Reliable and durable prosthetic material forms the platform for these approaches. Besides the most important properties like impermeability for blood, infection and thrombotic resistance, there are also properties which are not seen at first glance but can nevertheless play a key role in the healing process and long-term results, such as endothelialization and immunostimulation. To ensure the best possible properties of the graft, different variables of the grafts are continuously developed. Beside the choice of material and the weaving technique, Dacron sealing with gelatin is in clinical use for many years but is still being discussed. Collecting clinical experiences with sealed and unsealed grafts in aortic arch replacement led to the conclusion that blood loss through the prosthesis, especially in the early phase after the implantation of the graft, is lowered by gelatin sealing. Furthermore, binding of antimicrobiotic and antithrombotic agents to the collagen are promising approaches to a better prevention of these dreaded complications. More research examining the healing process of the prosthesis is needed in order to find out more about the influence of the prosthesis sealing.
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Aortic diseases are a rare but potentially life-threatening condition. We present a serum proteomic study for a spectrum of aortic diseases including thoracic aortic aneurysms (n = 11), chronic dissections (n = 9), acute aortic dissections (n = 11), and surgically treated dissections (n = 19) as well as healthy controls (n = 10) and patients of coronary heart disease (n = 10) to represent non-aortic cardiovascular disease. In total, we identified and quantified 425 proteins across all 70 samples. The different aortic diseases represented distinguishable proteome profiles. We identified protein clusters that positively or negatively correlate with disease severity, including increase of cytosolic tissue leakage proteins and decrease of components of the coagulation and complement system. Further, we identified a serum proteome fingerprint of acute aortic dissections, consisting, among others, of enriched inflammatory markers such as C-reactive protein and members of the S100 protein family. The study underlines the applicability of serum proteomics for the investigation of aortic diseases and highlights the possibility to establish disease-specific prognostic markers.
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The frozen elephant trunk technique has become a well-established treatment option for patients presenting all thoracic aortic pathologies including acute and chronic dissection, aortic aneurysms and even penetrating aortic ulcers involving the aortic arch and descending aorta. Nevertheless, there is a significant incidence of and risk for distal aortic reinterventions after the frozen elephant trunk. Indications mainly include a planned staged approach, diameter progression of downstream aortic segments and the development of distal stent-graft induced new entries (dSINEs). Endovascular stent-graft extension through conventional thoracic endovascular aortic repair (TEVAR) is a relatively simple and safe method to address any pathologies in the remaining descending thoracic aorta up to the level of the coeliac trunk. In fact, the frozen elephant trunk stent-graft provides an ideal proximal landing zone for any endovascular stent-graft extension. Postoperative outcomes are very promising with very low reported in-hospital mortality and morbidity. In case this 2-staged-approach fails to stabilize the remaining aorta, a 3-step procedure, namely open thoracoabdominal aortic replacement, is simplified because the anastomosis site has moved distally. Follow-up of all patients, following frozen elephant trunk implantation or distal stent-graft extension, is mandatory, ideally in an outpatient clinic dedicated to the aorta in order to identify disease progression or to detect any complications as soon as possible.
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Objectives: Our aim was to investigate the occurrence and clinical consequence of postoperative in-stent thrombus formation following the frozen elephant trunk (FET) procedure. Methods: Postoperative computed tomography angiography (CTA) scans of all 304 patients following the FET procedure between 04/2014 and 11/2021 were analysed retrospectively. Thrombus size and location were assessed in multiplanar reconstruction using IMPAX EE (Agfa HealthCare N.V., Morstel, Belgium) software. Patients' characteristics and clinical outcomes were evaluated between patients with and without thrombus formation. Results: During the study period, we detected a new postoperative in-stent thrombus in 19 patients (6%). These patients were significantly older (p = 0.009), predominantly female (p = 0.002) and were more commonly treated for aortic aneurysms (p = 0.001). In 15 patients (79%), the thrombi were located in the distal half of the FET stent-graft. Thrombus size was 18.9 mm (first quartile: 12.1; third quartile: 33.2). Distal embolisation occurred in 4 patients (21%) causing one in-hospital death caused by severe visceral ischaemia. Therapeutic anticoagulation was initiated in all patients. Overstenting with a conventional stent-graft placed within the FET stent-graft was the treatment in 2 patients (11%). Outcomes were comparable both groups. Female sex (p = 0.005; OR: 4.289) and an aortic aneurysm (p = 0.023; OR: 5.198) were identified as significant predictors for thrombus development. Conclusion: Postoperative new thrombus formation within the FET stent-graft is a new, rare, but clinically highly relevant event. The embolisation of these thrombi can result in dismal postoperative outcomes. More research is therefore required to better identify patients at risk and improve perioperative treatment.
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Background: Aim of this study was to report and to identify risk factors for distal aortic failure following aortic arch replacement via the frozen elephant trunk (FET) procedure. Methods: One hundred eighty-six consecutive patients underwent the FET procedure for acute and chronic aortic dissection. Our cohort was divided into patients with and without distal aortic failure. Distal aortic failure was defined as: (I) distal aortic reintervention, (II) aortic diameter dilatation to ≥ 6 cm or > 5 mm growth within 6 months, (III) development of a distal stent-graft-induced new entry (dSINE) and/or (IV) aortic-related death. Preoperative, intraoperative, postoperative and aortic morphological data were analyzed. Results: Distal aortic failure occurred in 88 (47.3%) patients. Forty-six (24.7%) required a distal reintervention, aortic diameter dilatation was observed in 9 (4.8%) patients, a dSINE occurred in 22 (11.8%) patients and 11 (6.4%) suffered an aortic-related death. We found no difference in the number of communications between true and false lumen (p = 0.25) but there were significantly more communications between Ishimaru zone 6-8 in the distal aortic failure group (p = 0.01). The volume of the thoracic descending aorta measured preoperatively and postoperatively within 36 months afterward was significantly larger in patients suffering distal aortic failure (p < 0.001; p = 0.011). Acute aortic dissection (SHR 2.111; p = 0.007), preoperative maximum descending aortic diameter (SHR 1.029; p = 0.018) and preoperative maximum aortic diameter at the level of the diaphragm (SHR 1.041; p = 0.012) were identified as risk factors for distal aortic failure. Conclusion: The incidence and risk of distal aortic failure following the FET procedure is high. Especially those patients with more acute and more extensive aortic dissections or larger preoperative descending aortic diameters carry a substantially higher risk of developing distal aortic failure. The prospective of the FET technique as a single-step treatment for aortic dissection seems low and follow-up in dedicated aortic centers is therefore paramount.
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OBJECTIVES: Our aim was to evaluate the mid-term outcomes of bovine pericardial tube graft repair for infectious aortic disease in any aortic segment. METHODS: Between May 2015 and July 2020, 45 patients were treated for infectious aortic disease of the native (n = 9) aorta or after (endo-)graft (n = 36) implantation with bovine pericardial tube grafts. Clinical, infectious details, outcomes and follow-up data were evaluated. RESULTS: All aortic segments underwent pericardial tube graft or bifurcational replacement: the aortic root (n = 12, 27%), ascending aorta (n = 18, 40%), aortic arch (n = 7, 16%), descending aorta (n = 5, 11%), thoraco-abdominal aorta (n = 6, 13%) and abdominal aorta (n = 18, 40%) including the iliac arteries (n = 14, 31%). Organ fistulation (n = 15, 33%) was the most common underlying pathology. Seven patients (16%) expired in-hospital secondary to ongoing sepsis (n = 5, 11%), respiratory failure (n = 1, 2%) and unknown cause (n = 1, 2%). A fungal infection was predictive for in-hospital mortality (P = 0.026, odds ratio: 19.470). After a median follow-up of 11 [first quartile: 2, third quartile 26] months, 9 additional patients (20%) expired and 1 patient developed a postoperative spondylodiscitis at the level of the aortic tube graft. Hence, freedom from proven aortic graft re-infection was 98%. CONCLUSIONS: Orthotopic aortic reconstruction using bovine pericardial tube grafts to treat infectious aortic disease is possible in any aortic segment. Organ fistulation is a frequently observed disease mechanism requiring concomitant treatment. Granted, the early attrition rate is substantial, but after the initial period, both survival and freedom from re-infection appear encouraging.
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Doenças da Aorta , Implante de Prótese Vascular , Animais , Aorta Abdominal , Aorta Torácica/cirurgia , Doenças da Aorta/cirurgia , Implante de Prótese Vascular/efeitos adversos , Bovinos , Humanos , Artéria Ilíaca , Resultado do Tratamento , Procedimentos Cirúrgicos VascularesRESUMO
OBJECTIVES: To evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on acute and elective thoracic and abdominal aortic procedures. METHODS: Forty departments shared their data on acute and elective thoracic and abdominal aortic procedures between January and May 2020 and January and May 2019 in Europe, Asia and the USA. Admission rates as well as delay from onset of symptoms to referral were compared. RESULTS: No differences in the number of acute thoracic and abdominal aortic procedures were observed between 2020 and the reference period in 2019 [incidence rates ratio (IRR): 0.96, confidence interval (CI) 0.89-1.04; P = 0.39]. Also, no difference in the time interval from acute onset of symptoms to referral was recorded (<12 h 32% vs > 12 h 68% in 2020, < 12 h 34% vs > 12 h 66% in 2019 P = 0.29). Conversely, a decline of 35% in elective procedures was seen (IRR: 0.81, CI 0.76-0.87; P < 0.001) with substantial differences between countries and the most pronounced decline in Italy (-40%, P < 0.001). Interestingly, in Switzerland, an increase in the number of elective cases was observed (+35%, P = 0.02). CONCLUSIONS: There was no change in the number of acute thoracic and abdominal aortic cases and procedures during the initial wave of the COVID-19 pandemic, whereas the case load of elective operations and procedures decreased significantly. Patients with acute aortic syndromes presented despite COVID-19 and were managed according to current guidelines. Further analysis is required to prove that deferral of elective cases had no impact on premature mortality.
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COVID-19 , Pandemias , Ásia , Procedimentos Cirúrgicos Eletivos , Europa (Continente) , Humanos , Itália , SARS-CoV-2 , SuíçaRESUMO
BACKGROUND: Unilateral or very asymmetric upper limb tremors with a jerky appearance are poorly investigated. Their clinical classification is an unsolved problem because their classification as essential tremor versus dystonic tremor is uncertain. To avoid misclassification as essential tremor or premature classification as dystonic tremor, the term indeterminate tremor was suggested. OBJECTIVES: The aim of this study was to characterize this tremor subgroup electrophysiologically and evaluate whether diagnostically meaningful electrophysiological differences exist compared to patients with essential tremor and dystonic tremor. METHODS: We enrolled 29 healthy subjects and 64 patients with tremor: 26 with dystonic tremor, 23 with essential tremor, and 15 patients with upper limb tremor resembling essential tremor but was unusually asymmetric and jerky (indeterminate tremor). We investigated the somatosensory temporal discrimination threshold, the short-interval intracortical inhibition, and the cortical plasticity by paired associative stimulation. RESULTS: Somatosensory temporal discrimination threshold was significantly increased in patients with dystonic tremor and indeterminate tremor, but it was normal in the essential tremor patients and healthy controls. Significant differences in short-interval intracortical inhibition and paired associative stimulation were not found among the three patient groups and controls. CONCLUSION: These results indicate that indeterminate tremor, as defined in this study, shares electrophysiological similarities with dystonic tremor rather than essential tremor. Therefore, we propose that indeterminate tremor should be considered as a separate clinical entity from essential tremor and that it might be dystonic in nature. Somatosensory temporal discrimination appears to be a useful tool in tremor classification. © 2019 International Parkinson and Movement Disorder Society.
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Distonia/complicações , Distúrbios Distônicos/complicações , Tremor/diagnóstico , Tremor/etiologia , Adulto , Idoso , Diagnóstico Diferencial , Distonia/diagnóstico , Distúrbios Distônicos/diagnóstico , Tremor Essencial/complicações , Tremor Essencial/diagnóstico , Tremor Essencial/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes , Limiar Sensorial/fisiologiaRESUMO
Certain fatty acids and sphingoid bases found at mucosal surfaces are known to have antibacterial activity and are thought to play a more direct role in innate immunity against bacterial infections. Herein, we analysed the antibacterial activity of sphingolipids, including the sphingoid base sphingosine as well as short-chain C6 and long-chain C16-ceramides and azido-functionalized ceramide analogs against pathogenic Neisseriae. Determination of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) demonstrated that short-chain ceramides and a ω-azido-functionalized C6-ceramide were active against Neisseria meningitidis and N. gonorrhoeae, whereas they were inactive against Escherichia coli and Staphylococcus aureus. Kinetic assays showed that killing of N. meningitidis occurred within 2 h with ω-azido-C6-ceramide at 1 X the MIC. Of note, at a bactericidal concentration, ω-azido-C6-ceramide had no significant toxic effect on host cells. Moreover, lipid uptake and localization was studied by flow cytometry and confocal laser scanning microscopy (CLSM) and revealed a rapid uptake by bacteria within 5 min. CLSM and super-resolution fluorescence imaging by direct stochastic optical reconstruction microscopy demonstrated homogeneous distribution of ceramide analogs in the bacterial membrane. Taken together, these data demonstrate the potent bactericidal activity of sphingosine and synthetic short-chain ceramide analogs against pathogenic Neisseriae.
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Antibacterianos/farmacologia , Ceramidas/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria meningitidis/efeitos dos fármacos , Esfingolipídeos/farmacologia , Esfingosina/farmacologia , Transporte Biológico/fisiologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Citometria de Fluxo , Células HEK293 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Microscopia Confocal , Staphylococcus aureus/efeitos dos fármacosRESUMO
Sphingolipids are major components of the plasma membrane. In particular, ceramide serves as an essential building hub for complex sphingolipids, but also as an organizer of membrane domains segregating receptors and signalosomes. Sphingomyelin breakdown as a result of sphingomyelinase activation after ligation of a variety of receptors is the predominant source of ceramides released at the plasma membrane. This especially applies to T lymphocytes where formation of ceramide-enriched membrane microdomains modulates TCR signaling. Because ceramide release and redistribution occur very rapidly in response to receptor ligation, novel tools to further study these processes in living T cells are urgently needed. To meet this demand, we synthesized nontoxic, azido-functionalized ceramides allowing for bio-orthogonal click-reactions to fluorescently label incorporated ceramides, and thus investigate formation of ceramide-enriched domains. Azido-functionalized C6-ceramides were incorporated into and localized within plasma membrane microdomains and proximal vesicles in T cells. They segregated into clusters after TCR, and especially CD28 ligation, indicating efficient sorting into plasma membrane domains associated with T cell activation; this was abolished upon sphingomyelinase inhibition. Importantly, T cell activation was not abrogated upon incorporation of the compound, which was efficiently excluded from the immune synapse center as has previously been seen in Ab-based studies using fixed cells. Therefore, the functionalized ceramides are novel, highly potent tools to study the subcellular redistribution of ceramides in the course of T cell activation. Moreover, they will certainly also be generally applicable to studies addressing rapid stimulation-mediated ceramide release in living cells.
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Azidas/metabolismo , Microdomínios da Membrana/metabolismo , Microscopia de Fluorescência/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Esfingolipídeos/metabolismo , Linfócitos T/metabolismo , Azidas/química , Células Cultivadas , Humanos , Ativação Linfocitária , Transporte Proteico , Agregação de Receptores , Transdução de Sinais , Esfingolipídeos/química , Linfócitos T/imunologiaRESUMO
OBJECTIVE: Because asthma disproportionately affects minorities, we evaluated the effects of parent mentors (PMs) on asthma outcomes in minority children. METHODS: This randomized, controlled trial allocated minority asthmatic children to the PM intervention or traditional asthma care. Intervention families were assigned PMs (experienced parents of asthmatic children who received specialized training). PMs met monthly with children and families at community sites, phoned parents monthly, and made home visits. Ten asthma outcomes and costs were monitored for 1 year. Outcomes were examined by using both intention-to-treat analyses and stratified analyses for high participants (attending >or=25% of community meetings and completing >or=50% of PM phone interactions). RESULTS: Patients were randomly assigned to PMs (n = 112) or the control group (n = 108). In intention-to-treat analyses, intervention but not control children experienced significantly reduced rapid-breathing episodes, asthma exacerbations, and emergency department (ED) visits. High participants (but not controls or low participants) experienced significantly reduced wheezing, asthma exacerbations, and ED visits and improved parental efficacy in knowing when breathing problems are controllable at home. Mean reductions in missed parental work days were greater for high participants than controls. The average monthly cost per patient for the PM program was $60.42, and net savings of $46.16 for high participants. CONCLUSIONS: For asthmatic minority children, PMs can reduce wheezing, asthma exacerbations, ED visits, and missed parental work days while improving parental self-efficacy. These outcomes are achieved at a reasonable cost and with net cost savings for high participants. PMs may be a promising, cost-effective means for reducing childhood asthma disparities.