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Abstract Background This study attempts to analyse physical fitness and basic anthropometric parameters of children and adolescents participating in the nationwide physical activity promotion programme “Athletics for All!” (AFA). The programme aims to establish a national system for diagnosing, selecting, recruiting, and identifying talents in youth training. It also aims to build a career development path for athletics, forming the basis of a new structure for youth training in Poland. The primary goal of this study was to assess physical fitness of AFA participants over the years of its implementation (2015–2022) and to identify the leading motor ability with consideration for age, gender, and body build parameters determined with Body Mass Index and Ponderal Index. Methods Nationwide measurements of basic anthropometric parameters as well as physical fitness tests were conducted among 31,790 girls (F) and 22,260 boys (M) participating in the AFA programme. Physical fitness assessments were performed using the OSF test (3 × 10 m shuttle run, standing broad jump, 1 kg medicine ball throw, 4-minute run). Comparative analysis of OSF test results, considering gender, was conducted using the independent samples T-test. The strength and direction of correlations between variables were calculated using the rho-Spearman coefficient. Results OSF test results were converted into points, considering age and gender. Gender was found to be a significantly differentiating factor in physical fitness of AFA participants. Among twelve- and fifteen-year-olds, statistically significant differences were observed in all analysed variables, i.e. in each of the four tests and the overall score. It was noted that the examined girls aged 11 to 17 exhibited higher levels of strength compared to their male counterparts. Statistical analysis revealed significant correlations between OSF test results and the age and body build indicators, with the strength of the correlations being negligible in most cases. Conclusions Participants of the nationwide programme “Athletics for All!” demonstrate a high level of physical fitness, with endurance being a fundamental motor ability. Physical fitness levels show significant correlations with the anthropometric parameters of children and adolescents. The study results confirm the need and justification for implementing physical activity promotion programmes for the younger generation.

Observation: A 61-year-old male patient presented with tongue and base floor of the mouth firm swelling with intact overlying mucosa with ballottement by bimanual palpation. Histopathological examination and immunodiagnosis revealed this mass as adult rhabdomyoma. Comments: Any tongue base or floor of the mouth mass with intact overlying mucosa should be approached by magnetic resonance imaging with great concern of rhabdomyoma.

Abstract Extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) are pivotal bioactive structures involved in various processes including inflammation. Herein we report the interactions between EVs and NETs during murine endotoxemia studied in situ directly in the vasculature (cremaster muscle, liver sinusoids) using intravital microscopy (IVM). We captured NETs and EV release in real time by both non- and polarized neutrophils in liver but not in cremaster vasculature. When comparing numbers of circulating EVs of various origin (nanoparticle tracking analysis—NTA, flow cytometry) with those interacting with endothelium and NETs (IVM) we observed that whereas platelet and monocyte/macrophage-derived EVs dominate in blood and peritoneal lavage, respectively, mostly neutrophil-derived EVs interact with the vascular lining, NETs and leukocytes. Despite the interaction, NETs do not affect EV formation as NET release inhibition did not alter EV release. However, EVs inhibit NETs formation and in particular, erythrocyte-derived EVs downregulate NET release and this effect is mediated via Siglec-E-dependent interactions with neutrophils. Overall, we report that EVs are present in NETs in vivo and they do modulate their release but the process in not bidirectional. Moreover, EVs isolated from body fluids might not reflect their importance in direct endothelial- and leukocyte-related interactions.

Abstract Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.

The objective of this study was to present a comparative analysis of the antimicrobial activity of methanolic leaf extracts from seven Juniperus L. species, together with a tentative analysis of their total flavonoid and o-dihydroxyphenolic acids content. The chemical analyses were performed by colorimetric methods and the antimicrobial activity was assessed via broth microdilution. The studied extracts showed total content of o-dihydroxyphenols in the range of 26 to 34 µg of caffeic acid equivalent/mg DE and total flavonoid content of 13 to 24 µg of quercetin equivalent/mg DE. The sensitivity of Gram-positive bacteria to the studied extracts differed significantly with the following order of activity: J. sabina var. balkanensis > J. communis ‘Laxa’ > J. formosana > J. pinchotii > J. ashei > J. excelsa ≈ J. sibirica. Weak activity was observed for all extracts against Gram-negative bacteria and Candida strains. The analysis of the MBC/MIC ratio showed that the extracts exhibited bactericidal effect against Gram-negative bacteria (MBC/MIC≤4), while bactericidal or bacteriostatic action (MBC/MIC>4) was determined towards Gram-positive bacteria. Moreover, these extracts showed fungicidal (MFC/MIC≤4) or fungistatic effect (MFC/MIC>4). Best antibacterial activity was registered for the J. sabina var. balkanensis leaf extract. The multivariate data analyses were carried out by SIMCA 16 (v16.0.2) software. The hierarchical cluster analysis and principal component analysis, based on phytochemical and antimicrobial data, classified the studied juniper species into four groups: 1. J. ashei; 2. J. excelsa, J. sibirica; 3. J. sabina var. balkanensis, J. communis Laxa, J. formosana; 4. J. pinchotii.

The human body is colonized by trillions of microorganisms in a symbiotic relationship. The oral cavity represents one of the most abundant microbial habitats in our body. Advances in sequencing techniques provide a more detailed understanding of the oral microbiota and how imbalances between bacteria, the phenomenon of dysbiosis, can affect not only the development of dental caries or inflammation within the oral cavity but also systemic diseases and cancers in distant locations. This narrative review evaluates the relationship between oral microbiota and its impact on gastrointestinal cancers. Using the keywords “oral microbiota ‘AND’ gastrointestinal cancers”, the PubMed Web of Science and Scopus databases were searched for articles published between 2014 and 2024. Based on the review, the relationship between oral microbiota and oral, esophageal, gastric, colorectal, hepatocellular, and pancreatic cancers was described. Potential oncogenic mechanisms exploited by the microbiota such as the production of pro-inflammatory cytokines, induction of abnormal immune responses, and disruption of cell metabolic pathways were assessed. Further research and a thorough understanding of the impact of the oral microbiota on the development of cancers of the gastrointestinal tract may play a key role in their prevention, diagnosis, and treatment in the future.

Introduction and objective: Obesity has become an important public health issue in Poland. Furthermore, it is one of the most common preventable causes of diseases and mortality. Pharmacological methods of treating obesity have been developing significantly in recent years.Tirzepatide is a new dual incretin receptor agonist that activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptors. The aim of this review is to assess the effectiveness of this medication in reducing body weight. Current state of knowledge: According to data from the Central Statistical Office (GUS) in Poland, 65% of men and 49% of women are struggling with the issue of excessive body weight [1]. Obesity in Polish society is steadily increasing in every age group. However, it affects most significantly children aged 7-13 years and adolescents. In 2022, the novel dual GLP and GIP-1 agonist has been registered for the treatment of type 2 diabetes which is not satisfactorily controlled. It can be also used together with diet and physical activity in patients diagnosed with obesity (BMI of 30 kg/m2 or more) or who are overweight (BMI 27-30 kg/m2) and have weight-related health problems such as hypertension, metabolic syndrome, dislipidaemia and diabetes mellitus [2]. Summary: The increasing prevalence of obesity leads to a dynamic search for the most effective pharmacological methods of treating obesity. The combined activation of GLP-1 and GIP receptors by Tirzepatide has been shown to have additional benefits beyond satisfying glucose control. The biological mechanism of action of this medication additionally causes decreased food intake, slowed gastric emptying and enhanced insulin secretion, all of which can contribute to weight reduction.

Introduction: Anticoagulants have been discovered and developed over past 100 years. At the beginning unfractionated heparin found its applications, just later to fade into the background of newer and more effective drugs. Patients have been treated with more progressive medications – Low-Molecule-Weight Heparin (LMWH), Vitamin K Antagonists (VKA) and Novel Oral Anticoagulants (NOAC). As for today, deemed a turning point in anticoagulant therapy are inhibitors of factor XI. It is a ground-breaking innovation as it ensures high prevention of thrombotic episodes and guarantees intact physiological hemostasis.Current State of Knowledge: The coagulation cascade and molecules part taking in that have been discovered and described extensively and in detail. Unfractionated heparin is the oldest out of all and despite its simple action mechanism and adverse effects, is still a requested drug. Its lighter form, low-molecule-weight-heparin (LMWH) is an enhancement to the previous treatment due to its higher bioavailability and fewer side effects. Vitamin K antagonists (VKAs) are widely spread in medical environment thanks to their expanded mechanism of action, oral administration and reversibility of their overdose, as well as their well-developed anti-side effect therapy. Novel Oral Anticoagulants (NOACs) have been introduced to the market about 10 years ago. In spite of NOACs short period of clinical use, they were a huge change to the previous treating methods. Currently, the newest innovation in anticoagulant therapy are inhibitors of factor XI and its clinical trials outcome is promising for the future.Summary: The present article discusses history of anticoagulant drugs, their mechanism of action and usage but also focuses on the recent perspectives and developments as new anticoagulant drugs are being put to the test in therapeutic trials. The review underlines the importance of improvements in old therapeutic methods and exploring the new, more suitable ones.

Abstract Background Machine learning (ML) methods to build prediction models starting from electrocardiogram (ECG) signals are an emerging research field. The aim of the present study is to investigate the performances of two ML approaches based on ECGs for the prediction of new-onset atrial fibrillation (AF), in terms of discrimination, calibration and sample size dependence. Methods We trained two models to predict new-onset AF: a convolutional neural network (CNN), that takes as input the raw ECG signals, and an eXtreme Gradient Boosting model (XGB), that uses the signal’s extracted features. A penalized logistic regression model (LR) was used as a benchmark. Discrimination was evaluated with the area under the ROC curve, while calibration with the integrated calibration index. We investigated the dependence of models’ performances on the sample size and on class imbalance corrections introduced with random under-sampling. Results CNN's discrimination was the most affected by the sample size, outperforming XGB and LR only around n = 10.000 observations. Calibration showed only a small dependence on the sample size for all the models considered. Balancing the training set with random undersampling did not improve discrimination in any of the models. Instead, the main effect of imbalance corrections was to worsen the models’ calibration (for CNN, integrated calibration index from 0.014 [0.01, 0.018] to 0.17 [0.16, 0.19]). The sample size emerged as a fundamental point for developing the CNN model, especially in terms of discrimination (AUC = 0.75 [0.73, 0.77] when n = 10.000, AUC = 0.80 [0.79, 0.81] when n = 150.000). The effect of the sample size on the other two models was weaker. Imbalance corrections led to poorly calibrated models, for all the approaches considered, reducing the clinical utility of the models. Conclusions Our results suggest that the choice of approach in the analysis of ECG should be based on the amount of data available, preferring more standard models for small datasets. Moreover, imbalance correction methods should be avoided when developing clinical prediction models, where calibration is crucial.

Introduction: The increasing participation of young individuals in sports necessitates a comprehensive understanding of the intricate relationship between nutrition and athletic performance during the critical adolescent years. This introduction sets the stage for an exploration of the dynamic nutritional needs of young athletes, emphasizing the pivotal role of nutrition in supporting growth, energy metabolism, and overall athletic achievement. Current State of Knowledge: The current state of knowledge encompasses an in-depth analysis of key nutritional considerations for young athletes. Examining energy and macronutrient requirements, micronutrient considerations, hydration strategies, and optimal timing of nutrition, this section synthesizes existing research to provide evidence-based guidelines. Furthermore, it addresses the unique challenges posed by different sports and the importance of tailored nutritional approaches for diverse athletic endeavors. The evolving landscape of sports nutrition is also explored, with a specific focus on the benefits and potential risks associated with protein and creatine supplementation. Summary: In summary, this article serves as a comprehensive resource for athletes, coaches, and parents seeking to navigate the intricate intersection of nutrition and young athletes. By elucidating evidence-based strategies and addressing the potential drawbacks and risks associated with certain supplements, the article aims to empower stakeholders with the knowledge needed to make informed decisions regarding the nutritional well-being of young athletes. It underscores the importance of individualized approaches, recognizing the diversity of young athletes and advocating for adaptable nutritional strategies that contribute to both immediate performance gains and sustained health and athletic success.

Introduction The anterior cruciate ligament (ACL) is a prevalent sports-related injury, constituting nearly half of knee injuries. This narrative review explores the evolution of ACL reconstruction surgeries, emphasizing graft types and their pros and cons. Current state of knowledge The ideal ACL graft choice depends on factors like age, lifestyle, and demands. Autografts are the current standard, with the Quadriceps Tendon graft offering similar outcomes and fewer complications. Allografts are a secondary option for older, low-demand patients due to a shorter recovery period. Artificial grafts have limited use, lacking strong evidence for clinical advantages but may be considered for suturing torn ACL stumps and in cases were quick recovery is essential. Summary Contemporary orthopedic practitioners must possess comprehensive knowledge of various ACL reconstruction graft types to tailor interventions precisely to individual patient requirements. The selection of a graft should be rooted in a profound comprehension of patients' lifestyles, medical histories, and specific demands, thereby mitigating the subjective impact of any associated limitations for the patient.

Anterior chest wall depression known as Pectus excavatum (PE) , is currently the most common congenital chest wall deformation, with incidence estimated at 1/400 births, five times more frequently in boys than girls (5:1 ratio in occurrence). 1 Etiology of this deformity is formed by several hypothesis, including overgrowth of the ribs, developmental failure of the bony thorax or weakness and abnormal flexibility of the sternum. While theoretical concepts of its origin may differ, the common ground is the characteristics of said deformation: a posterior depression of the sternum and the lower costal cartilages. 2 Surgical treatment options were described since 1949 with Ravitch procedure and since then a number of new ones has been developed. For many years Ravitch and Nuss procedures were the main way to treat pectus excavatum, with a growing bias towards latter one. Since the Nuss procedure characterizes with less invasive approach and fever overall complications 3 its popularity outgrew Ravitch procedure and currently is described as MIRPE – Minimally Invasive Pectus Excavatum Repair. 4 However afterward then many new techniques were developed, focusing on reducing overall procedure risks, improving patient safety and quality of life and including new technical possibilities. The aim of this study was to gather and evaluate current literature to highlight new treatment options.

Introduction: Obesity is one of the most challenging and popular problem in nowadays society. Overweight and obesity are connected with chronic complications, such as arterial hypertension, atherosclerotic cardiovascular disease and type 2 diabetes. Nonsurgical methods of weight loss were not positively conducted in significant part of obese population. It has given a chance to develop part of medicine known as bariatric surgery. Obesity is identified as an risk factor for sexual dysfunction. The aim of this article is to summarize the main findings of studies about the influence of bariatric surgery on sexual functions of obese male patients. Materials and methods: The study is based on medical articles gathered from PubMed database spanning the years 2016-2023 and article from National Institutes of Health and from Nutritionhospitalaria. The research was conducted through the analysis of keywords such as ”Obesity”, „Bariatric Surgery”, Sexual Dysfunction”, „Men”. Results: This review indicated that surgically inducted weight loss could improve sexual function in obese men. It is connected with important increase in IIEF score and serum testosteron level. It is a need for further clinical studies to explore association of sexual function after bariatric surgery.

Introduction: Alzheimer's disease (AD) remains a pervasive and challenging neurodegenerative disorder with profound implications for individuals, families, and societies. As the most prevalent cause of dementia globally, AD's prevalence is set to rise significantly in the context of an aging population. This introductory section emphasizes the urgent need for a comprehensive understanding of the disease, encompassing both its molecular intricacies and the socio-economic burden. With age being the primary risk factor, recent research has delved into the complex interplay of genetic predisposition and environmental influences, reshaping our understanding of AD from a multifactorial perspective. Current State of Knowledge: Advancements in Alzheimer's research have led to a nuanced understanding of its pathology. Traditionally characterized by amyloid-beta plaques and tau tangles, recent insights from neuroimaging and biomarker studies have revealed the intricate nature of these pathologies and their roles in disease progression. Genetic studies, including genome-wide association analyses, have identified susceptibility loci, notably the APOE gene. Simultaneously, environmental factors, such as air pollution and lifestyle choices, are recognized contributors to AD risk. The therapeutic landscape has evolved, with ongoing investigations into anti-amyloid and anti-tau therapies, lifestyle interventions, and precision medicine approaches. The synthesis of these diverse findings highlights the dynamic nature of Alzheimer's research and its potential to shape future treatment modalities. Summary: In summary, this article provides a comprehensive overview of the current state of knowledge regarding Alzheimer's disease. From understanding its evolving pathology to exploring the interplay of genetic and environmental factors, the multifactorial nature of AD is underscored. The therapeutic landscape is actively advancing, presenting a hopeful outlook for future treatments.

Introduction and purpose: Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had been spreading rapidly throughout the world, mainly affecting respiratory system. Except pulmonary symptoms, skin lesions might also occur. The precise percentage of patients with confirmed COVID-19 who presented cutaneous manifestations is still unknown (0.2% - 20.4%). Part of the skin lesions might be drug-induced. Brief description of the state of knowledge: Cutaneous manifestations in the course of the coronavirus disease could be divided into six main groups: maculopapular rash, urticarial lesions, chilblain‐like lesions, vesicular eruptions, petechial/purpuric lesions and livedoid lesions. The most common skin lesions are maculopapular eruptions (47%). Trunk is the most affected location, whereas pruritus is the most frequent additional symptom among patients with skin lesions associated with coronavirus disease. These lesions appear mainly in elderly patients except pseudo chilblains which are present among children and young adults with SARS-Cov-2 infection. The majority of cutaneous manifestations occur after COVID-19 systemic symptoms, but the appearance of vesicular lesions before the respiratory signs was also reported. Cutaneous manifestations resolved spontaneously at different times, ranging from a few days to 2-4 weeks. Moreover, patients with severe course of COVID-19 with maculopapular rash have better prognosis (2% mortality rate) in comparison to patients who developed livedoid lesions in course of the coronavirus disease (10% mortality rate). Summary: Pseudo-chilblains and vesicular lesions are the most specific cutaneous manifestations of coronavirus disease. Healthcare professionals should pay attention to patients who present skin symptoms in the course of COVID-19. Cutaneous manifestations can facilitate the doctor the diagnosis and even estimate the severity of coronavirus disease.

Phosphodiesterase 2 A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cerebral cortex and hippocampus, PDE2A expression level is upregulated in Fmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a+/− mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a+/− females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of Glutamate receptor (GluR1) in CA1, producing reduced mGluR-dependent Long-term Depression. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer's disease, schizophrenia, FXS as well as other forms of ASD.

Allogeneic transplantation is a multi-step process involving many clinicians and laboratory personnel working together to achieve a common goal—to maximize the recipients’ chance of survival and to improve their quality of life. One of the key elements of the process is to ensure high quality, accuracy, and reliability of histocompatibility testing. This manuscript presents: the development and organizational principles of the national system of supervision and control of histocompatibility laboratories in Poland, problems faced by these laboratories, availabe proficiency testing schemes, as well as suggestions and prospects for the future raised by members of the Polish histocompatibility community.

BackgroundTelemedicine, a term that encompasses several applications and tasks, generally involves the remote management and treatment of patients by physicians. It is known as transversal telemedicine when practiced among health care professionals (HCPs). ObjectiveWe describe the experience of implementing our telemedicine Eumeda platform for HCPs over the last 10 years. MethodsA web-based informatics platform was developed that had continuously updated hypertext created using advanced technology and the following features: security, data insertion, dedicated software for image analysis, and the ability to export data for statistical surveys. Customizable files called “modules” were designed and built for different fields of medicine, mainly in the ophthalmology subspecialty. Each module was used by HCPs with different authorization profiles. Implementation (Results)Twelve representative modules for different projects are presented in this manuscript. These modules evolved over time, with varying degrees of interconnectivity, including the participation of a number of centers in 19 cities across Italy. The number of HCP operators involved in each single module ranged from 6 to 114 (average 21.8, SD 28.5). Data related to 2574 participants were inserted across all the modules. The average percentage of completed text/image fields in the 12 modules was 65.7%. All modules were evaluated in terms of access, acceptability, and medical efficacy. In their final evaluation, the participants judged the modules to be useful and efficient for clinical use. ConclusionsOur results demonstrate the usefulness of the telemedicine platform for HCPs in terms of improved knowledge in medicine, patient care, scientific research, teaching, and the choice of therapies. It would be useful to start similar projects across various health care fields, considering that in the near future medicine as we know it will completely change.

This study aims to evaluate the applicability of a text mining approach for extracting UUX-related issues from a dataset of user comments and not to evaluate the Instagram (IG) app. This study analyses textual data mined from reviews in English written by IG mobile application users. The article’s authors used text mining (based on the LDA algorithm) to identify the main UUX-related topics. Next, they mapped the identified topics with known theoretical constructs to place them in their nomological network relevant to the usability (the 5Es framework by Quesenbery) and UX (the Honeycomb model by Morville). Finally, to expand the study with an emotional diagnosis, sentiment analysis was performed on two levels: (i) for each recognised topic, and (ii) for the full dataset to uncover general insights into users’ emotions within all reviews. The case study of the IG app confirms the usefulness of user feedback data for software development and points out that the review data have the potential for the early detection of frustration and negative feelings introduced during the use of the application. Conducting conventional UUX evaluations with users is problematic since they are remotely located, and the user-generated content of a social app undergoes continuous and frequent changes. Thus, the consecutive stages of the proposed methodology, based on text mining algorithms, constitute a proposed framework for examining the user-perceived quality projection of applications from user feedback, and they are the main contribution of this article. The used approach can be valuable for helping developers, designers and researchers to reveal user problems and fulfil user satisfaction regarding UUX aspects for specific software features.

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery. Results: 2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers. Conclusion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

Abstract Background Local myogenesis, neoangiogenesis and homing of progenitor cells from the bone marrow appear to contribute to repair of the infarcted myocardium. Implantation into heart tissues of autologous skeletal myoblasts has been associated with improved contractile function in animal models and in humans with acute myocardial ischemia. Since heart infarction is most prevalent in individuals of over 40 years of age, we tested whether culture methods available in our laboratory were adequate to obtain sufficient numbers of differentiated skeletal myoblasts from muscle biopsy specimens obtained from patients aged 41 to 91. Methods and results No matter of donor age, differentiated skeletal muscle cells could be produced in vitro in amounts adequate for cellular therapy (≥300 millions). Using desmin as a cytoplasmic marker, about 50% cultured cells were differentiated along myogenic lineages and expressed proteins proper of skeletal muscle (myosin type I and II, actin, actinin, spectrin and dystrophin). Cytogenetic alterations were not detected in cultured muscle cells that had undergone at least 10 population doublings. Molecular methods employed for the screening of persistent viral infections evidenced that HCV failed to replicate in muscle cells cultured from one patient with chronic HCV infection. Conclusion The proposed culture methods appear to hold promise for aged patients not only in the field of cardiovascular medicine, but also in the urologic and orthopedic fields.

Abstract Background Tat is being tested as a component of HIV vaccines. Tat activity has been mainly investigated on cells of lymphoid/hematopoietic lineages. HIV-1, however, is known to infect many different cells of both solid organs and mucosal surfaces. The activity of two-exon (aa 1–101) and synthetic (aa 1–86) Tat was studied on mammary and amniotic epithelial cells cultured under low serum conditions. Results small concentrations of Tat (100 ng/ml) stimulated cell proliferation. Tat antibodies neutralized the mitogenic Tat activity. Changes of gene expression in Tat-treated cells were evaluated by RT-PCR and gene-array methods. Within 4 hours of treatment, exposure to Tat is followed by up-regulation of some cell cycle-associated genes (transcription factors, cyclin/cdk complexes, genes of apoptotic pathways) and of genes relevant to HIV pathogenesis [chemokine receptors (CXCR4, CCR3), chemotactic cytokines (SDF-1, RANTES, SCYC1, SCYE1), IL6 family cytokines, inflammatory cytokines, factors of the TGF-beta family (TGFb, BMP-1, BMP-2)]. Up-regulation of anti-inflammatory cytokines (IL-10, IL-19, IL-20), a hallmark of other persistent viral infections, was a remarkable feature of Tat-treated epithelial cell lines. Conclusion extracellular Tat is mitogenic for mammary and amniotic epithelial cells and stimulates the expression of genes of pathogenetic interest in HIV infection. These effects may favor virus replication and may facilitate the mother-to-child transmission of virus.

Background: Induction of anesthesia is a critical part of anesthetizing patients with end-stage renal disease, as they are at risk of wide hemodynamic fluctuation due to their pathophysiological alterations in the cardiovascular system. It is desirable to use pharmacological agents that provide hemodynamic stability with fewer adverse effects. Aims and Objectives: This study aimed to evaluate the effects of propofol and etomidate by comparing hemodynamic variables such as a change in mean arterial pressure (MAP) and heart rate (HR) during induction, laryngoscopy, and up to 10 min after tracheal intubation as a primary outcome and any associated adverse effect as a secondary outcome. Methods: After getting institutional ethical committee approval, 60 American Society of Anesthesiologist Grade III patients aged 20–60 years, scheduled for renal transplantation, were randomized into two groups (Group P: propofol 1% and Group E: etomidate). The dose of induction agents was targeted to achieve a bispectral index value of 40. Hemodynamic variables were recorded at induction, laryngoscopy, and up to 10 min after tracheal intubation. Adverse effects related to the study drug were recorded. Results: The decrease in MAP in Group P was statistically significant (P < 0.05) as compared to Group E, at induction of anesthesia. We observed a significant increase in HR at induction of anesthesia in Group E (P < 0.05). The incidence of myoclonus was 0 versus 73.3% in Groups P and E, respectively, while pain on injection and hypotension were more in Group P (P < 0.05). Conclusions: In conclusion, etomidate provides better hemodynamic stability with fewer adverse effects in patients with end-stage renal disease.

Activating pretreatments are used to tune surface composition and structure of bimetallic-alloy catalysts. Herein, the activation-induced changes in material properties of a nanoporous Ag0.03Au0.97 alloy and their subsequent evolution under steady-state CH3OH oxidation conditions are investigated. Activation using O3 results in AgO and Au2O3, strongly enriching the near-surface region in Ag. These oxides reduce in the O2/CH3OH mixture, yielding CO2 and producing a highly Ag-enriched surface alloy. At the reaction temperature (423 K), Ag realloys gradually with Au but remains enriched (stabilized by surface O) in the top few nanometers, producing methyl formate selectively without significant deactivation. At higher temperatures, bulk diffusion induces sintering and Ag redistribution, leading to a loss of activity. These findings demonstrate that material properties determining catalytic activity are dynamic and that metastable (kinetically trapped) forms of the material may be responsible for catalysis, providing guiding principles concerning the activation of heterogeneous catalysts for selective oxidation.