Mitigating sTNF/TNFR1 activation on VGluT2 + spinal cord interneurons improves immune function after mid-thoracic spinal cord injury.

Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individual's outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-kß dependent in VGluT2 + INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics.

Magnetic Resonance Imaging Features and Functional Score in Patients Requiring Total Knee Arthroplasty.

Introduction Knee osteoarthritis (KOA) is a progressive degenerative disease, with an increasing prevalence among the population. The degenerative changes in KOA affect the cartilage, menisci, synovial tissue, and subchondral bone. The treatment for patients in advanced stages of the disease is total knee arthroplasty (TKA). The purpose of this descriptive study is to identify the MRI features in the case of patients with KOA who did not obtain an improvement in symptoms and joint function after the non-surgical treatments and who applied for surgical treatment, i.e. TKA. Also, we aimed to identify the correlations between the MRI changes and the functional score of the patients, as well as the inter-variable correlations. Materials and methods The study was conducted in the Department of Orthopedics and Traumatology at the University Emergency Hospital of Bucharest between January 1, 2023, and January 31, 2024. It included 50 patients who required TKA. This study is a prospective, observational, and descriptive analysis focusing on patients scheduled for TKA. Results The patients in the study group who required TKA had a Knee Society Score (KSS) ranging from 35 to 70 and a KSS function score between 24 and 60. Among them, 98% had tricompartmental lesions of the articular cartilage, and 100% presented with osteophytes, even when they were not identifiable radiologically. Additionally, 58% of the patients had changes in the infrapatellar fat pad, 66% presented with joint effusion without any traumatic history, and 86% of the patients had partial or complete lesions of the anterior cruciate ligament. Conclusion The MRI pattern of the patient who requires TKA consists of the presence of articular cartilage lesions in more than two compartments with exposure of the subchondral bone and diameter greater than 1 cm, meniscus lesions (>grade 2), meniscus extrusion (>grade 1), the presence of bone marrow lesions (BMLs) in the medial or lateral compartment of the femur or tibia, hyperintense signal of the infrapatellar fat pad, anterior cruciate ligament (ACL) lesions (>grade 2), and the presence of osteophytes together with the presence of effusion in the suprapatellar bursa. BMLs and changes in the infrapatellar fat pad may lead to the opening of new research perspectives explaining the complex changes in KOA in relation to the inflammatory process and gene expression.

Comparable long-term functional outcomes of subvastus and medial parapatellar approach in total knee arthroplasty: A 10-year follow-up study.

Background: Surgeons usually use the medial parapatellar or subvastus approaches for total knee arthroplasty (TKA). The subvastus approach is rapidly gaining recognition to reduce damage to the extensional mechanism and recover faster after surgery. This study compares the long-term outcomes of the conventional medial parapatellar and subvastus approaches in primary TKA during a minimum 10-year follow-up. Methods: In a retrospective longitudinal follow-up study from 2008 to 2013, 60 eligible patients for primary TKA were included. The patients were divided into two groups: one undergoing TKA with the subvastus approach (n = 30) and the other with the conventional medial parapatellar approach (n = 30). Postoperatively, the patients were followed up for 10-15 years. Patients were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Society Score (KSS), and Visual Analogue Scale index for pain. Results: The time required to perform an active straight leg raise (SLR) was significantly shorter in the subvastus group (p < 0.001) at early postoperation evaluation. Patients in the subvastus group had lower pain and better knee functional scores at the one-year follow-up (p < 0.05). There was no difference between the two groups regarding duration of hospitalisation, blood loss, operation time, length of the scar, and postoperative complications. Both approaches had similar long-term results regarding pain and functional scores of WOMAC (6.2 ± 1.2 vs. 6.3 ± 1.3, p-value = 0.69) and KSS scores (93.1 ± 6.8 vs. 95.0 ± 3.2, p-value = 0.42). Conclusion: The subvastus approach was associated with a shorter time to achieve active SLR, higher functional scores, and better pain relief at early postoperative evaluations. However, both techniques had similar long-term outcomes in terms of pain and functional scores, as measured by the WOMAC and KSS scales. Level of Evidence: II.

Demographic characteristics and clinical-radiological correlation in patients with indications for Total Knee Arthroplasty: A cross-sectional study.

OBJECTIVE: The objective of this study is to correlate clinical symptoms and functionality, using the KOOS (Knee Injury and Osteoarthritis Outcome Score) and KSS (Knee Society Score System) scores, with the radiographic changes, using the Kellgren-Lawrence classification, in patients with knee osteoarthritis and indications for Total Knee Arthroplasty (TKA). METHODS: 120 patients (189 knees) with gonarthrosis and indications for TKA were included in the study. Demographic questionnaires were applied, and clinical and functional assessment was carried out using the KOOS and KSS scores. Knee radiographs were taken and graded according to Kellgren-Lawrence. The clinical scores were compared with the radiographic classification to establish a correlation between these two measurements. Statistical analysis was performed using the τ-Kendall correlation test. RESULTS: Weak and inversely proportional correlations were found between the clinical scores and the radiographic classification. Among clinical scores evaluated, KSS showed the highest correlation with Kellgren-Lawrence classification (τ = -0.356; p < 0.001), followed by KOOS-quality of life (τ = -0.176; p = 0.004), KOOS-total score (τ = -0.166; p = 0.004), KOOS-function in daily living (τ = -0.160; p = 0.005) and KOOS-symptoms (τ = -0.159; p = 0.006). KOOS-pain (τ = -0.149; p = 0.01) and KOOS-sport and recreation function (τ = -0.142; p = 0.025) scores had the weakest correlations. CONCLUSION: There is a weak correlation between the clinical-functional scores of TKA candidates and their radiographic classification by Kellgren-Lawrence. Among clinical scores evaluated, KSS had the strongest negative correlation with the radiographic classification.

In vivo RNA sequencing reveals a crucial role of Fus3-Kss1 MAPK pathway in Candida glabrata pathogenicity.

Candida glabrata is an important and increasingly common pathogen of humans, particularly in immunocompromised hosts. Despite this, little is known about how this fungus causes disease. Here, we applied RNA sequencing and an in vivo invasive infection model to identify the attributes that allow this organism to infect hosts. Fungal transcriptomes show a dramatic increase in the expression of Fus3 and Kss1, two mitogen-activated protein kinases (MAPKs), during invasive infection. We further demonstrate that they are both highly induced under a combination of serum and high CO2 conditions. Deletion of both FUS3 and KSS1, but neither gene alone, results in a reduced fungal burden in organs, as well as in the gastrointestinal tract in the DSS (Dextran Sulfate Sodium)-induced colitis model. Similarly, the defect in persistence in macrophages and attenuated adhesion to epithelial cells are observed when FUS3 and KSS1 are both disrupted. The fus3 kss1 double mutant also displays defects in the induction of virulence attributes such as genes required for iron acquisition and adhesion and in the anti-fungal drug tolerance. The putative downstream transcription factors Ste12 (1), Ste12 (2), Tec1, and Tec2 are found to be involved in the regulation of these virulence attributes. Collectively, our study indicates that an evolutionary conserved MAPK pathway, which regulates mating and filamentous growth in Saccharomyces cerevisiae, is critical for C. glabrata pathogenicity. IMPORTANCE: The MAPK signaling pathway, mediated by closely related kinases Fus3 and Kss1, is crucial for controlling mating and filamentous growth in Saccharomyces cerevisiae, but this pathway does not significantly impact hyphal development and pathogenicity in Candida albicans, a commensal-pathogenic fungus of humans. Furthermore, deletion of Cpk1, the ortholog of Fus3 in pathogenic fungus Cryptococcus neoformans, has no effect on virulence. Here, we demonstrate that the MAPK pathway is crucial for the pathogenicity of Candida glabrata, a fungus that causes approximately one-third of cases of hematogenously disseminated candidiasis in the United States. This pathway regulates multiple virulence attributes including the induction of iron acquisition genes and adhesins, as well as persistence in macrophages and organs. Our work provides insights into C. glabrata pathogenesis and highlights an example in which regulatory rewiring of a conserved pathway confers a virulent phenotype in a pathogen.

Analysis of rehabilitation effect of electroacupuncture for patients after total knee arthroplasty.

PURPOSE: To investigate the effect of electroacupuncture on the rehabilitation of patients after total knee arthroplasty (TKA). MATERIALS AND METHODS: Eighty patients with knee osteoarthritis who underwent total knee arthroplasty randomly divided into two groups, with 40 patients in each group. The control group was treated with traditional rehabilitation methods. In addition to traditional rehabilitation treatment, patients in the experimental group received electroacupuncture after operation, while patients in the control group received fake electroacupuncture. Both groups started electroacupuncture treatment and fake electroacupuncture treatment on the third day after operation for 10 consecutive days Data of patients in both groups were collected before surgery, three days after surgery, two weeks after surgery and one month after surgery, including the visual analogue scale(VAS), Knee Society Score (KSS) and range of motion (ROM). RESULTS: Compared with before treatment, after the treatment cycle, the VAS, KSS and ROM of both groups were significantly improved (p = 0.001, p = 0.001). Compared with the control group, the ROM and KSS of the experimental group were significantly improved at two weeks after surgery and one month after surgery, and the VAS was significantly decreased, with statistical significance (p < 0.05). CONCLUSIONS: Electroacupuncture therapy has a positive effect on the recovery of patients after total knee arthroplasty, which can alleviate the pain after total knee arthroplasty, promote the recovery of knee function, which is worthy of clinical promotion.

Electroacupuncture therapy combined with routine rehabilitation therapy can better promote the recovery of the knee after total knee replacement; significantly reduce the pain of the knee joint.Electroacupuncture therapy combined with routine rehabilitation therapy can effectively improve the function of the knee joint and promote the improvement of the joint motion of the knee joint.Electroacupuncture has short treatment time, quick effect, and high patient compliance and is worth applying to support recovery after total knee replacement.

The effects of mineral trioxide aggregate and second-generation autologous growth factor on pulpotomy via TNF-α and NF-kß/p65 pathways.

This study aims to investigate the effect of Mineral Trioxide Aggregate (MTA), a bioactive endodontic cement, and Concentrated Growth Factor (CGF), a second-generation autologous growth factor, on pulpotomy-induced pulp inflammation. The study utilized the maxillary anterior central teeth of thirty-six young male Sprague Dawley rats. Forty-eight teeth were randomly assigned to two groups (12 rats/group; 24 teeth/group) based on the capping material (MTA or CGF). Subsequently, two subgroups (MTAG and CGFG) were formed per group (12 teeth/group) based on the time following pulpotomy (2-weeks and 4-weeks). The central teeth of the 12 animals assigned to the control group (CG) were not manipulated in any way, both in the 2-week group and in the 4-week group. Tissue samples extracted from rats at the end of the experiment were stained with H&E for histopathological analysis. For immunohistochemical analysis, primary antibodies for TNF-α and NF-kß/65 were incubated. Data obtained from semi-quantitative analysis were assessed for normal distribution using Skewness-Kurtosis values, Q-Q plot, Levene's test, and the Shapiro-Wilk test on statistical software. A P value < 0.05 was considered significant. When compared with the control group, both MTAG and CGFG showed increased edematous and inflammatory areas. In MTAG, edematous and inflammatory areas decreased significantly from the 2nd week (2(2-2), 2(1-2)) to the 4th week (1(1-1), 1(0-1)), while in CGFG, edematous areas decreased (2(2-3), 1.5(1-2)), and inflammatory areas increased significantly (2(2-3), 3(2-2.5)). When compared with the control group, TNF-α and NF-kß/p65 positivity were higher in both MTAG and CGFG. In MTAG, TNF-α [2(1.5-2)] and NF-kß/p65 [1.5(1-2)] positivity decreased significantly from the 2nd week to the 4th week [TNF-α: 1(1-1), NF-kß/p65: 1(1-2)], while no significant change was observed in CGFG. In conclusion, this study revealed a reduction in cells showing TNF-α and NF-kß/p65 positivity in the MTA treatment group compared to the CGF group. Although MTA demonstrated more favorable results than CGF in mitigating pulpal inflammation within the scope of this study, further experimental and clinical investigations are warranted to obtain comprehensive data regarding CGF.

Do octogenarian patients undergoing total knee replacement return to physical activity? / ¿Los pacientes octogenarios sometidos a reemplazo total de rodilla regresan a la actividad física?

BACKGROUND AND OBJECTIVES: It has been shown that total knee replacement improves functional capacity and physical activity; however, the influence of age remains unclear. The objective is evaluate the pre and postoperative physical activity measured with the Knee Society Score (KSS) score and the Tegner score. MATERIALS AND METHODS: A retrospective cohort analysis was conducted on patients who underwent total knee replacement (TKR) between January 2016 and December 2019 at our institution. Demographic variables (age, sex, and body mass index), activities of daily living, age-adjusted Charlson Comorbidity Index, American Society of Anesthesiologists score, the Knee Society Score (KSS) in its clinical (KSSc) and functional (KSSf) subscales, the Tegner functional scale, activity variables from the 2011 KSS version, and pain assessment using the visual analog scale were collected. Differences in these variables were analyzed between two age groups: group A (between 65 and 79 years old) and group B (80 years or older). RESULTS: A total of 450 patients were evaluated (group A=245, group B=167). Group A showed a Tegner improvement of 1.19 (95% CI: 1.06-1.31), whereas group B averaged 0.61 (95% CI: 0.43-0.80) (P<.001). Age >80 was an independent risk factor for less Tegner improvement. In KSSc, group A improved by 43 points (95% CI: 40.82-46.14), while group B showed a greater increase of 53 points (95% CI: 49.74-57.80). Adjusted for confounders, those>80 showed significantly higher KSSc improvement (12.8 points). For KSSf, group A improved by 33.91 points (95% CI: 31.07-36.75), and group B by 15.57 points (95% CI: 11.78-19.35). Adjusted for confounders, patients >80 had less improvement than those <80 (19 points). CONCLUSIONS: Patients who underwent TKR experienced improvements in physical and functional activity parameters. While these improvements were seen in the entire population, they were most notable in patients younger than 80 years.

Balancing roles between phosphatidylinositols and sphingolipids in regulating immunity and ER stress responses in pi4kß1,2.

Plant immune regulation is complex. In addition to proteins, lipid molecules play critical roles in modulating immune responses. The mutant pi4kß1,2 is mutated in two phosphatidylinositol 4-kinases PI4Kß1 and ß2 involved in the biosynthesis of phosphatidylinositol 4-phosphate (PI4P). The mutant displays autoimmunity, short roots, aberrant root hairs, and a heightened sensitivity to ER stress. In a forward genetic screen designed to dissect pi4kß1,2 autoimmunity, we found that Orosomucoid-like 1 (ORM1) is required for the phenotypes of pi4kß1,2, including short root and ER stress sensitivity. The orm1 mutations lead to increased long-chain base and ceramide levels in the suppressors. We also found that the basic region/leucine Zipper motif (bZIP) 28 and 60 transcription factors, central regulators of ER stress response, are required for its autoimmunity and root defect. In comparison, the defense-related phytohormones salicylic acid (SA) and N-hydroxypipecolic acid (NHP) are required for its autoimmunity but plays a minor role in its root phenotypes. Further, we found that wild-type plants overexpressing ORM1 are autoimmune, displaying short roots and increased ceramide levels. The autoimmunity of the ORM1 overexpression lines is dependent on SA, NHP, and bZIP60. As ORM1 is a known negative regulator of sphingolipid biosynthesis, our study uncovers a balancing role between PIs and sphingolipids in regulating immunity and ER stress responses in pi4kß1,2.

Limitations of the knee society score in kinematically aligned total knee arthroplasty.

Purpose: The Knee Society Scoring System (KSS) is a frequently used outcome score which quantifies functional patients' outcomes before and after total knee arthroplasty (TKA). Several problems arise when trying to implement KSS for obtaining postoperative outcomes after more personalised aligned TKAs. Scoring for valgus femorotibial angle (FTA) intervals outside moderate ranges is often poorly explained, the specific version of KSS used for outcome collection is frequently unclear and the exact measuring methods are typically not described in the literature. The aims of this systematic review were to investigate the latest user practice, the application of KSS and its limitations after kinematically aligned (KA) TKA. Methods: A systematic literature search following PRISMA guidelines was conducted on PubMed, Embase, Medline and Scopus to identify potentially relevant articles for this review, published from the beginning of January 2013 until the end of January 2023. Broad Mesh terms such as 'kinematic alignment', 'total knee arthroplasty' and 'knee society score' were used for building search strategy in each database accordingly. Articles reporting postoperative values of the objective surgeon-assessed KSS after KA TKA or KA and mechanically aligned TKA were included. For assessing included randomised control trials (RCTs), an Agency for Healthcare Research and Quality's design-specific scale for assessing RCTs was used. The non-RCTs were assessed by using the Joanna Briggs Institute Critical Appraisal Tool. The Ottawa-Newcastle Score system was also used. Studies were additionally evaluated for their radiological methodology by using a five-question checklist (Radiological Assessment Qualit criteria). Results: The initial search identified 167 studies, of which 129 were considered for screening. Ten studies reporting outcomes after KA TKA did not use the objective surgeon-assessed part of KSS for clinical outcome measurement, and 30 studies reporting outcomes after KA TKA did not use KSS at all for clinical and/or functional outcomes. From the 10 included studies, only six have used the latest KSS score (2011), the rest using its 1989 variant; and out of these six studies, only two presented values of the FTA, which is needed for calculating the KSS's 'alignment' subcomponent, the rest presenting hip-knee-ankle angle (HKA) values. Additionally, when converting these HKA values to FTA intervals, the authors of this systematic review found that KA TKA FTA intervals display limits, which tend to be outside the 'well-scored' KSS anatomical alignment interval. Conclusion: The inconsistent and nonstandardised use of the surgeon-assessed KSS across studies reviewed compromises assessment reliability and patient outcome scores. To enhance precision and comparability, it is crucial to standardise the KSS application, incorporating personalised alignment strategies for more accurate patient evaluations. Level of Evidence: Level III.

Ropinirole reverses the effects of neuroinflammation, and cellular demise by downregulating the MARK4-NFκß signaling system in Alzheimer's disease.

Ropinirole (ROP) is a dopamine agonist that can cross the blood-brain barrier (BBB), which is crucial for drugs targeting neurological conditions like Alzheimer's disease (AD). The rationale for the current research is to investigate the potential of ROP as an inhibitor of Microtubule affinity regulating kinase 4 (MARK4)-NFκß in neurodegenerative diseases, specifically AD. The interaction between ROP and MARK4-NFκß holds significant promise in the realm of drug discovery and therapeutic interventions for diseases like AD. Molecular docking and biophysical characterization demonstrate how ROP effectively hinders MARK4 activity, offering detailed insights into their molecular interactions. The present research also investigates the biological aspect of MARK4 shows promise in treating AD, with neuroinflammation playing a crucial role in the disease's progression. Aß42 and ROP were co-administered directly into the cells for the establishment of the AD model. We confirmed that ROP can inhibit the path of MARK4 activity, as evidenced by biophysical characterization, and can enhance the cell viability, lowers the expression of MARK4, decrease the rate of oxidative stress, and attenuate the expression of NFκß, leading to reduced neuronal apoptosis in an in vitro-induced Aß model. Overall, this research provides valuable mechanistic insights into the neuroprotective potential of ROP and its ability to target the MARK4-NFκß pathway.

Computerized Versus Traditional Approaches for Total Knee Arthroplasty: A Quantitative Analysis of Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index.

Total knee arthroplasty (TKA) is a common surgery for osteoarthritis, with increasing prevalence expected in the near future. This systematic review and meta-analysis compared the effectiveness of computerized TKA versus traditional TKA, focusing on postoperative outcomes measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and the Knee Society score (KSS). A search on PubMed and Cochrane databases on November 14, 2023 for retrospective randomized controlled trials (RCTs) yielded data on WOMAC and KSS. The search strategy was predefined, and methodological quality of studies was critically appraised. Two researchers extracted data. Unpaired t-testing assessed the mean monthly changes in KSS and WOMAC for computer-aided versus traditional TKA. Review Manager 5.3 was used for data synthesis and analysis. Out of 729 records, five RCTs enrolling 339 patients were eligible and analyzed using a random effects meta-analysis. The mean monthly ΔKSS score differed significantly between the traditional and computerized groups (11.47 ± 8.76 vs. 9.26 ± 6.05, respectively; p < 0.01). However, the pooled mean difference estimate showed no significant differences (D = 0.20, 95% CI = -0.53 to 0.93, p = 0.59), with high heterogeneity (I2 = 85%, p < 0.001). The mean monthly ΔWOMAC score also differed significantly (-14.18 ± 21.54 vs. -18.43 ± 20.65, respectively; p < 0.05), but again, no significant differences were found in the pooled estimate (D = 0.17, 95% CI = -0.46 to 0.79, p = 0.60), with moderate heterogeneity (I2 = 28%, p = 0.24).There is no significant difference in KSS or WOMAC outcomes between traditional and computerized TKA. The study suggests the need for further research with longer follow-up periods, more timepoints, and a broader range of patient outcome measures to fully evaluate the advantages and disadvantages of each method.

Poria cocos polysaccharides improve alcoholic liver disease by interfering with ferroptosis through NRF2 regulation.

The active ingredient in Poria cocos, a parasitic plant belonging to the family Polyporaceae, is Poria cocos polysaccharide (PCP). PCP exhibits liver protection and anti-inflammatory effects, although its effect on alcoholic liver disease (ALD) remains unstudied. This study investigated the mechanism of PCP in improving ALD by regulating the Nrf2 signaling pathway. After daily intragastric administration of high-grade liquor for 4 hours, each drug group received PCPs or the ferroptosis inhibitor ferrostatin-1. The Nrf2 inhibitor ML385 (100 mg/kg/day) group was intraperitoneally injected, after which PCP (100 mg/kg/day) was administered by gavage. Samples were collected after 6 weeks for liver function and blood lipid analysis using an automatic biochemical analyzer. In the alcoholic liver injury cell model established with 150 mM alcohol, the drug group was pretreated with PCP, Fer-1, and ML385, and subsequent results were analyzed. The results revealed that PCP intervention significantly reduced liver function and blood lipid levels in alcohol-fed rats, along with decreased lipid deposition. PCP notably enhanced Nrf2 signaling expression, regulated oxidative stress levels, inhibited NF-κß, and its downstream inflammatory signaling pathways. Furthermore, PCP upregulated FTH1 protein expression and reduced intracellular Fe2+, suggesting an improvement in ferroptosis. In vitro studies yielded similar results, indicating that PCP can reduce intracellular ferroptosis by regulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factors.

Impact of L-Arginine on diabetes-induced neuropathy and myopathy: Roles of PAI-1, Irisin, oxidative stress, NF-κß, autophagy and microRNA-29a.

BACKGROUND: T2DM is a chronic disorder with progressive neuromuscular alterations. L-arginine (ARG) is the most common semi-essential amino acid having several metabolic functions. AIM: to investigate the impact of L-arginine in combating diabetic-induced neuromyopathy and its possible mechanisms. MATERIALS & METHODS: 24 rats were divided into CON, CON+ARG, DC, DC+ARG. Behavioral tests, Body weight (BW), fasting blood glucose (FBG), insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), plasminogen activator inhibitor-1 (PAI-1), and irisin were done. Creatine kinase-MM (CK-MM), interleukin 4 (IL-4), interleukin 6 (IL-6), TAC, MDA, expression of microRNA-29a mRNA & light chain 3 protein were determined in muscle. Histological and NF-κß immunohistochemical expression in muscle and nerve were assessed. RESULTS: ARG supplementation to diabetic rats improved altered behavior, significantly increased BW, insulin, TAC, irisin and Il-4, decreased levels of glucose, microRNA-29a, NF-κß and LC3 expression, PAI-1, CK-MM and restored the normal histological appearance. CONCLUSIONS: ARG supplementation potently alleviated diabetic-induced neuromuscular alterations.

Signal Peptide Peptidase and PI4Kß1/2 play opposite roles in plant ER stress response and immunity.

The Arabidopsis pi4kß1,2 mutant is mutated in the phosphatidylinositol 4-kinase (PI4K) ß1 and PI4Kß2 enzymes which are involved in the biosynthesis of phosphatidylinositol 4-phosphate (PI4P), a minor membrane lipid with important signaling roles. pi4kß1,2 plants display autoimmunity and shorter roots. Though the pi4kß1,2 mutant has been extensively characterized, the source of its autoimmunity remains largely unknown. In this study, through a genetic suppressor screen, we identified multiple partial loss-of-function alleles of signal peptide peptidase (spp) that can suppress all the defects of pi4kß1,2. SPP is an intramembrane cleaving aspartic protease. Interestingly, pi4kß1,2 plants display enhanced ER stress response and mutations in SPP can suppress such phenotype. Furthermore, reduced ER stress responses were observed in the spp single mutants. Overall, our study reveals a previously unknown function of PI4Kß and SPP in ER stress and plant immunity.

Unveiling the challenges of UTUC biopsies and cytology: insights from a global real-world practice study.

PURPOSE: Diagnostic ureteroscopy (dURS) is optional in the assessment of patients with upper tract urothelial carcinoma (UTUC) and provides the possibility of obtaining histology. METHODS: To evaluate endoscopic biopsy techniques and outcomes, we assessed data from patients from the CROES-UTUC registry. The registry includes multicenter prospective collected data on diagnosis and management of patients suspected having UTUC. RESULTS: We assessed 2380 patients from 101 centers. dURS with biopsy was performed in 31.6% of patients. The quality of samples was sufficient for diagnosis in 83.5% of cases. There was no significant association between biopsy techniques and quality (p = 0.458). High-grade biopsy accurately predicted high-grade disease in 95.7% and high-risk stage disease in 86%. In ureteroscopic low-grade tumours, the prediction of subsequent low-grade disease was 66.9% and low-risk stage Ta-disease 35.8%. Ureteroscopic staging correctly predicted non-invasive Ta-disease and ≥ T1 disease in 48.9% and 47.9% of patients, respectively. Cytology outcomes did not provide additional value in predicting tumour grade. CONCLUSION: Biopsy results adequately predict high-grade and high-risk disease, but approximately one-third of patients are under-staged. Two-thirds of patients with low-grade URS-biopsy have high-risk stage disease, highlighting the need for improved diagnostics to better assess patient risk and guide treatment decisions. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (ClinicalTrials.gov NCT02281188; https://clinicaltrials.gov/ct2/show/NCT02281188 ).

Kinin-kallikrein system: New perspectives in heart failure.

Heart failure (HF) is a pervasive clinical challenge characterized by compromised cardiac function and reduced quality of life. The kinin-kallikrein system (KSS), a multifaceted peptide cascade, has garnered substantial attention due to its potential role in HF. Through activation of B1 and/or B2 receptors and downstream signaling, kinins modulate various physiological processes, including inflammation, coagulation, pain, blood pressure control, and vascular permeability. Notably, aberrations in KKS components have been linked to HF risk. The elevation of vasodilatory bradykinin (BK) due to kallikrein activity reduces preload and afterload, while concurrently fostering sodium reabsorption inhibition. However, kallikrein's conversion of prorenin to renin leads to angiotensinsII upregulation, resulting in vasoconstriction and fluid retention, alongside increased immune cell activity that fuels inflammation and cardiac remodeling. Importantly, prolonged KKS activation resulting from volume overload and tissue stretch contributes to cardiac collagen loss. The conventional renin-angiotensin-aldosterone system (RAAS) inhibitors used in HF management may inadvertently intensify KKS activity, exacerbating collagen depletion and cardiac remodeling. It is crucial to balance the KKS's role in acute cardiac damage, which may temporarily enhance function and metabolic parameters against its detrimental long-term effects. Thus, KKS blockade emerges as a promising strategy to impede HF progression. By attenuating the link between immune system function and tissue damage, KKS inhibition can potentially reduce cardiac remodeling and alleviate HF symptoms. However, the nuanced roles of BK in various acute conditions necessitate further investigation into the sustained benefits of kallikrein inhibitors in patients with chronic HF.

Amino acid metabolism and MAP kinase signaling pathway play opposite roles in the regulation of ethanol production during fermentation of sugarcane molasses in budding yeast.

Sugarcane molasses is one of the main raw materials for bioethanol production, and Saccharomyces cerevisiae is the major biofuel-producing organism. In this study, a batch fermentation model has been used to examine ethanol titers of deletion mutants for all yeast nonessential genes in this yeast genome. A total of 42 genes are identified to be involved in ethanol production during fermentation of sugarcane molasses. Deletion mutants of seventeen genes show increased ethanol titers, while deletion mutants for twenty-five genes exhibit reduced ethanol titers. Two MAP kinases Hog1 and Kss1 controlling the high osmolarity and glycerol (HOG) signaling and the filamentous growth, respectively, are negatively involved in the regulation of ethanol production. In addition, twelve genes involved in amino acid metabolism are crucial for ethanol production during fermentation. Our findings provide novel targets and strategies for genetically engineering industrial yeast strains to improve ethanol titer during fermentation of sugarcane molasses.

Polymorphism rs5780218, rs12998 and rs10158616 in KISS1 gene among the Hubei province Chinese girls with the central precocious puberty.

PURPOSE: Central precocious puberty (CPP) results from early activation of the hypothalamic-pituitary-gonadal (HPG) axis. To elucidate the molecular genetic basis of CPP, we here investigated the effects of polymorphism rs5780218, rs12998 and rs10158616 in KISS1 gene on CPP susceptibility. METHODS: The three KISS1 gene polymorphisms were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Sanger sequencing in 422 healthy Hubei Chinese girls and 384 Hubei Chinese girls with CPP. RESULTS: Single-locus analysis demonstrated that rs5780218 and rs12998 were significantly associated with CPP susceptibility in Hubei Chinese girls. Haplotype analysis exhibited that the AGG carrying the risk allele A of rs5780218 and the -GG carrying the protective allele - of rs5780218 were associated with increased and decreased CPP susceptibility in Hubei Chinese girls, respectively. The following meta-analysis confirmed the contribution of rs5780218 and rs12998 on CPP susceptibility in Chinese girls. CONCLUSIONS: rs5780218 and rs12998 in the KISS1 gene may participate in genetic susceptibility to CPP in Chinese girls, and the KISS1 gene rs5780218 may serve as a genetic biomarker of CPP. However, the present findings should be validated in future studies with larger sample sizes in other ethnic populations.

Functional and Clinical Outcomes of Total Knee Arthroplasty: A Prospective Study.

INTRODUCTION: A key to successful patient outcomes following knee procedures like total knee arthroplasty (TKA) is achieving normal knee alignment. Normal mechanical balance in the joints must be restored in order to lessen the failure rate of TKA, and precise assessment of lower extremity alignment and component location is thought to be the primary determinant of a good clinical outcome over the long term. OBJECTIVE: The aim of this study was to assess the early functional and clinical outcomes of TKA by analyzing post-operative mechanical axis and Knee Society Score (KSS) data. The study also aimed to investigate the importance of achieving neutral mechanical alignment in TKA for long-term results. METHODS: A prospective and retrospective observational study was conducted, involving 40 patients with primary osteoarthritis who underwent bilateral or unilateral TKA. Demographic information, pre-operative comorbidities, knee abnormalities, and radiographic assessment were collected. Post-operative mechanical axis and implant placement were evaluated using CT scanograms. Clinical and functional assessments were performed using the Knee Society Score at regular intervals. The KSS scores were obtained at six-month intervals following surgery. The scores were categorized as excellent, very good, good, fair, or poor based on predefined criteria. RESULTS: A total of 47 knees from 40 patients were analyzed. The mean age of the study population was 65.6 years. Female patients accounted for 67.5% of the sample. The majority of patients (57.4%) achieved an excellent KSS score, followed by very good (25.5%) and good (17%) scores. The mean KSS score significantly improved from 177 points pre-surgery to 225 points post-surgery. The post-operative mechanical axis ranged from 1.1 degrees valgus to 9 degrees valgus, with a mean value of 3.5 degrees valgus. The range of motion improved from 10 to 90 degrees post-operatively, with a mean range of 0-110 degrees. CONCLUSION: This study suggests that total knee replacement surgery resulted in positive outcomes, with most patients achieving excellent or very good scores on the Knee Society scale. Proper axial and rotational alignment of the components during TKA enhanced functional outcomes and contributed to long-term clinical success. Restoration of neutral mechanical alignment and optimal component placement may lead to lower revision rates and increased durability after TKA. Further studies with larger sample sizes are needed to validate these findings.