RESUMEN
Background: Patient-Specific Surgical Guides (PSSGs) are advocated for reducing radiation exposure, operation time and enhancing precision in surgery. However, existing accuracy assessments are limited to specific surgeries, leaving uncertainties about variations in accuracy across different anatomical sites, three-dimensional (3D) printing technologies and manufacturers (traditional vs. printed at the point of care). This study aimed to evaluate PSSGs accuracy in traumatology and orthopaedic surgery, considering anatomical regions, printing methods and manufacturers. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Studies were eligible if they (1) assessed the accuracy of PSSGs by comparing preoperative planning and postoperative results in at least two different planes (2) used either computer tomography or magnetic resonance imaging (3) covered the field of orthopaedic surgery or traumatology and (4) were available in English or German language. The 'Quality Assessment Tool for Quantitative Studies' was used for methodological quality assessment. Descriptive statistics, including mean, standard deviation, and ranges, are presented. A random effects meta-analysis was performed to determine the pooled mean absolute deviation between preoperative plan and postoperative result for each anatomic region (shoulder, hip, spine, and knee). Results: Of 4212 initially eligible studies, 33 were included in the final analysis (8 for shoulder, 5 for hip, 5 for spine, 14 for knee and 1 for trauma). Pooled mean deviation (95% confidence interval) for total knee arthroplasty (TKA), total shoulder arthroplasty (TSA), total hip arthroplasty (THA) and spine surgery (pedicle screw placement during spondylodesis) were 1.82° (1.48, 2.15), 2.52° (1.9, 3.13), 3.49° (3.04, 3.93) and 2.67° (1.64, 3.69), respectively. Accuracy varied between TKA and THA and between TKA and TSA. Conclusion: Accuracy of PSSGs depends on the type of surgery but averages around 2-3° deviation from the plan. The use of PSSGs might be considered for selected complex cases. Level of Evidence: Level 3 (meta-analysis including Level 3 studies).
RESUMEN
Emergency general surgeons often provide care to severely ill patients requiring surgical interventions and intensive support. One of the primary drivers of morbidity and mortality is perioperative bleeding. In general, when addressing life threatening haemorrhage, blood transfusion can become an essential part of overall resuscitation. However, under all circumstances, indications for blood transfusion must be accurately evaluated. When patients decline blood transfusions, regardless of the reason, surgeons should aim to provide optimal care and respect and accommodate each patient's values and target the best outcome possible given the patient's desires and his/her clinical condition. The aim of this position paper was to perform a review of the existing literature and to provide comprehensive recommendations on organizational, surgical, anaesthetic, and haemostatic strategies that can be used to provide optimal peri-operative blood management, reduce, or avoid blood transfusions and ultimately improve patient outcomes.
Asunto(s)
Transfusión Sanguínea , Consenso , Humanos , Transfusión Sanguínea/métodos , Pérdida de Sangre Quirúrgica/prevención & control , Cirugía General , Cirugía de Cuidados IntensivosRESUMEN
BACKGROUND: It is important to learn more about the prevalence, severity and characteristics (i.e., which cognitive abilities are especially affected) of cognitive impairment in kidney transplant patients. Furthermore, the impact of living vs. deceased donor renal transplantation on cognitive outcome in this patient group needs further studies. METHODS: Fifty-nine patients (43 men, age 55 ± 13 years) who received a deceased donor or living donor kidney transplant, completed a comprehensive neuropsychological test assessment. Neuropsychological tests explored the cognitive domains of verbal and visual memory, attention, and executive functions. RESULTS: Fifteen percent of the patients had mild, 25% moderate, and 15% severe cognitive impairment. The level of domain-specific cognitive deficit differed between verbal memory, attention, and executive functions (χ2(2) = 7.11, p = 0.029). On average, patients showed the highest deficit in executive functions, and the lowest deficit in verbal memory. Patients who received a kidney graft from a deceased donor were more likely to have a cognitive impairment than those who received a kidney graft from a living donor (OR = 3.03, 95% CI [0.99,9.32], Wald χ2(1) = 3.74, p = 0.053). This effect was independent of time on dialysis as well as of creatinine levels, or creatinine clearance. CONCLUSIONS: Our results show that in kidney transplant patients with cognitive impairment, the cognitive domain of executive functions is the most affected one. This might be detrimental for quality of life. The fact that patients who received living donor kidneys seem to do better in terms of cognition than patients with deceased donor kidneys deserves more attention in future research.
RESUMEN
OBJECTIVES: Data regarding the occurrence of complications specifically during pediatric anesthesia for endoscopic procedures is limited. By evaluating such data, factors could be identified to assure proper staffing and preparation to minimize adverse events and improve patient safety during flexible endoscopy. METHODS: This retrospective cohort study included children undergoing anesthesia for gastroscopy, colonoscopy, bronchoscopy, or combined endoscopic procedures over 10-year period. The primary study aim was to evaluate the incidence of complications and identify risk factors for adverse events. RESULTS: Overall, 2064 endoscopic procedures including 1356 gastroscopies (65.7%), 93 colonoscopies (4.5%), 235 bronchoscopies (11.4%), and 380 combined procedures (18.4%) were performed. Of the 1613 patients, 151 (7.3%) patients exhibited an adverse event, with respiratory complications being the most common (65 [3.1%]). Combination of gastrointestinal endoscopies did not lead to an increased adverse event rate (gastroscopy: 5.5%, colonoscopy: 3.2%). Diagnostic endoscopy as compared to interventional had a lower rate. If bronchoscopy was performed, the rate was similar to that of bronchoscopy alone (19.5% vs. 20.4%). Age < 5.8 years or body weight less than 20 kg, bronchoscopy, American Society of Anesthesiologists status ≥ 2 or pre-existing anesthesia-relevant diseases, and urgency of the procedure were independent risk factors for adverse events. For each risk factor, the risk for events increased 2.1-fold [1.8-2.4]. CONCLUSIONS: This study identifies multiple factors that increase the rate of adverse events associated anesthesia-based endoscopy. Combined gastrointestinal procedures did not increase the risk for adverse events while combination of bronchoscopy to gastrointestinal endoscopy showed a similar risk as bronchoscopy alone.
Asunto(s)
Broncoscopía , Colonoscopía , Humanos , Estudios Retrospectivos , Factores de Riesgo , Niño , Femenino , Masculino , Preescolar , Lactante , Broncoscopía/efectos adversos , Broncoscopía/métodos , Adolescente , Colonoscopía/efectos adversos , Colonoscopía/métodos , Colonoscopía/estadística & datos numéricos , Incidencia , Anestesia/efectos adversos , Anestesia/métodos , Gastroscopía/efectos adversos , Gastroscopía/métodos , Endoscopía Gastrointestinal/efectos adversos , Endoscopía Gastrointestinal/métodos , Endoscopía Gastrointestinal/estadística & datos numéricosRESUMEN
Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient's clinical condition, and the host's immune status should be assessed continuously to optimize the management of patients with complicated IAIs.
Asunto(s)
Infecciones Intraabdominales , Humanos , Infecciones Intraabdominales/tratamiento farmacológico , Factores de Riesgo , Antibacterianos/uso terapéuticoRESUMEN
BACKGROUND: Postoperative paralytic ileus (POI) is a significant concern following gastrointestinal tumor surgery. Effective preventive and therapeutic strategies are crucial but remain elusive. Current evidence from randomized-controlled trials on pharmacological interventions for prevention or treatment of POI are systematically reviewed to guide clinical practice and future research. MATERIALS AND METHODS: Literature was systematically searched for prospective randomized-controlled trials testing pharmacological interventions for prevention or treatment of POI after gastrointestinal tumor surgery. Meta-analysis was performed using a random effects model to determine risk ratios and mean differences with 95% CI. Risk of bias and evidence quality were assessed. RESULTS: Results from 55 studies, involving 5078 patients who received experimental interventions, indicate that approaches of opioid-sparing analgesia, peripheral opioid antagonism, reduction of sympathetic hyperreactivity, and early use of laxatives effectively prevent POI. Perioperative oral Alvimopan or intravenous administration of Lidocaine or Dexmedetomidine, while safe regarding cardio-pulmonary complications, demonstrated effectiveness concerning various aspects of postoperative bowel recovery [Lidocaine: -5.97 (-7.20 to -4.74)h, P <0.0001; Dexmedetomidine: -13.00 (-24.87 to -1.14)h, P =0.03 for time to first defecation; Alvimopan: -15.33 (-21.22 to -9.44)h, P <0.0001 for time to GI-2 ] and length of hospitalization [Lidocaine: -0.67 (-1.24 to -0.09)d, P =0.02; Dexmedetomidine: -1.28 (-1.96 to -0.60)d, P =0.0002; Alvimopan: -0.58 (-0.84 to -0.32)d, P <0.0001] across wide ranges of evidence quality. Perioperative nonopioid analgesic use showed efficacy concerning bowel recovery as well as length of hospitalization [-1.29 (-1.95 to -0.62)d, P =0.0001]. Laxatives showed efficacy regarding bowel movements, but not food tolerance and hospitalization. Evidence supporting pharmacological treatment for clinically evident POI is limited. Results from one single study suggest that Neostigmine reduces time to flatus and accelerates bowel movements [-37.06 (-40.26 to -33.87)h, P <0.0001 and -42.97 (-47.60 to -38.35)h, P <0.0001, respectively] with low evidence quality. CONCLUSION: Current evidence concerning pharmacological prevention and treatment of POI following gastrointestinal tumor surgery is limited. Opioid-sparing concepts, reduction of sympathetic hyperreactivity, and laxatives should be implemented into multimodal perioperative approaches.
Asunto(s)
Neoplasias Gastrointestinales , Seudoobstrucción Intestinal , Complicaciones Posoperatorias , Humanos , Seudoobstrucción Intestinal/prevención & control , Seudoobstrucción Intestinal/etiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Neoplasias Gastrointestinales/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , PiperidinasRESUMEN
BACKGROUND: Laparoscopy is widely adopted across nearly all surgical subspecialties in the elective setting. Initially finding indication in minor abdominal emergencies, it has gradually become the standard approach in the majority of elective general surgery procedures. Despite many technological advances and increasing acceptance, the laparoscopic approach remains underutilized in emergency general surgery and in abdominal trauma. Emergency laparotomy continues to carry a high morbidity and mortality. In recent years, there has been a growing interest from emergency and trauma surgeons in adopting minimally invasive surgery approaches in the acute surgical setting. The present position paper, supported by the World Society of Emergency Surgery (WSES), aims to provide a review of the literature to reach a consensus on the indications and benefits of a laparoscopic-first approach in patients requiring emergency abdominal surgery for general surgery emergencies or abdominal trauma. METHODS: This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of 54 experts then critically revised the manuscript and discussed it in detail, to develop a consensus on a position statement. RESULTS: A total of 323 studies (systematic review and meta-analysis, randomized clinical trial, retrospective comparative cohort studies, case series) have been selected from an initial pool of 7409 studies. Evidence demonstrates several benefits of the laparoscopic approach in stable patients undergoing emergency abdominal surgery for general surgical emergencies or abdominal trauma. The selection of a stable patient seems to be of paramount importance for a safe adoption of a laparoscopic approach. In hemodynamically stable patients, the laparoscopic approach was found to be safe, feasible and effective as a therapeutic tool or helpful to identify further management steps and needs, resulting in improved outcomes, regardless of conversion. Appropriate patient selection, surgeon experience and rigorous minimally invasive surgical training, remain crucial factors to increase the adoption of laparoscopy in emergency general surgery and abdominal trauma. CONCLUSIONS: The WSES expert panel suggests laparoscopy as the first approach for stable patients undergoing emergency abdominal surgery for general surgery emergencies and abdominal trauma.
Asunto(s)
Traumatismos Abdominales , Laparoscopía , Guías de Práctica Clínica como Asunto , Humanos , Abdomen , Traumatismos Abdominales/cirugía , Urgencias Médicas , Laparoscopía/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios RetrospectivosRESUMEN
Roux-en-Y gastric bypass (RYGB) in patients with body mass index (BMI) ≥ 50 kg/m2 is a challenging procedure and BMI ≥ 50 kg/m2 has been identified as independent risk factor for postoperative complications and increased morbidity in previous studies. The objective of the present study was to assess whether a BMI ≥ 50 kg/m2 and various established risk factors maintain their significance in patients undergoing fully robotic RYGB (rRYGB). A single-center analysis of prospectively collected data of 113 consecutive patients undergoing standardized rRYGB with robotic stapling technique and hand-sewn gastrojejunostomy using the daVinci Xi system. Surgical outcomes were analyzed considering a number of individual perioperative risk factors including BMI ≥ 50 kg/m2. The mean BMI of the total cohort was 50.6 ± 5.5 kg/m2 and 63.7% of patients had a BMI ≥ 50 kg/m2. There were no major surgical and perioperative complications in patients with BMI ≥ 50 kg/m2 as well as in those with BMI < 50 kg/m2 after rRYGB. We identified female sex and surgeon experience but neither body weight, BMI, metabolic disorders, ASA nor EOSS scores as independent factors for shorter operation times (OT) in multivariate analyses. Complication rates and length of hospital stay (LOS) did not significantly differ between patients with potential risk factors and those without. rRYGB is a safe procedure in both, patients with BMI ≥ 50 kg/m2 and with BMI < 50 kg/m2. Higher body weight and BMI did affect neither OT nor LOS. A fully robotic approach for RYGB might help to overcome "traditional" risk factors identified in conventional laparoscopic bariatric surgery. However, larger and prospective studies are necessary to confirm these results.
Asunto(s)
Derivación Gástrica , Laparoscopía , Obesidad Mórbida , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Femenino , Derivación Gástrica/efectos adversos , Derivación Gástrica/métodos , Obesidad Mórbida/cirugía , Índice de Masa Corporal , Procedimientos Quirúrgicos Robotizados/métodos , Estudios Prospectivos , Resultado del Tratamiento , Estudios Retrospectivos , Pérdida de Peso , Factores de Riesgo , Laparoscopía/métodosRESUMEN
Enhanced perioperative care protocols become the standard of care in elective surgery with a significant improvement in patients' outcome. The key element of the enhanced perioperative care protocol is the multimodal and interdisciplinary approach targeted to the patient, focused on a holistic approach to reduce surgical stress and improve perioperative recovery. Enhanced perioperative care in emergency general surgery is still a debated topic with little evidence available. The present position paper illustrates the existing evidence about perioperative care in emergency surgery patients with a focus on each perioperative intervention in the preoperative, intraoperative and postoperative phase. For each item was proposed and approved a statement by the WSES collaborative group.
Asunto(s)
Procedimientos Quirúrgicos Electivos , Atención Perioperativa , Humanos , Atención Perioperativa/métodos , Procedimientos Quirúrgicos Electivos/métodosRESUMEN
Antibiotic therapy following surgical perianal abscess drainage is debated, but may be necessary for high-risk patients. Frailty has been shown to increase the risk of unfavorable outcomes in elderly surgical patients. This study aims to identify high-risk patients by retrospectively analyzing a single-center cohort and using a pretherapeutic score to predict the need for postoperative antibiotics and extended nursing care following perianal abscess drainage surgery. The perianal sepsis risk score was developed through univariable and multivariable analysis. Internal validation was assessed using the area under receiver-operating characteristic curve. Elderly, especially frail patients exhibited more severe perianal disease, higher frequency of antibiotic therapy, longer hospitalization, poorer clinical outcomes. Multivariable analysis revealed that scores in the 5-item modified frailty index, severity of local infection, and preoperative laboratory markers of infection independently predicted the need for prolonged hospitalization and anti-infective therapy after abscess drainage surgery. These factors were combined into the perianal sepsis risk score, which demonstrated better predictive accuracy for prolonged hospitalization and antibiotic therapy compared with chronological age or frailty status alone. Geriatric assessments are becoming increasingly important in clinical practice. The perianal sepsis risk score identifies high-risk patients before surgery, enabling early initiation of antibiotic therapy and allocation of additional nursing resources.
RESUMEN
Intra-abdominal infections (IAI) are among the most common global healthcare challenges and they are usually precipitated by disruption to the gastrointestinal (GI) tract. Their successful management typically requires intensive resource utilization, and despite the best therapies, morbidity and mortality remain high. One of the main issues required to appropriately treat IAI that differs from the other etiologies of sepsis is the frequent requirement to provide physical source control. Fortunately, dramatic advances have been made in this aspect of treatment. Historically, source control was left to surgeons only. With new technologies non-surgical less invasive interventional procedures have been introduced. Alternatively, in addition to formal surgery open abdomen techniques have long been proposed as aiding source control in severe intra-abdominal sepsis. It is ironic that while a lack or even delay regarding source control clearly associates with death, it is a concept that remains poorly described. For example, no conclusive definition of source control technique or even adequacy has been universally accepted. Practically, source control involves a complex definition encompassing several factors including the causative event, source of infection bacteria, local bacterial flora, patient condition, and his/her eventual comorbidities. With greater understanding of the systemic pathobiology of sepsis and the profound implications of the human microbiome, adequate source control is no longer only a surgical issue but one that requires a multidisciplinary, multimodality approach. Thus, while any breach in the GI tract must be controlled, source control should also attempt to control the generation and propagation of the systemic biomediators and dysbiotic influences on the microbiome that perpetuate multi-system organ failure and death. Given these increased complexities, the present paper represents the current opinions and recommendations for future research of the World Society of Emergency Surgery, of the Global Alliance for Infections in Surgery of Surgical Infection Society Europe and Surgical Infection Society America regarding the concepts and operational adequacy of source control in intra-abdominal infections.
Asunto(s)
Cavidad Abdominal , Infecciones Intraabdominales , Cirujanos , Femenino , Humanos , MasculinoRESUMEN
Laparotomy incisions provide easy and rapid access to the peritoneal cavity in case of emergency surgery. Incisional hernia (IH) is a late manifestation of the failure of abdominal wall closure and represents frequent complication of any abdominal incision: IHs can cause pain and discomfort to the patients but also clinical serious sequelae like bowel obstruction, incarceration, strangulation, and necessity of reoperation. Previous guidelines and indications in the literature consider elective settings and evidence about laparotomy closure in emergency settings is lacking. This paper aims to present the World Society of Emergency Surgery (WSES) project called ECLAPTE (Effective Closure of LAParoTomy in Emergency): the final manuscript includes guidelines on the closure of emergency laparotomy.
Asunto(s)
Técnicas de Cierre de Herida Abdominal , Hernia Incisional , Humanos , Laparotomía/efectos adversos , Técnicas de Cierre de Herida Abdominal/efectos adversos , Técnicas de Sutura/efectos adversos , Hernia Incisional/etiología , Reoperación/efectos adversosRESUMEN
Many countries are facing an aging population. As people live longer, surgeons face the prospect of operating on increasingly older patients. Traditional teaching is that with older age, these patients face an increased risk of mortality and morbidity, even to a level deemed too prohibitive for surgery. However, this is not always true. An active 90-year-old patient can be much fitter than an overweight, sedentary 65-year-old patient with comorbidities. Recent literature shows that frailty-an age-related cumulative decline in multiple physiological systems, is therefore a better predictor of mortality and morbidity than chronological age alone. Despite recognition of frailty as an important tool in identifying vulnerable surgical patients, many surgeons still shun objective tools. The aim of this position paper was to perform a review of the existing literature and to provide recommendations on emergency laparotomy and in frail patients. This position paper was reviewed by an international expert panel composed of 37 experts who were asked to critically revise the manuscript and position statements. The position paper was conducted according to the WSES methodology. We shall present the derived statements upon which a consensus was reached, specifying the quality of the supporting evidence and suggesting future research directions.
Asunto(s)
Fragilidad , Humanos , Anciano , Anciano de 80 o más Años , Laparotomía , Anciano Frágil , Consenso , ComorbilidadRESUMEN
Acute mesenteric ischemia is a severe illness, which if untreated, rapidly leads to a critical condition with sepsis, multiple organ failure and death in affected patients. The diagnosis and initiation of treatment of acute mesenteric ischemia should be performed as early and expeditiously as possible and follows the principle of the shortest possible time to reperfusion. Otherwise, the outcome of the patient rapidly deteriorates. The treatment algorithm should be adapted to the pathogenesis of the ischemia, the clinical condition and symptoms of the patients. With clinical signs of peritonitis, intestinal gangrene must be assumed and the abdomen should be surgically explored to detect and treat possible foci of sepsis at an early stage. The treatment of acute mesenteric ischemia should always be performed by an interdisciplinary team with all surgical and interventional options for intestinal revascularization as well as comprehensive intensive care medicine according to the standards of the Intestinal Stroke Center described in the literature. A short duration to revascularization and treatment in this interdisciplinary concept improves the outcome of patients with acute mesenteric ischemia. The World Society of Emergency Surgery provides expert consensus-based recommendations for the diagnosis and treatment of acute mesenteric ischemia; however, there is still a significant lack of broad high-quality evidence for this critical illness. Recommendations of the German specialist societies are urgently needed to ensure appropriate care, from the initial diagnostics to treatment and aftercare, for patients with suspected mesenteric ischemia in this country.
Asunto(s)
Isquemia Mesentérica , Humanos , Isquemia Mesentérica/diagnóstico , Isquemia Mesentérica/cirugía , Intestinos/cirugía , Isquemia/diagnóstico , Isquemia/cirugía , Procedimientos Quirúrgicos Vasculares/efectos adversos , Cuidados CríticosRESUMEN
PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.
Asunto(s)
Trastornos Congénitos de Glicosilación , Fosfotransferasas (Fosfomutasas) , Humanos , Trastornos Congénitos de Glicosilación/genética , Trastornos Congénitos de Glicosilación/terapia , Trastornos Congénitos de Glicosilación/metabolismo , Glicosilación , Fosfotransferasas (Fosfomutasas)/genética , Aminoácidos/metabolismo , LípidosRESUMEN
Sigmoid volvulus is a common surgical emergency, especially in elderly patients. Patients can present with a wide range of clinical states: from asymptomatic, to frank peritonitis secondary to colonic perforation. These patients generally need urgent treatment, be it endoscopic decompression of the colon or an upfront colectomy. The World Society of Emergency Surgery united a worldwide group of international experts to review the current evidence and propose a consensus guidelines on the management of sigmoid volvulus.
Asunto(s)
Enfermedades del Colon , Vólvulo Intestinal , Humanos , Anciano , Vólvulo Intestinal/cirugía , Vólvulo Intestinal/complicaciones , Descompresión Quirúrgica , Vértebras Lumbares/cirugía , Enfermedades del Colon/cirugíaRESUMEN
Objective: The pro-inflammatory cytokine interleukin-1ß (IL-1ß) plays a central role in host defense against infections. High systemic IL-1ß levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1ß release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1ß release by human monocytes via nicotinic acetylcholine receptor (nAChR) subunits α7, α9 and/or α10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R). Methods: Different human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1ß was measured in cell culture supernatants. Patch-clamp and intracellular Ca2+ imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain. Results: The inhibitory effect of nAChR agonists on the BzATP-induced IL-1ß release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal via eNOS to inhibit the BzATP-induced IL-1ß release. Moreover, NO donors (SNAP, S-nitroso-N-acetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1ß release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, Xenopus laevis oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification. Conclusion: We provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1ß release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders.
Asunto(s)
Leucocitos Mononucleares , Receptores Purinérgicos P2X7 , Humanos , Ratones , Animales , Interleucina-1beta/metabolismo , Leucocitos Mononucleares/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Monocitos/metabolismo , Adenosina Trifosfato/metabolismo , Óxido Nítrico Sintasa/metabolismoRESUMEN
PURPOSE: The anterolateral ligament (ALL) is an important structure for controlling anterolateral rotatory stability of the knee. Its assessment, however, is difficult using standardized MRI images. The goal of this study was to assess the reliability of judging the integrity of the ALL on multi-planar reformatted (MPR) MRI images and on standard coronal reformatted (SCR) MRI images in knees with an anterior cruciate ligament (ACL) rupture. METHODS: Forty-eight patients (14 females, 34 males, 30 ± 6 years (mean age ± standard deviation)) with acute ACL ruptures (< 2 weeks) and no additional knee injuries (except segond fractures) were included. Images were assessed by two independent raters twice with at least a 2-week interval in between. The assessment was first performed on SCR images and thereafter on MPR images. Images were judged for assessability of the ALL and then the integrity of the ALL was rated. RESULTS: Depending on rater and read, the ALL was judged as "torn" in between 5 (10.4%) and 11 (22.9%) patients out of 48 patients on SCR images. On MRP images, the ALL was judged as "torn" in between 5 (10.4%) and 6 (12.5%) patients out of 48 patients, depending on rater and read. Inter- and intra-rater reliability for the assessment of the ALL using MPR images was "substantial" to "almost perfect". Inter- and intra-rater reliability for the assessment using SCR was "fair" to "substantial". CONCLUSION: MPR images should be used when assessing the integrity of the ALL. Assessment quality is independent of patient positioning during MRI acquisition and the ALL can be displayed in full length on one image. LEVEL OF EVIDENCE: Level III.