Proteases Inhibition Assessment on PC12 and NGF Treated Cells after Oxygen and Glucose Deprivation Reveals a Distinct Role for Aspartyl Proteases

Hypoxia is a severe stressful condition and induces cell death leading to neuronal loss both to the developing and adult nervous system. Central theme to cellular death is the activation of different classes of proteases such as caspases calpains and cathepsins. In the present study we investigated the involvement of these proteases, in the hypoxia-induced PC12 cell death. Rat PC12 is a model cell line for experimentation relevant to the nervous system and several protocols have been developed for either lethal hypoxia (oxygen and glucose deprivation OGD) or ischemic preconditioning (IPS). Nerve Growth Factor (NGF) treated PC12 differentiate to a sympathetic phenotype, expressing neurites and excitability. Lethal hypoxia was established by exposing undifferentiated and NGF-treated PC12 cells to a mixture of N2/CO2 (93:5%) in DMEM depleted of glucose and sodium pyruvate for 16 h. The involvement of caspases, calpains and lysosomal cathepsins D and E to the cell death induced by lethal OGD was investigated employing protease specific inhibitors such as z-VAD-fmk for the caspases, MDL28170 for the calpains and pepstatin A for the cathepsins D and E. Our findings show that pepstatin A provides statistically significant protection from cell death of both naive and NGF treated PC12 cells exposed to lethal OGD. We propose that apart from the established processes of apoptosis and necrosis that are integral components of lethal OGD, the activation of cathepsins D and E launches additional cell death pathways in which these proteases are key partners

The effect of biologic agents currently used for rheumatoid arthritis on the central nervous system of healthy rats

The aim of this study was to investigate the development of behavioral and memory disorders on healthy adult rats, after chronic, systematic administration of methotrexate and the biologic agents, Tocilizumab (anti-IL6) and Infliximab (anti-TNFa), that are used for Rheumatoid Arthritis. 35 adult male Wistar rats, 12 weeks old, were used in this study. The rats were divided into 5 groups (n=7): a control group (CTRL), which was submitted to tests without receiving any drug, a placebo group (PLC) which received normal saline (i.p.), a methotrexate group (MTX) receiving 0.25mg/kg of the drug (i.p.), an infliximab group (INFL) receiving 6mg/kg of the drug (i.p.), and a tocilizumab group (TCZ) receiving 8mg/kg of the drug (i.p.). The drug infusion was performed weekly. After 30 days of drug administration, behavioral tests were performed to assess the rats’ stress levels and memory. The performed behavioral tests were (1) the Elevated-plus maze test, (2) the Elevated-zero maze test and (3) the Olfactory social memory test. The results were analyzed using Oneway-ANOVA and Kruskal-Wallis tests through SPSS 25.0. The MTX group spent significantly less time in the open arms of the mazes, compared to the CTRL group (P<0.001) and the PLC group (p=0.05), and needed less time during the second encounter compared to the first, when assessed in the olfactory social memory test (p=0.002). The TCZ and INFL groups spent more time in the open areas of both mazes compared to PLC and MTX groups (p=0.033). Based on the results of this study, the administration of biologic agents improves stress levels and shows a potentially anxiolytic effect, without significantly affecting memory

Validation of the Surgical Outcome Risk Tool (SORT) and SORT v2 for Predicting Postoperative Mortality in Patients with Pancreatic Cancer Undergoing Surgery

BACKGROUND: Pancreatic cancer surgery is related to significant mortality, thus necessitating the accurate assessment of perioperative risk to enhance treatment decision making. A Surgical Outcome Risk Tool (SORT) and SORT v2 have been developed to provide enhanced risk stratification. Our aim was to validate the accuracy of SORT and SORT v2 in pancreatic cancer surgery. METHOD: Two hundred and twelve patients were included and underwent pancreatic surgery for cancer. The surgeries were performed by a single surgical team in a single tertiary hospital (2016-2022). We assessed a total of four risk models: SORT, SORT v2, POSSUM (Physiology and Operative Severity Score for the enumeration of Mortality and Morbidity), and P-POSSUM (Portsmouth-POSSUM). The accuracy of the model was evaluated using an observed-to-expected (O:E) ratio and the area under the curve (AUC). RESULTS: The 30-day mortality rate was 3.3% (7 patients). Both SORT and SORT v2 demonstrated excellent discrimination traits (AUC: 0.98 and AUC: 0.98, respectively) and provided the best-performing calibration in the total analysis. However, both tools underestimated the 30-day mortality. Furthermore, both reported a high level of calibration and discrimination in the subgroup of patients undergoing pancreaticoduodenectomy, with previous ERCP, and CA19-9 ≥ 500 U/mL. CONCLUSIONS: SORT and SORT v2 are efficient risk-assessment tools that should be adopted in the perioperative pathway, shared decision-making (SDM) process, and counseling of patients with pancreatic cancer undergoing surgery

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Inadvertent injection of succinylcholine as an epidural test dose

AbstractBackground and objectivesEpidural action of neuromuscular blocking agents could be explained under the light of their physicochemical characteristics and epidural space properties. In the literature there are few cases of accidental neuromuscular agent's epidural administration, manifesting mainly with neuromuscular blockade institution or fasciculations.Case reportWe report a case of accidental succinylcholine administration as an epidural test dose, in a female patient undergoing scheduled laparotomy, under combined general and epidural anesthesia. Approximately 2min after the succinylcholine injection the patient complained for shortness of breath, while mild fasciculations appeared in her trunk and face, managed by immediate general anesthesia institution. With the exception of a relatively longer duration of neuromuscular blockade compared with intravenous administration, no neurological or cardiovascular sequelae or other symptoms of local or systemic toxicity were observed.ConclusionsOral administration of diazepam seems to lessen the adverse effects from accidental epidural administration of succinylcholine. The meticulous and discriminative labeling of syringes, as well as keeping persistent cautions during all anesthesia procedures remains of crucial importance

Inadvertent injection of succinylcholine as an epidural test dose

Background and objectives: Epidural action of neuromuscular blocking agents could be explained under the light of their physicochemical characteristics and epidural space properties. In the literature there are few cases of accidental neuromuscular agent's epidural administration, manifesting mainly with neuromuscular blockade institution or fasciculations. Case report: We report a case of accidental succinylcholine administration as an epidural test dose, in a female patient undergoing scheduled laparotomy, under combined general and epidural anesthesia. Approximately 2 min after the succinylcholine injection the patient complained for shortness of breath, while mild fasciculations appeared in her trunk and face, managed by immediate general anesthesia institution. With the exception of a relatively longer duration of neuromuscular blockade compared with intravenous administration, no neurological or cardiovascular sequelae or other symptoms of local or systemic toxicity were observed. Conclusions: Oral administration of diazepam seems to lessen the adverse effects from accidental epidural administration of succinylcholine. The meticulous and discriminative labeling of syringes, as well as keeping persistent cautions during all anesthesia procedures remains of crucial importance. Resumo: Justificativa e objetivos: A ação epidural de agentes bloqueadores neuromusculares pode ser explicadas à luz de suas características físico-químicas e propriedades do espaço epidural. Na literatura existem poucos casos sobre a administração acidental em espaço epidural de agente neuromuscular, manifestando-se principalmente com a instituição de bloqueio neuromuscular ou fasciculações. Relato de caso: Relatamos um caso de administração acidental de succinylcholine como uma dose teste epidural em uma paciente submetida à laparotomia programada, sob anestesia combinada geral e peridural. Aproximadamente dois minutos após a injeção de succinylcholine, a paciente queixou-se de falta de ar, enquanto fasciculações leves apareceram em seu tronco e rosto, tratadas com a instituição imediata de anestesia geral. Exceto pela duração relativamente longa do bloqueio neuromuscular em comparação com a administração intravenosa, sequelas neurológicas ou cardiovasculares ou outros sintomas de toxicidade local ou sistémica não foram observados. Conclusões: A administração oral de diazepam parece diminuir os efeitos adversos da administração epidural acidental de succinilcolina. A meticulosidade e discriminação dos rótulos das seringas, bem como os cuidados persistentes mantidos durante todos os procedimentos de anestesia continuam sendo de importância crucial. Keywords: Succinylcholine, Epidural administration, Accidental, Neuromuscular blocking agents, Fasciculations, Diazepam, Palavras-chave: Succinilcolina, Administração epidural, Acidental, Agentes bloqueadores neuromusculares, Fasciculações, Diazepa

Inadvertent injection of succinylcholine as an epidural test dose

Abstract Background and objectives: Epidural action of neuromuscular blocking agents could be explained under the light of their physicochemical characteristics and epidural space properties. In the literature there are few cases of accidental neuromuscular agent's epidural administration, manifesting mainly with neuromuscular blockade institution or fasciculations. Case report: We report a case of accidental succinylcholine administration as an epidural test dose, in a female patient undergoing scheduled laparotomy, under combined general and epidural anesthesia. Approximately 2 min after the succinylcholine injection the patient complained for shortness of breath, while mild fasciculations appeared in her trunk and face, managed by immediate general anesthesia institution. With the exception of a relatively longer duration of neuromuscular blockade compared with intravenous administration, no neurological or cardiovascular sequelae or other symptoms of local or systemic toxicity were observed. Conclusions: Oral administration of diazepam seems to lessen the adverse effects from accidental epidural administration of succinylcholine. The meticulous and discriminative labeling of syringes, as well as keeping persistent cautions during all anesthesia procedures remains of crucial importance

The Immunomodulatory Effect of Various Anaesthetic Practices in Patients Undergoing Gastric or Colon Cancer Surgery: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Background: Gastric and colorectal carcinomas are associated with increased mortality and an increasing incidence worldwide, while surgical resection remains the primary approach for managing these conditions. Emerging evidence suggests that the immunosuppression induced by the chosen anaesthesia approach, during the perioperative period, can have a significant impact on the immune system and consequently the prognosis of these patients. Aim: This systematic review aims to comprehensively summarize the existing literature on the effects of different anaesthesia techniques on immune system responses, focusing on cellular immunity in patients undergoing the surgical removal of gastric or colorectal carcinomas. There is no meta-analysis investigating anaesthesia’s impact on immune responses in gastric and colorectal cancer surgery. Anaesthesia is a key perioperative factor, yet its significance in this area has not been thoroughly investigated. The clinical question of how the anaesthetic technique choice affects the immune system and prognosis remains unresolved. Methods: Major electronic databases were searched up to February 2023 to May 2023 for relevant randomized controlled trials (RCTs). The study protocol has been registered with Prospero (CRD42023441383). Results: Six RCTs met the selection criteria. Among these, three RCTs investigated the effects of volatile-based anaesthesia versus total intravenous anaesthesia (TIVA), while the other three RCTs compared general anaesthesia alone to the combination of general anaesthesia with epidural anaesthesia. According to our analysis, there were no significant differences between TIVA and volatile-based anaesthesia, in terms of primary and secondary endpoints. The combination of general anaesthesia with epidural analgesia had a positive impact on NK cell counts (SMD 0.61, 95% CI 0.28 to 0.94, I2 0.0% at 24 and 72 h after the operation), as well as on CD4+ cells (SMD 0.59, CI 95% 0.26 to 0.93, I2 0.0%). However, the CD3+ cell count, CD4+/CD8+ ratio, neutrophil-to-lymphocyte ratio (NLR), IL-6 and TNF-α levels remained unaffected. Conclusions: The combination of epidural analgesia and general anaesthesia can potentially improve, postoperatively, the NK cell count and CD4+ cell levels in gastric or colon surgery patients. However, the specific impact of TIVA or volatile-based anaesthesia remains uncertain. To gain a better understanding of the immunomodulatory effects of anaesthesia, in this particular group of cancer patients, further well-designed trials are required

Local Wound Infiltration for Thyroidectomized Patients in the Era of Multimodal Analgesia

The first few hours following thyroidectomy are the most crucial for pain management. Adequate postoperative pain control, reduction in opioid abuse and the possibility of implementing one-day operations are the considered parameters when developing the postoperative analgesic strategy. A study of the available literature was conducted, exploring the efficacy of (open) thyroidectomy wound infiltration. Seventeen full-text RCTs were extracted. Local anesthetics and non-steroidal anti-inflammatory drugs were infiltrated. Emphasis was given to postoperative pain scores and requirements for rescue analgesia with opioids. Most authors agree that local wound infiltration for thyroidectomized patients is effective in the management of postoperative pain parameters. In the era of multimodal analgesia, thyroidectomy wound infiltration could represent an essential adjunct contributing to lower VAS scores and reduced opioid requirements