Search Results (185)

Background: Fibromyalgia is a chronic syndrome characterized by widespread pain and complex pathophysiology, requiring new therapeutic approaches. This study aims to investigate the effects of resistance training (RT) before hyperalgesia induction on pain sensitivity, IL-6 and IL-10 expression in skeletal muscle, and thalamic serotonin levels in a fibromyalgia (FM)-like rat model. Methods: Wistar female rats aged 12 months were divided into four groups: untrained neutral saline (UNS), untrained acid saline (UAS), RT neutral saline (RTN), and RT acid saline (RTA). Both the RTN and RTA groups were subjected to an RT protocol comprising vertical ladder climbing three times a week throughout 14 weeks. The UAS and RTA groups received 100 µL of neutral, sterile saline (pH 4.0) in the left gastrocnemius muscle, while the UNS and RTN groups received 100 µL of neutral saline (pH 7.4). Mechanical hyperalgesia was assessed using Von Frey’s electronic esthesiometer. Expression of interleukins 6 (IL-6) and 10 (IL-10) was analyzed in skeletal muscle, and serotonin expression was quantified in the thalamus. Results: After hyperalgesia induction, the RT groups demonstrated higher paw withdrawal thresholds than the UAS group (p < 0.05). Both IL-6 and IL-10 expression was lower in the RTA group compared to the UAS group (p < 0.05). Thalamic serotonin expression was higher (p < 0.05) in the RTA group compared to the UAS group. Conclusion: Previous RT was able to prevent mechanical hyperalgesia experienced by rats after its induction by acid saline by preventing the increase in the IL-6 and IL-10 levels in skeletal muscle and preventing the decrease in thalamic serotonin expression. Full article

Background/Objectives: Philadelphia has experienced a surge in illicit fentanyl adulterated with alpha-2 agonist sedatives. Initially, xylazine (“tranq”) was the predominant adulterant, and a novel multimodal withdrawal protocol was effective at mitigating symptoms. However, since mid-2024, medetomidine—a more potent sedative—has largely supplanted xylazine. Clinicians have reported more severe, treatment-resistant opioid withdrawal during this transition. To assess whether a previously effective withdrawal management protocol retained efficacy after the emergence of medetomidine as the primary fentanyl adulterant in a community. Methods: We conducted a retrospective cohort study of patients receiving protocol-based opioid withdrawal treatment at two emergency departments in Philadelphia between September 2022 and April 2025. Patients were divided into the xylazine era (September 2022–July 2024) and medetomidine era (August 2024–April 2025). The primary outcome was a change in Clinical Opioid Withdrawal Scale (COWS) score from pre- to post-treatment. Secondary outcomes included rates of discharge against medical advice (AMA) and ICU admission, as well as the impact of a revised treatment protocol. Results: Among 1269 encounters with full data, 616 occurred during the xylazine era and 770 during the medetomidine era. Median COWS reduction was greater in the xylazine group (−9.0 vs. −4.0 points, p < 0.001), with more patients achieving symptom relief (COWS ≤ 4: 65.6% vs. 14.2%, p < 0.001). ICU admission occurred in 8.5% of xylazine era patients and 16.8% of medetomidine era patients (p < 0.001). Rates of AMA were higher during the medetomidine era as well (6.5% vs. 3.6%) (p = 0.038). Revision of treatment protocols showed promise. Conclusions: The protocol was significantly less effective during the medetomidine era, though a protocol change may be helping. Findings highlight the need to adapt withdrawal treatment protocols in response to changes in the illicit drug supply. Full article

Therapy resistance remains a major barrier to improving outcomes in HER2-positive breast cancer, with dormant tumor cells (DTCs) and cancer stem cells (CSCs) playing critical roles in recurrence and treatment failure. Herein, we investigated the interplay between dormancy and CSCs features in HER2-amplified breast cancer cell models and evaluated the role of the JAK1–STAT3 axis in sustaining these therapy-resistant phenotypes. Using an in vitro dormancy model induced by HER2 inhibition, we observed a reversible quiescent state characterized by decreased proliferation and viability, accompanied by a significant increase in the CSC marker CD44. CD44 expression was rapidly induced following HER2 inhibition, preceding measurable effects on cell viability, and persisted throughout the dormancy phase. CD44-positive populations showed reduced sensitivity to HER2 inhibition and displayed robust proliferative recovery upon therapy withdrawal. Functional studies revealed that the inhibition of JAK1, but not STAT3, impaired the recovery of CD44-positive populations and decreased their proliferative capacity, suggesting a critical role for JAK1 in maintaining the CSC phenotype during therapy. These findings underscore the importance of CD44 as a marker and mediator of therapy resistance and suggest that targeting CD44-positive cells or the JAK1 signaling axis could improve the efficacy of HER2-targeted therapies. Our study provides novel insights into the mechanisms underlying dormancy and CSC induction in HER2-positive breast cancer and highlights potential strategies to mitigate therapy resistance and prevent disease recurrence. Full article

This paper introduces an acoustic-based monitoring system for high-speed CNC drilling, aimed at optimizing processes and enabling real-time machine state detection. High-fidelity acoustic sensors capture sound signals during drilling operations, allowing the identification of critical events such as tool engagement, material breakthrough, and tool withdrawal. Advanced signal processing techniques, including spectrogram analysis and Fast Fourier Transform, extract dominant frequencies and acoustic patterns, while machine learning algorithms like DBSCAN clustering classify operational states such as cutting, breakthrough, and returning. Experimental studies on materials including acrylic, PTFE, and hardwood reveal distinct acoustic profiles influenced by material properties and drilling conditions. Smoother sound patterns and lower dominant frequencies characterize PTFE drilling, whereas hardwood produces higher frequencies and rougher patterns due to its density and resistance. These findings demonstrate the correlation between acoustic emissions and machining dynamics, enabling non-invasive real-time monitoring and predictive maintenance. As AI power increases, it is expected to extract in-situ process information and achieve higher resolution, enhancing precision in data interpretation and decision-making. A key contribution of this project is the creation of an open sound library for drilling processes, fostering collaboration and innovation in intelligent manufacturing. By integrating big data concepts and intelligent algorithms, the system supports continuous monitoring, anomaly detection, and process optimization. This AI-ready hardware enhances the accuracy and efficiency of drilling operations, improving quality, reducing tool wear, and minimizing downtime. The research establishes acoustic monitoring as a transformative approach to advancing CNC drilling processes and intelligent manufacturing systems. Full article

Background and Clinical Significance: Statins are a widely used drug class associated with a plethora of muscular side effects ranging from the subclinical elevation of creatine kinase to fulminant rhabdomyolysis. Cardiac myopathy secondary to statin treatment is rare and was recently reported as a part of statin-induced necrotizing autoimmune myopathy (SINAM). Its occurrence outside of this context is still debated. Case Presentation: We present the case of a 60-year-old male who developed atorvastatin-induced rhabdomyolysis, without associated hydroxymethyl glutaryl coenzyme A reductase (HMGCR) antibodies, with clinical findings of cardiac failure and severe ECG anomalies. The symptoms slowly regressed with statin withdrawal, and the patient made a full recovery. We discuss the recently proposed statin-associated cardiomyopathy (SACM) and the possible mechanisms. We compare our case to the three other cases of statin-induced cardiac myositis found in the literature. Conclusions: We believe that in vulnerable patients, as was our case, statins can determine significant subacute cardiac toxicity. This would seem to occur in the context of severe skeletal muscle injury, probably due to higher metabolic resistance on the part of the myocardium. Also, the available evidence suggests myocardial involvement should be actively investigated in SINAM patients, preferably by cardiac MRI. Full article

The “angiogenesis switch”—defined as the active process by which solid tumors develop their own circulation—plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the “angiogenic switch” acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents. Full article

Methamphetamine (METH) use disorder (MUD) is a public health catastrophe. Herein, we used a METH self-administration model to assess behavioral responses to the dopamine receptor D1 (DRD1) antagonist, SCH23390. Differential gene expression was measured in the dorsal striatum after a 30-day withdrawal from METH. SCH23390 administration reduced METH taking in all animals. Shock Resistant (SR) rats showed greater incubation of METH seeking, which was correlated with increased Creb1, Cbp, and JunD mRNA expression. Cytoplasmic polyadenylation element binding protein 4 (Cpeb4) mRNA levels were increased in shock-sensitive (SS) rats. SS rats also showed increased protein levels for cleavage and polyadenylation specificity factor (CPSF) and germ line development 2 (GLD2) that are CPEB4-interacting proteins. Interestingly, GLD2-regulated GLUN2A mRNA and its protein showed increased expression in the shock-sensitive rats. Taken together, these observations identified CPEB4-regulated molecular mechanisms acting via NMDA GLUN2A receptors as potential targets for the treatment of METH use disorder. Full article

This study evaluates the efficacy of a new florfenicol-based drug, both in vitro and in vivo, in Nile tilapia (Oreochromis niloticus) against pathogens commonly found in fish farming and its withdrawal period. The drug’s efficacy was tested using prophylactic, metaphylactic, and therapeutic approaches against Streptococcus agalactiae (serotypes Ib and III) and Francisella orientalis. The minimum inhibitory concentration of florfenicol was 4, 5, and 128 μg/mL for the different pathogens. Fish mortality was lower in the prophylactic treatment compared to the metaphylactic and therapeutic treatments for S. agalactiae. No difference in mortality was observed for F. orientalis across treatments. Mild to moderate lesions suggestive of intoxication were observed, mainly in the liver of fish treated with overdoses or exposed to low temperatures. Florfenicol reduced mortality rates, especially with early treatment (metaphylactic), in fish experimentally challenged with the pathogens. Moreover, prophylactic antimicrobial use is not recommended, as it promotes the selection of multidrug-resistant bacterial strains. Additionally, the residual concentration of the drug in muscle tissue lasted for a shorter period than that recommended by the manufacturer, and at lower concentrations than required by national and international legislation. Full article

The continued and improper use of antibiotics has resulted in the emergence of antibiotic resistance (AR). The dissemination of antibiotic-resistant microorganisms occurs via a multitude of pathways, including the food supply. The failure to comply with the regulatory withdrawal period associated with the treatment of domestic animals or the illicit use of antibiotics as growth promoters has contributed to the proliferation of antibiotic-resistant bacteria in meat and dairy products. It was demonstrated that not only do animal and human pathogens act as donors of antibiotic resistance genes, but also that lactic acid bacteria can serve as reservoirs of genes encoding for antibiotic resistance. Consequently, the consumption of fermented foods also presents a potential conduit for the dissemination of AR. This review provides an overview of the potential for the transmission of antibiotic resistance in a range of traditional and novel foods. The literature data reveal that foodborne microbes can be a significant factor in the dissemination of antibiotic resistance. Full article

This paper examines the splitting tensile properties of rubberized polyethylene-engineered cementitious composites (RPECC) through static and dynamic experimental tests, highlighting the effects of thermal cycles, impact strain rates, and rubber powder substitution rates for fine aggregates. Damage patterns, ultimate tensile strength, time-dependent stress curves, dynamic failure strain, and the dynamic increase factor of the RPECC are presented. The microstructure of the material is analyzed using scanning electron microscopy and energy-dispersive X-ray spectroscopy. Experimental results reveal that incorporating rubber powders significantly enhances the deformability and ductility of RPECC in splitting tension. However, a high content of rubber powders, such as a substitution percentage of 30%, significantly reduces static and the dynamic ultimate tensile strength of the RPECC by 16.8% and 34.2%, respectively. Microstructural examinations indicate that thermal cycling weakens the internal adhesion between the rubber particles, polyethylene fibers, and the ECC matrix, resulting in the frequent withdrawal of fibers and the formation of calcium hydroxide, which diminishes the material tensile strength by up to 20.6% in static tests and 45.1% in dynamic tests. Despite these challenges, the RPECC with 20% rubber achieves a favorable balance between splitting the tensile properties and thermal resistance, even after undergoing 270 heat-cool cycles, suggesting its potential applicability in harsh environments. Full article

This study evaluates the perfection of the crystal structure of single-crystal turbine blade castings made from the CMSX-4 nickel superalloy. The analysis included primary and secondary crystal orientation measurements using the Ω-scan method and the novel OD-EFG X-ray diffractometer. The selected microstructural parameters of the single crystals were also analyzed, including the assessment of stereological parameters and the degree of porosity. A creep test was performed according to standard procedures and under conditions simulating real operational environments. The model single-crystal turbine blades were manufactured using the Bridgman–Stockbarger method, with variable withdrawal rates of 1 and 3 mm/min. Heat treatment of the single-crystal castings involved solution treatment followed by double aging. The evaluation of structural perfection was carried out in three states: as-cast, after solution heat treatment, and after double aging. The crystallographic orientation of the blades was determined on both the airfoil and the root part. The study determined how crystallographic orientation and microstructural parameters influence the creep resistance of the castings. It was found that in the as-cast condition, the greatest influence on high creep strength has a small deviation of the primary and constant value of secondary crystal orientation along the height of the blade casting. After heat treatment, the highest creep resistance was obtained for the blade manufactured at a withdrawal rate at 1 mm/min. Full article

The use of supraphysiologic testosterone, particularly when alternated with an anti-androgen agent in men with metastatic castration-resistant prostate cancer (CRPC), has demonstrated promising results in clinical trials. As the use of this therapy in clinical practice is more widely adopted, there will be a growing need to understand the mechanisms of resistance. To that end, we independently derived three separate cell models of testosterone-sensitive CRPC. From each CRPC line, high dose testosterone-resistance (HTR) lines were selected. We demonstrated the differential response of the three CRPC lines to a high dose of testosterone in vitro and in vivo. We subsequently demonstrated the resistance of the HTR lines to testosterone and varying responses to testosterone withdrawal in vivo. The heterogeneity in responses to hormonal manipulation is correlated with varying levels of androgen receptor expression within the population. Overall, we show that we have developed three models of HTR that can be used to study the mechanisms of high dose testosterone resistance and identify potential therapeutic targets. Full article

Background/Objectives: Negative symptoms (NSs) significantly impair the outcome of schizophrenia, primarily due to their effect on quality of life and their resistance to pharmacological treatments. Several scales have been developed to assess the various dimensions of NSs, including avolition, anhedonia, alogia, social withdrawal, and blunted affect. While observer-rated scales are the most commonly used, self-assessment tools remain underutilized. However, self-assessments offer a promising approach for gaining insights into the personal experiences of individuals. The objective of this review was to identify and report the psychometric properties of self-assessment scales for NSs that are relevant for both research and clinical practice, with a focus on tools that assess multiple domains of NSs in order to support comprehensive evaluations and tailored therapeutic strategies. Methods: We conducted an exhaustive literature review following PRISMA guidelines to identify self-evaluation scales that evaluate several domains of NSs in the MEDLINE and Web of Science databases. The COSMIN checklist was used to assess the methodological quality of each tool. Results: Our review identified five self-assessment scales. Among these, two scales received a Grade A recommendation for use in clinical or research practice: the Self-evaluation Negative Symptom (SNS), which assesses the five domains of NSs, and the Motivation And Pleasure Scale Self-report (MAP-SR), which evaluates anhedonia, avolition, and social withdrawal. Conclusions: The SNS and the MAP-SR are the only tools with sufficient psychometric properties, making them reliable for use in both research and clinical practice. Despite the development of self-assessment tools for NSs, their integration into research and clinical settings remains limited, highlighting the need for increased utilization to enhance the understanding and management of these symptoms. Full article

Antibacterial drugs (commonly known as antibiotics) are essential for eradicating bacterial infections. Nowadays, antibacterial discovery has become an imperative need due to the lack of efficacious antibiotics, the ever-increasing development of multi-drug resistance (MDR), and the withdrawal of many pharmaceutical industries from antibacterial discovery programs. Currently, drug discovery is widely recognized as a multi-objective optimization problem where computational approaches could play a pivotal role, enabling the identification of novel and versatile antibacterial agents. Yet, tackling complex phenomena such as the multi-genic nature of bacterial infections and MDR is a major disadvantage of most of the modern computational methods. To the best of our knowledge, perturbation-theory machine learning (PTML) appears to be the only computational approach capable of overcoming the aforementioned limitation. The present review discusses PTML modeling as the most suitable cutting-edge computational approach for multi-objective optimization in antibacterial discovery. In this sense, we focus our attention on the development and application of PTML models for the prediction and/or design of multi-target (multi-protein or multi-strain) antibacterial inhibitors in the context of small organic molecules, peptide design, and metal-containing nanoparticles. Additionally, we highlight future applications of PTML modeling in the context of novel drug-like chemotypes with multi-protein and/or multi-strain antibacterial activity. Full article

This review investigates the levels of antibiotic residues in animal products, types of antibiotics, and their possible impact on human health in Africa. The literature search involved the use of a systematic survey using data that were published from Africa from 2015 to 2024. The search terms used the Boolean operators with keywords such as antibiotics, antibiotic residues, antibiotics in animal products in Africa, and impact on human health. Only research conducted in Africa was used in the present study. The findings showed that the most prevalent groups of antibiotic residues were aminoglycoside, macrolides, β-lactams, fluoroquinolones, tetracyclines sulfonamides, and phenicols. Tetracycline showed the most prevalent antibiotic residue with 43% mostly from East Africa, followed by sulfonamides at 19%, and β-lactams at 16%; most of the antibiotic residue levels were higher than the World Health Organization permissible limit. Noncompliance with withdrawal periods and maximum residue limits for antibiotics used in food-producing animals may lead to negative outcomes such as allergic reactions, teratogenicity, carcinogenicity, microbiome alterations, and, most notably, antibiotic resistance. As a result, there is a need for constant monitoring of antibiotic residues in animal products in addition to the consideration of alternatives to antibiotics in order to avoid their health implications. Full article