Identification of Key Genes Associated with Tumor Microenvironment Infiltration and Survival in Gastric Adenocarcinoma via Bioinformatics Analysis.

OBJECTIVE: Gastric carcinoma (GC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related deaths globally. The tumor microenvironment plays a significant role in the pathogenesis, prognosis, and response to immunotherapy. However, the immune-related molecular mechanisms underlying GC remain elusive. Bioinformatics analysis of the gene expression of GC and paracancerous healthy tissues from the same patient was performed to identify the key genes and signaling pathways, as well as their correlation to the infiltration of the tumor microenvironment (TME) by various immune cells related to GC development. METHODS: We employed GSE19826, a gene expression profile from the Gene Expression Omnibus (GEO), for our analysis. Functional enrichment analysis of Differentially Expressed Genes (DEGs) was conducted using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database. RESULTS: Cytoscape software facilitated the identification of nine hub DEGs, namely, FN1, COL1A1, COL1A2, THBS2, COL3A1, COL5A1, APOE, SPP1, and BGN. Various network analysis algorithms were applied to determine their high connectivity. Among these hub genes, FN1, COL1A2, THBS2, COL3A1, COL5A1, and BGN were found to be associated with a poor prognosis for GC patients. Subsequent analysis using the TIMER database revealed the infiltration status of the TME concerning the overexpression of these six genes. Specifically, the abovementioned genes demonstrated direct correlations with cancer-associated fibroblasts, M1 and M2 macrophages, myeloid-derived suppressor cells, and activated dendritic cells. CONCLUSION: Our findings suggest that the identified hub genes, particularly BGN, FN1, COL1A2, THBS2, COL3A1, and COL5A1, play crucial roles in GC prognosis and TME cell infiltration. This comprehensive analysis enhances our understanding of the molecular mechanisms underlying GC development and may contribute to the identification of potential therapeutic targets and prognostic markers for GC patients.

Efficacy of Granulocyte Colony-Stimulating Factor in Acute on Chronic Liver Failure: A Systematic Review and Survival Meta-Analysis.

BACKGROUND: Acute-on-chronic liver failure (ACLF) mostly occurs when there is an acute insult to the liver in patients with pre-existing liver disease, and it is characterized by a high mortality rate. Various therapeutic approaches have been used thus far, with orthotopic liver transplantation being the only definitive cure. Clinical trials and meta-analyses have investigated the use of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived stem cells. Some studies have suggested that G-CSF may have a significant role in the management and survival of patients with ACLF. However, the results are conflicting, and the efficacy of G-CSF still needs to be confirmed. AIM: The aim was to assess the efficacy of G-CSF in patients with ACLF. METHODS: Electronic databases were searched until May 2023 for randomized controlled trials investigating the use of G-CSF in adult patients with ACLF. Outcome measures were the effects of G-CSF on overall survival, changes in liver disease severity scores, complications of cirrhosis, other G-CSF-related adverse effects, and all-cause mortality. The study's protocol has been registered with Prospero (CRD42023420273). RESULTS: Five double-blind randomized controlled trials involving a total of 421 participants met the inclusion criteria. The use of G-CSF demonstrated a significant effect on overall survival (HR 0.63, 95% CI 0.41 to 0.95, and I2 48%), leading to a decreased mortality (LogOR-0.97, 95% CI -1.57 to -0.37, and I2 37.6%) and improved Model for End-Stage Liver Disease (MELD) scores (SMD -0.87, 95% CI -1.62 to -0.13, and I2 87.3%). There was no correlation between the improvement of the Child-Pugh score and the use of G-CSF(SMD -2.47, 95% CI -5.78 to 0.83, and I2 98.1%). The incidence of complications of cirrhosis did not decrease significantly with G-CSF treatment (rate ratio 0.51, 95% CI 0.26 to 1.01, and I2 90%). A qualitative synthesis showed that the use of G-CSF is safe. CONCLUSIONS: The administration of G-CSF has demonstrated a positive impact on overall survival, liver function, and the MELD score. The presence of heterogeneity in the included studies prohibits conclusive recommendations.

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.

Efficacy and safety of parenteral and local application of tramadol in mandibular third molar extraction: a qualitative systematic review of current evidence.

PURPOSE: To assess the efficacy and safety of perioperative parenteral administration or submucosal infiltration of tramadol for perioperative pain control on the basis of pain intensity or analgesics consumption and perioperative outcomes in mandibular third molar surgery. MATERIAL-METHODS: An electronic database search was conducted up to 10 November 2022 to retrieve all randomized controlled trials (RCTs), assessing the analgesic efficacy of parenteral use of tramadol implemented as an adjunct to local anesthesia or intraoperative sedation/general anesthesia, in surgical extraction of mandibular third molars. Modified Jadad scale and Cochrane bias tool were used for the qualitative appraisal. RESULTS: Nineteen RCTs were selected for qualitative analysis. Nine studies involved intravenous, and 5 intramuscular administration of tramadol, while 5 evaluated submucosal infiltration with tramadol. Intravenous or intramuscular tramadol provided a weaker analgesic effect compared with non-steroidal anti-inflammatory drugs (NSAIDs), while intravenous tramadol induced an enhanced analgesic effect than oral tramadol. Parenteral administration of tramadol improved the quality of postoperative analgesia versus placebo. No notable adverse effects were recorded. CONCLUSIONS: Parenteral or submucosal infiltration of tramadol constitutes an effective and safe alternative analgesic approach in surgical extraction of mandibular third molars, yet the nociceptive effect of this analgesic modality could not supersede that of NSAIDs. TRIAL REGISTRATION: PROSPERO No CRD42021227574.

Efficacy and safety of probiotics in the treatment of irritable bowel syndrome: A systematic review and meta-analysis of randomised clinical trials using ROME IV criteria.

BACKGROUND: Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder which affects a great number of patients globally. Clinical trials and meta-analyses have evaluated different therapies for IBS. Some of them have shown that probiotics play a significant role in the management of IBS-patients. Nevertheless, results are controversial, and the efficacy of the administration of probiotics remains to be confirmed, especially in regard to which type of probiotic-strains are beneficial. AIM: The aim of the present meta-analysis is to assess the efficacy and safety of the administration of probiotics to IBS-patients with a diagnosis based on Rome IV criteria, which is performed for the first time. METHODS: Electronic databases (Pubmed, Scopus and Cochrane) were searched until 26.01.2023 for randomized controlled trials (RCTs) studying the administration of probiotics in adult IBS-patients, who were categorized according to the Rome IV criteria. The risk of bias was assessed using the Cochrane Risk of Bias tool (ROB) 2.0. Weighted and standardized mean difference with the 95% confidence intervals were used for the synthesis of the results. Primary outcomes were the decrease of IBS-Symptom Severity Score (IBS-SSS) and decrease of abdominal pain. The secondary outcomes were the improvement in quality of life (QoL) and the decrease of bloating. Lastly, the adverse effects of probiotics were evaluated. The protocol of the study has been registered at protocols.io (DOI dx.doi.org/10.17504/protocols.io.14egn218yg5d/v1). RESULTS: Six double-blind (N = 970) placebo-control RCTs fulfilled the inclusion criteria and overall, nine different strains of probiotics were examined. No significant reduction in IBS-SSS (WMD -43.2, 95% CI -87.5 to 1.0, I2 = 82.9%) was demonstrated, whereas a significant decrease regarding abdominal pain (SMD -0.94, 95% CI -1.53 to -0.35, I2 = 92,2) was shown. Furthermore, no correlation between improvement of QoL and the use of probiotics (SMD -0.64, 95% CI -1.27 to 0.00, I2 = 93,9%) was shown. However, probiotics were associated with a significant reduction in bloating (SMD -0.28, 95% CI -0.47 to -0.09, I2 = 36,0%). A qualitative synthesis was conducted about adverse events and showed that the use of probiotics' is safe without severe adverse events. CONCLUSIONS: The administration of probiotics to IBS-patients demonstrated a positive effect on pain and bloating, but due to significant heterogeneity and confounding factors, that were not examined in the included studies, a definitive statement cannot be made. Moreover, probiotics did not lead to an improvement in other parameters. There is a need for larger RCTs in IBS-patients diagnosed according to Rome IV (not III) criteria and especially it is essential to be conducted RCTs which examine the administration of specific strains and have similar methodological characteristics.

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.

Effect of common OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 polymorphisms on perioperative analgesic and propofol demands on patients subjected to thyroidectomy surgery.

BACKGROUND: Perioperative anesthetic and/or analgesic demand present considerable variation, and part of that variation appears to be genetic in origin. Here we investigate the impact of common polymorphisms in OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 genes, on the intra-operative consumption of remifentanil and propofol, as well as the postoperative analgesic needs, in patients subjected to thyroidectomy surgery. METHODS: We conducted a prospective cohort study with 90 patients scheduled to undergo elective thyroidectomy, under total intravenous anesthesia achieved by target control infusion (TCI) of propofol and remifentanil. Postoperative analgesics were administered by protocol and on-demand by the individual patient. Genotyping was established by PCR-RFLP methods. Genotyping data, intra-operative hemodynamics, and total consumption of remifentanil and propofol, as well as postoperative analgesic needs and pain perception, were recorded for each individual. RESULTS: Patients with the ABCB1 3435TT genotype appeared to experience significantly less pain within one hour post-operatively, compared to C carriers [mean VAS (SD) = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], a finding limited to those seeking rescue analgesic treatment. Intra-operatively, homozygotes patients for the minor allele of OPRM1 A118G and CYP2B6 G516T appeared to consume less remifentanil [mean (SD) = 9.12 (1.01) vs. 13.53 (5.15), for OPRM1 118GG and A carriers] and propofol [median (range) = 14.95 (11.53, 1359.5) vs. 121.4 (1.43, 2349.4), for CYP2B6 516TT and G carriers, respectively] but the difference was not statistically significant in our sample. CONCLUSIONS: The ABCB1 C3435T polymorphism appears to affect the postoperative perception of surgical pain among patients with low pain threshold. The small number of minor allele homozygotes for the OPRM1 A118G and CYP2B6 G516T polymorphisms precludes a definitive conclusion regarding the inclusion of the latter in a TCI-programming algorithm, based on the results of this study. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12616001598471.

Perceived treatment satisfaction in patients with systemic rheumatic diseases treated with biologic therapies: results of a self-reported survey.

Biological agents are widely used for the management of systemic rheumatic diseases (SRDs) and their therapeutic implications have been expanded beyond inflammatory arthropathies to more complicated autoimmune disorders, such as systemic lupus erythematosus, vasculitis, and systemic sclerosis. The aim of this study was to investigate treatment satisfaction and overall experience of SRDs' patients receiving biologics as well as to explore patient's perspectives on the quality of services provided by rheumatology departments and to determine factors related to the level of satisfaction. We performed a synchronous correlation study. Patients with SRDs answered an anonymous questionnaire assessing their satisfaction and how treatment with biologics has affected their quality of life and functionality. Sample consisted by 244 patients (65.2% women), with mean age of 50.4 years, and the most common diagnosis was rheumatoid arthritis (37.3%). Sixty one percent of patients received intravenous therapy and 39% subcutaneously. Overall, 80.5% of the patients reported a positive/very positive effect of their treatment on their life. The average total patient satisfaction from the unit was 79.8%. The presence of mental disease was significantly associated with less positive impact of the treatment on patients' life, worse quality of life, and greater pain. In conclusion, patients with a broad spectrum of SRDs were generally satisfied and treatment with biologic regimens appeared to have a positive impact on several aspects of their life. The majority of patients were at least satisfied with all the characteristics of the unit staff and better quality of life was associated with greater satisfaction about the Unit and more positive affect of the treatment in patients' life.

Efficacy of branched chain amino acids supplementation in liver cirrhosis: A systematic review and meta-analysis.

BACKGROUND: Branched chain amino acids' (BCAAs) beneficial role in the management of hepatic encephalopathy is already well established, whereas a number of randomized clinical trials (RCTs) have showed promising results examining BCAA supplementation in the management of other aspects of liver cirrhosis. Current results in the light of BCAAs' biochemical properties make them an attractive supplementation option, in addition to standard pharmaceutical treatment of cirrhosis. AIM: The aim of this systematic review is to summarize the current literature and assess the efficacy of BCAA supplementation in patients with liver cirrhosis. METHODS: Major electronic databases and grey literature sources were searched up to October 4th, 2021 for RCTs assessing the supplementation of BCAA against an active comparator, diet or placebo in patients with liver cirrhosis. RESULTS: Twenty RCTs fulfilled selection criteria. Relative to other interventions BCAAs showed beneficial effect regarding muscle mass (SMD 0.21, 95% CI 0.01 to 0.4, I2 0%), but no effect regarding fat mass. Furthermore, BCAAs were associated with significant increase in plasma albumin concentration (SMD 0.52, CI 95% 0.18 to 0.86, I2 84.99%), reduction in occurrence of serious cirrhotic complications (logOR -046, CI 95% -0.78 to -0.13, I2 0%) and increase in body mass index (WMD 0.24, CI 95% 0.08 to 0.40, I2 0%). On the other hand, no significant effect was noted concerning the incidence of mortality. CONCLUSION: Supplementation with BCAA seems to improve significant prognostic factors for patients with cirrhosis, with potential positive impact in mortality. Heterogeneity of study findings attributed to many factors limit overall conclusion and results require further assessment.

The inhibitory effect of tocilizumab on systemic bone loss and tendon inflammation in a juvenile Collagen-Induced arthritis rat model.

PURPOSE OF THE STUDY: Reduced Bone Mineral Density (BMD) is a prevalent comorbidity in Juvenile Idiopathic Arthritis (JIA). Enthesitis and other tendon abnormalities, such as tenosynovitis, tendinitis and tendon ruptures are, also, common extra-articular manifestations of the disease. The aim of the present study was to investigate the effect of tocilizumab, an antibody that binds the Interleukin-6 (IL-6) Receptor, on inflammation-related bone loss and tendon inflammation in an animal model of JIA. MATERIALS AND METHODS: The Collagen-Induced Arthritis (CIA) model was induced in male rats followed by intraperitoneal administration of tocilizumab for 8 weeks. Methotrexate, the most widely used Disease-Modifying Antirheumatic Drug in the management of JIA, was, also, administered, either as a monotherapy or as an add-on therapy to tocilizumab. BMD was evaluated with Micro-Computed Tomography (Micro-CT) and histopathological examination. Tendon damage was, also, assessed histologically. Finally, two pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNF-a) and Interleukin-23 (IL-23) were quantified in tendon tissues by ELISA analysis. RESULTS: Tocilizumab-treated animals exhibited a significantly improved trabecular microarchitecture on micro-CT analysis and histological examination. Tendon morphology was also improved. Anti-IL-6 treatment led to a significant decrease in TNF-a and IL-23 expression in tendon tissue. CONCLUSIONS: The results of the present study provide evidence that tocilizumab reduces inflammation-related bone loss and suppresses tendon inflammation in a juvenile CIA rat model. These findings offer perspectives for the management of osteoporosis and enthesitis in JIA.

Relationships Between Resting Energy Expenditure and Transcranial Doppler Measurements in Patients With and Without Brain Death.

Introduction Brain metabolism deteriorates during brain death, suggesting that cerebral metabolic measurements could serve as a prognostic factor. The application of transcranial Doppler can be useful in evaluating patients evolving to brain death. Resting energy expenditure is lower than expected in patients with brain death, and this is caused by the decrease in cerebral blood flow and consequently lower oxygen supply. The primary aim of this retrospective study is to investigate the early metabolic changes in patients with clinical criteria of brain death and examine if these changes are related to a gradual decrease in blood flow velocities in the middle cerebral artery. Methods All consecutive patients from 1st June 2018 to 30th April 2022, admitted to the ICU with brain injury and a GCS ≤ 8, were included retrospectively in the study. Patients were allocated into two groups: Group A, patients without clinical signs of brain death (n = 32), and Group B, patients with brain death (n = 34). In each group, three sets of metabolic measurements were performed concomitantly with cerebral blood flow velocities using transcranial Doppler (a) upon admission to the ICU, (b) once hemodynamic stabilization was obtained, and (c) 48 hours after their hemodynamic stabilization or when brain death was confirmed by clinical criteria. Resting energy expenditure (REE) measurements were performed using a metabolic computer. Cerebral blood flow velocities were measured after a period of 30 min using a 2-MHZ 2D ultrasound probe. Results Brain-dead patients had a significant decrease in their metabolic parameters as the cerebral blood flow velocities recorded with the transcranial Doppler deteriorated, (REE Group A = 1667.65 ± 597 vs Group B = 1376.12 ± 615, p = 0.05 and REE predicted Group A = 113.19 ± 44.9 vs Group B = 93.29 ± 41.5, p = 0.066 for measurement 1; REE Group A = 1844 ± 530.9 vs Group B = 1219.97 ± 489, p < 0.001 and REE predicted Group A = 124.38 ± 39 vs Group B = 81.35 ± 30.4, p < 0.001 for measurement 2; REE Group A = 1750.97 ± 414, p < 0.001 and REE predicted Group A = 116.38 ± 19.2 vs Group B = 56.09 ± 19.6, p < 0.001 for measurement 3). Multiple stepwise regression analysis revealed a strong relationship between age, the worsening of the blood flow velocities pattern, and the decrease in REE (multiple R = 0.264, F = 5.55, p = 0.009). Furthermore, a statistically significant correlation was found between temperature and REE (correlation coefficient = 0.500, 0.674, 0.784 for measurements 1, 2, and 3, respectively, and p < 0.001 for all measures). Conclusions In brain-dead patients, the gradual decrease in cerebral blood flow leads to a decrease in REE as well as thermogenetic control. These changes can be detected early after the patient's admission to the ICU.

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients.

BACKGROUND: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. METHODS: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. RESULTS: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. CONCLUSION: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

Modulation of nociception and pain-evoked neurobehavioral responses by levetiracetam in a craniotomy pain model.

Traditional and novel analgesic modalities have been extensively tested for post-craniotomy pain management, yet the role of newer antiepileptic drugs in this area remains obscure. This study investigates the impact of levetiracetam (LEV) on pain modulation and neurobehavioral performance in a craniotomy model. Fifty-six Wistar rats were randomly assigned into seven groups: no intervention (CTRL), administration of placebo or LEV with no further intervention (PBO and LEV, respectively), and sham-operation or craniotomy in placebo (PBO-SHAM and PBO-CR, respectively) or LEV-treated rats (LEV-SHAM and LEV-CR, respectively). Pain was assessed by the rat grimace scale before, and at 8 and 24 h after craniotomy, following intraperitoneal injections of LEV (100 mg/kg twice daily) or normal saline two consecutive days before and on the craniotomy day. Elevated plus-maze and olfactory social memory tests were performed at 24- and 48 h post-craniotomy, respectively. Upon testing conclusion blood samples were collected for cytokines estimation. Levetiracetam administration enhanced antinociception in sham and craniotomy groups. In the elevated plus-maze test, LEV-CR rats spent more time in investigating open arms and performed more open arm entries than PBO-SHAM and PBO-CR animals. The olfactory test revealed no between-groups difference in acquisition time during first contact with a juvenile rat, while LEV-CR rats spent less time to recognize the same juvenile rat compared to PBO-SHAM and PBO-CR groups. Furthermore, LEV-treatment attenuated cortisol, interleukin-6 and TNF-a release, in sham and craniotomy animals. In conclusion, preemptive use of LEV decreases nociception, improves pain-evoked behavior and attenuates stress response in rats subjected to craniotomy.

Infliximab and Tocilizumab Reduce Anxiety-Like Behaviour and Improve Cognitive Performance in a Juvenile Collagen-Induced Arthritis Rat Model.

Anxiety disorders and cognitive decline are highly prevalent in rheumatic diseases, including Juvenile Idiopathic Arthritis (JIA). In this study, we investigated the effect of long-term treatment with infliximab and tocilizumab on anxiety-like behaviour and cognitive performance in a juvenile collagen-induced arthritis (CIA) rat model. Forty-nine rats with established moderate arthritis were randomly allocated into 7 equal groups: negative control, vehicle, methotrexate, infliximab, tocilizumab, methotrexate + infliximab and methotrexate + tocilizumab groups. Behavioural tests were performed to evaluate anxiety-like behaviour and cognitive function. Neuropathological changes were investigated by histological examination at the level of the hippocampus, the amygdala and the prefrontal cortex. Also, the expression of Brain-Derived Neurotrophic Factor (BDNF), a biomarker associated with neuronal survival and plasticity, was determined in the hippocampus and the amygdala by RT-qPCR. We found that both infliximab and tocilizumab reduced anxiety-like behaviour in the elevated-plus and elevated-zero maze tests. Tocilizumab, also, improved cognitive function in the olfactory social memory and passive avoidance tests. Anti-cytokine treatment reversed the histopathological changes in the brain induced by CIA. BDNF expression was higher in all treatment groups and especially those receiving monoclonal antibodies combined with methotrexate. Our data provide evidence that chronic infliximab and tocilizumab treatment reduces anxiety-like behaviour, improves cognitive function, reverses neuropathological changes and increases central BDNF expression in a juvenile arthritis rat model. These findings may be translated to humans to address behavioural comorbidities associated with JIA.

Effects of long-term infliximab and tocilizumab treatment on anxiety-like behavior and cognitive function in naive rats.

BACKGROUND: Circulating cytokines have been proposed to be implicated in the development of mood disorders and cognitive impairment. This study aims to examine the effect of chronic treatment with infliximab, a tumor necrosis factor-alpha (TNF-alpha) inhibitor, and tocilizumab, an antibody against interleukin-6 (IL-6) receptor on anxiety-like behavior and cognitive function. METHODS: Twenty-eight male, Wistar rats were randomly allocated into negative control, vehicle, infliximab and tocilizumab groups. After 8 weeks of intraperitoneal drug administration, rats performed the elevated-plus maze, the elevated-zero maze, the olfactory social memory and the passive avoidance tests. Brain sections at the level of the hippocampus, the amygdala and the prefrontal cortex were histologically examined. Finally, hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: Infliximab group exhibited a significantly higher number of entries and time spent into the open arms of the mazes, showing a lower level of anxiety. In the olfactory social memory test, tocilizumab significantly increased the ratio of interaction. Both infliximab- and tocilizumab-treated animals had a significantly lower latency time in the passive avoidance test that suggests an improved memory. Histological examination revealed similar morphology and neuronal density between groups. BDNF expression levels were significantly increased in the groups receiving anti-cytokine treatment. CONCLUSIONS: Our findings suggest that long-term peripheral TNF-alpha and IL-6 inhibition improves anxiety and cognitive function in rats and leads to an increased BDNF expression in the brain.

Analgesic Efficacy and Safety of Local Infiltration Following Lumbar Decompression Surgery: A Systematic Review of Randomized Controlled Trials.

This systematic review aims to appraise available clinical evidence on the efficacy and safety of wound infiltration with adjuvants to local anesthetics (LAs) for pain control after lumbar spine surgery. A database search was conducted to identify randomized controlled trials (RCTs) pertinent to wound infiltration with analgesics or miscellaneous drugs adjunctive to LAs compared with sole LAs or placebo. The outcomes of interest were postoperative rescue analgesic consumption, pain intensity, time to first analgesic request, and the occurrence of adverse events. Twelve double-blind RCTs enrolling 925 patients were selected for qualitative analysis. Most studies were of moderate-to-good methodological quality. Dexmedetomidine reduced analgesic requirements and pain intensity within 24 h postoperatively, while prolonged pain relief was reported by one RCT involving adjunctive clonidine. Data on local magnesium seem promising yet difficult to interpret. No clear analgesic superiority could be attributed to steroids. Τramadol co-infiltration was equally effective as sole tramadol but superior to LAs. No serious adverse events were reported. Due to methodological inconsistencies and lack of robust data, no definite conclusions could be drawn on the analgesic effect of local infiltrates in patients undergoing lumbar surgery. The probable positive analgesic efficacy of adjunctive dexmedetomidine and magnesium needs further evaluation.

Infliximab and tocilizumab reduce anxiety-like behavior, improve cognitive performance and reverse neuropathological alterations in juvenile rats with severe autoimmune arthritis.

Several studies have demonstrated that rheumatic diseases, including Juvenile Idiopathic Arthritis (JIA), are associated with anxiety-like behavior and a cognitive decline. Infliximab, a Tumor Necrosis Factor-alpha (TNF-a) inhibitor, and tocilizumab, an antibody against Interleukin-6 (IL-6) receptor, are commonly used in the treatment of JIA. Here, we aimed to evaluate the effects of infliximab and tocilizumab on anxiety symptoms and cognitive function in a juvenile model of severe autoimmune arthritis. We found that both infliximab and tocilizumab improved anxiety-like behavior in the elevated-plus and elevated-zero maze tests. Tocilizumab, also, improved cognitive performance in the passive avoidance and olfactory social memory tests. Histological examination showed that anti-cytokine treatment reversed the histopathological alterations in the brain induced by arthritis. Further, infliximab and tocilizumab treatment increased Brain-Derived Neurotrophic Factor (BDNF) expression in the hippocampal and amygdaloid area of rat brain. In summary, our findings provide evidence that infliximab and tocilizumab have a beneficial effect on anxiety-like behavior and cognitive function and alleviate neuropathological alterations in a juvenile rat model of severe arthritis, suggesting that inhibition of TNF-a and IL-6 in the periphery, may be associated with a mood and memory enhancement in JIA patients.

Effects of Long-Term Methotrexate, Infliximab, and Tocilizumab Administration on Bone Microarchitecture and Tendon Morphology in Healthy Wistar Rats.

Objective Rheumatic diseases are associated with bone loss, both systemic and periarticular, and tendon abnormalities. The aim of this study is to examine the effect of three antiarthritic drugs, methotrexate, an anti-folate metabolite; infliximab, a Tumor Necrosis Factor-alpha (TNF-α) inhibitor; and tocilizumab, an antibody against Interleukin-6 (IL-6) receptor, on bone microarchitecture and tendon morphology in the absence of an inflammatory state. Materials and methods Thirty-five, 8- to 9-week-old, male, Wistar rats were randomly allocated into five groups: negative control (CTRL), vehicle (VEH), methotrexate (MTX), infliximab (INFX), and tocilizumab (TCZ). After 8 weeks of antiarthritic drug intraperitoneal administration, animals were euthanized and rat tibiae and patellar tendons were histologically examined. Results All sections exhibited normal bone microarchitecture. Histological scores in all groups corresponded to normal bone mineral density. No no apparent differences in tenocyte morphology and architecture of collagen fibers were observed. Conclusions The results of this study indicate that long-term administration of methotrexate, infliximab, and tocilizumab had no effect on bone microarchitecture and tendon morphology in rats in the absence of an inflammatory condition.

Infliximab prevents systemic bone loss and suppresses tendon inflammation in a collagen-induced arthritis rat model.

Reduced Bone Mineral Density (BMD) and tendon abnormalities, such as tenosynovitis and enthesitis, are prevalent comorbidities in patients with rheumatoid arthritis (RA). The aim of the present study was to investigate the effect of chronic treatment with infliximab on BMD and tendon inflammation in an animal model of inflammatory arthritis. Collagen-Induced Arthritis (CIA) was induced in rats, followed by long-term intraperitoneal administration of infliximab. Two additional groups of animals received methotrexate either as a monotherapy or as a co-treatment to infliximab. BMD was evaluated by Micro-Computed Tomography (Micro-CT) and bone histological examination. Tendon inflammation was assessed histologically and by quantitative ELISA analysis of pro-inflammatory cytokines in tendon tissues. Both methotrexate and infliximab treatment alleviated joint inflammation and reduced paw edema. Infliximab-treated animals exhibited an improved trabecular microarchitecture on micro-CT and histological analysis compared to both non-treated and methotrexate-treated animals. Infliximab almost reversed the pathological changes in tendons induced by CIA. Finally, we observed statistically significant declines in tendon TNF-a and IL-23 levels after infliximab treatment. Our study provides evidence that infliximab prevents arthritis-related osteoporosis and suppresses tendon inflammation in an animal model of inflammatory arthritis, in addition to controlling disease activity. These findings offer perspectives for the management of osteoporosis and enthesitis in RA.