Comparative Analysis of Response to Cardiac Resynchronisation Therapy Upgrades in Patients with Implantable Cardioverter-Defibrillators and Pacemakers.

Introduction: The efficacy of de novo cardiac resynchronisation therapy (CRT) in patients with heart failure (HF), left ventricular systolic dysfunction (LVSD), and a broad QRS morphology is well established. However, the optimal stage for upgrading patients with existing pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) and HF with high-burden right ventricular (RV) pacing remains uncertain. Thus, this multicentre retrospective analysis compared patients with pre-existing PPMs or ICDs who underwent CRT upgrades to investigate the appropriate stage for CRT implantation in these patients and to assess the validity of treating both PPM and ICD recipients under the same recommendation level in the current guidelines. Materials and Methods: A total of 151 participants underwent analysis in this study, comprising 93 upgrades to cardiac resynchronisation therapy with pacemaker (CRT-P) and 58 upgrades to cardiac resynchronisation therapy with defibrillator (CRT-D) across three centres in the UK. The aim of the study was to investigate the safety and efficacy of upgrading to CRT from an existing conventional pacemaker or an ICD in the context of high-burden RV pacing. The analysis was conducted separately for each group, assessing changes in echocardiographic parameters, functional New York Heart Association (NYHA) class, and procedure-related complications. Results: The PPM group had a higher percentage RVP burden compared to the ICD group. Post-upgrade, NYHA functional class and EF and LV volumes improved in both groups; however, the response to an upgrade from a pacemaker was greater compared to an upgrade from an ICD. Post-procedural complication risks were similar across the two subgroups but significantly higher compared to de novo implantation. Conclusions: Within the CRT-P subgroup, participants exhibited better responses than their CRT-D counterparts, evident both in echocardiographic improvements and clinical outcomes. Furthermore, patients with non-ischemic cardiomyopathy (NICM) were better responders than those with ischaemic cardiomyopathy. These findings suggest that international guidelines should consider approaching each subgroup separately in the future.

The Histological and Biochemical Assessment of Monoiodoacetate-Induced Knee Osteoarthritis in a Rat Model Treated with Salicylic Acid-Iron Oxide Nanoparticles.

Iron oxide nanoparticles (IONPs) represent an important advance in the field of medicine with application in both diagnostic and drug delivery domains, offering a therapeutic approach that effectively overcomes physical and biological barriers. The current study aimed to assess whether oral administration of salicylic acid-functionalized iron oxide nanoparticles (SaIONPs) may exhibit beneficial effects in alleviating histological lesions in a murine monoiodoacetate (MIA) induced knee osteoarthritis model. In order to conduct our study, 15 Wistar male rats were randomly distributed into 3 work groups: Sham (S), MIA, and NP. At the end of the experiments, all animals were sacrificed for blood, knee, and liver sampling. Our results have shown that SaIONPs reached the targeted sites and also had a chondroprotective effect represented by less severe histological lesions regarding cellularity, altered structure morphology, and proteoglycan depletion across different layers of the knee joint cartilage tissue. Moreover, SaIONPs induced a decrease in malondialdehyde (MDA) and circulating Tumor Necrosis Factor-α (TNF-α) levels. The findings of this study suggest the therapeutic potential of SaIONPs knee osteoarthritis treatment; further studies are needed to establish a correlation between the administrated dose of SaIONPs and the improvement of the morphological and biochemical parameters.

The Potential Benefic Effect of Nicotinamide Riboside in Treating a Murine Model of Monoiodoacetate-Induced Knee Osteoarthritis.

Knee osteoarthritis (KOA), one of the most common orthopedic disorders concerning the adult population worldwide, is a condition characterized by progressive destruction of the articular cartilage and the presence of an inflammatory process. The aim of our study was to assess whether nicotinamide riboside (NR), a popular anti-aging supplement, can reduce the rate of cartilage destruction and alleviate the inflammatory response compared to the commonly prescribed collagen supplement in a murine monoiodoacetate (MIA)-induced KOA model. Twenty Wistar rats were randomly assigned to 4 groups: sham (S), MIA and NR, MIA and hydrolyzed collagen (HC), and MIA. At the end of the experiment, the right knees and blood samples were collected for histological assessment and biochemical evaluation of nitric oxide, malondialdehyde, total antioxidant capacity, reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, myeloperoxidase, and tumoral necrosis factor-alpha (TNF-α). The study determined that the treatment with NR in a similar dose with HC decreased blood/serum levels of oxidative stress biomarkers and the histological lesions in almost the same manner. The present findings suggest that NR may exhibit chondroprotective and anti-inflammatory effects in MIA-induced KOA in rats.

Optimization Techniques of Single-Detergent Based Protocols for Heart Tissue Decellularization.

The extracellular matrix (ECM) scaffolds are considered a gold standard for the engineering of appropriate grafts used in regenerative medicine for tissue repair, and decellularization of myocardial tissue is one of the most studied processes for obtaining natural ECM to date. Decellularization methods, agents used, or treatment durations can be varied to optimize cardiac tissue decellularization parameters. In this work we performed a morphological and morphometric analysis of cardiac tissue subjected to decellularization protocols based on Sodium Deoxycholate (SD) or Sodium Lauryl Sulfate (SLS) to identify factors that allow optimization of single-detergent based protocols for cardiac ECM manufacturing. For this, Wistar rat hearts (n=10) were subjected to 5 different decellularization protocols (n=2) and then histologically processed to achieve H&E or Azan trichrome stained sections for the morphological and morphometric analysis of the obtained ECM. The results of this study showed that SLS alters the spatial distribution of cardiac ECM collagen fibers, and SD can be successfully used in tailoring single-based detergent decellularization protocols by appropriately adjusting the application times of hypo/hyperosmotic shocks, which increases the lytic action of the detergent, and the washing times for the efficient elimination of cellular residues.

Simple Universal Whole-Organ Resin-Embedding Protocol for Display of Anatomical Structures.

Whole-organ plastic resin casting is a very useful method for preserving rare pathological specimens for forensic/anatomical studies and for teaching/research purposes. Many techniques have been proposed over time, but most of them use special non-commercially available resin mixtures, lengthy protocols, and are overall not easily implemented in any anatomy/pathology department that might need such a procedure for rapid organ preservation. Here, we utilized anatomical sections of the human brain, heart, kidneys, spleen, large intestine, and lungs from on-display organs that were fixed for more than 1 year in 10% neutral-buffered formalin and from a freshly processed cadaver for teaching purposes in our Human Anatomy Department, and we optimized a fast-processing protocol without the use of any clearing agents, which yields solid, clear, cylindrical resin casting blocks. The resulting protocol, which takes no longer than 4 days, proves that at least three commonly used epoxy resins from hobby shops can be utilized without any restrictions, and the use of resin or glycerin vacuum-forced impregnation even offers two choices of intrinsic contrast, depending on the nature of the preparation. A number of innovations have been included here and compared to existing publications, such as the use of a system of permanent fixation plexiglas rods that maintain the organ in the desired position and become invisible in the final block, the use of UVC sterilization of the tissue to ensure a long shelf life of the block, and the utilization of cheap cylindrical polypropylene food containers as casting molds. Altogether, we present a simple resin-embedding protocol that can be made available to any department/institution without the need for expensive materials and specially trained personnel.

Imaging Aspects of Enchondromas in Pediatric Patients.

Enchondromas are benign tumors located primarily in long bones, some of which can be accidentally discovered during imaging exams conducted for other pathologies. These benign cartilaginous tumors are hard to differentiate from low grade chondrosarcomas, which require periodic follow ups. The purpose of this study was to identify the incidence of enchondromas in pediatric patients, to determine medical imaging criteria (Computed Tomography-CT and Magnetic Resonance Imaging-MRI) in order to differentiate enchondromas from other atypical cartilaginous tumors, and to identify a potential correlation between imaging aspects and clinical signs. The aim of this study was to review imaging findings of enchondromas in children.

Partial Decellularization as a Method to Improve the Biocompatibility of Heart Tissue Implants.

Increasing the biocompatibility of some biological implants through tissue engineering is important for regenerative medicine, which recently has a rapid development dynamic. In this study we used tree different washing protocols, respectively with Sodium Lauryl Sulfate (SLS), with Sodium Deoxycholate (SD), and with saline (Sa) to achieve partial decellularization of 2-3mm thick cross-sections through Wistar rat hearts. Pieces of the heart tissue were either histologically analyzed to evaluate the decellularization processes or implanted for 5 days on 9-day-old chick embryo chorioallantoic membrane (CAM) and then histologically analyzed to evaluate CAM-implant interactions. Histological analysis of SLS or SD washed tissues showed different microscopic features of the decellularization processes, SLS-washing leading to the formation of a completely decellularized ECM layer at the periphery of the heart tissue. Both detergents induced changes in the spatial arrangement of collagen fibers of the heart tissue. Histological analysis of the CAM implants shoved that the peripheral zone with complete decellularization induced by SLS increased the biocompatibility of heart tissue implants by favoring neovascularization and cell migration. These results suggested that the biocompatibility of the heart tissue implant can be modulated by the appropriate use of a SLS-based decellularization protocol.

Liver Histopathological Changes Related to Intraperitoneal Administration of Salicylic Acid/Fe3O4 Nanoparticles to C57BL/6 Mice.

With a simple synthesis and easy engineering of physicochemical properties, iron oxide nanoparticles (IONPs) have become widely used in multiple biomedical applications. The study of IONPs toxicity has become an important issue, especially as the results reported so far are contradictory and range from lack of toxicity to cellular toxicity. The aim of this study was to evaluate the histopathological changes induced in mouse liver by long-term intraperitoneal injection of low doses of IONPs functionalized with salicylic acid (SaIONPs). The study was performed on C57BL/6 mice that received by intraperitoneal injection (IP), every two days, 0.6ml of SaIONPs aqueous suspension (35mg/kg body weight SaIONPs that contained 20mg/kg body weight of Fe3O4) for 28 days. The results of this study showed that the cumulative dose of 105mg/kg body weight SaIONPs (62mg/kg body weight of Fe3O4) induced histopathological changes in the subcapsular region of the mouse liver, possible by the release of salicylic acid into the peritoneal cavity. The cumulative dose of 244mg/kg body weight SaIONPs (145mg/kg body weight of Fe3O4) induced liver centrilobular necrosis, which requires the use of lower doses in biological applications. However, this may prove to be beneficial in the case of targeted accumulation of SaIONPs.

Subtle vascular and astrocytic changes in the brain of coronavirus disease 2019 (COVID-19) patients.

BACKGROUND AND PURPOSE: In the central nervous system, a multitude of changes have been described associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, such as microglial activation, perivascular lymphocyte cuffing, hypoxic-ischaemic changes, microthrombosis, infarcts or haemorrhages. It was sought here to assess the vascular basement membranes (vBMs) and surrounding perivascular astrocytes for any morphological changes in acute respiratory syndrome (coronavirus disease 2019, COVID-19) patients. METHODS: The light microscopy morphology of the vBMs and perivascular astrocytes from brains of 14 patients with confirmed SARS-CoV-2 infection was analysed and compared to four control patients utilizing fluorescent immunohistochemistry for collagen IV and astrocytes (GFAP), endothelia (CD31), tight junction 1 (TJ1) adhesion protein, as well as the aquaporin 4 (AQP4) water channel. On 2D and 3D deconvoluted images from the cortex and white matter, vessel densities, diameters, degree of gliosis, collagen IV/GFAP and GFAP/AQP4 colocalizations were calculated, as well as the fractal dimension of astrocytes and vBMs viewed in tangential planes. RESULTS: Fractal dimension analysis of the GFAP-stained astrocytes revealed lower branching complexities and decreased GFAP/collagen IV colocalization for COVID-19 patients. Interestingly, vBMs showed significantly increased irregularities (fractal dimension values) compared to controls. Vessel diameters were increased in COVID-19 cases, especially for the white matter, TJ1 protein decreased its colocalization with the endothelia, and AQP4 reduced its co-expression in astrocytes. CONCLUSIONS: Our data on the irregularity of the basement membranes, loss of endothelial tight junction, reduction of the astrocyte end-feet and decrease of AQP4 suggest subtle morphological changes of the blood-brain barrier in COVID-19 brains that could be linked with indirect inflammatory signalling or hypoxia/hypercapnia.

Administration Routes as Modulators of the Intrahepatic Distribution and Anti-Anemic Activity of Salicylic Acid/Fe3O4 Nanoparticles.

The liver is a key organ in the pharmacokinetics of iron oxide nanoparticles (IONPs). This paper examined how the intravenous (IV) or intragastric (IG) route of administration influenced the intrahepatic distribution or therapeutic effects of IONPs. Wistar rats, some with bleeding-induced anemia, and iron oxide nanoparticles functionalized with salicylic acid (SaIONPs), with an average hydrodynamic diameter of 73 nm, compatible with rat sinusoid fenestrations, were used in this study. Light microscopy and multispectral camera analysis of Prussian blue labeled SaIONPs allowed mapping of intrahepatic nanoparticle deposits and revealed intrahepatic distribution patterns specific to each route of administration: loading of Kupffer cells and periportal hepatocytes when the IV route was used and predominant loading of hepatocytes when the IG route was used. Reducing the time to return to baseline values for hemoglobin (HGB) in rats with bleeding-induced anemia with IV or IG therapy has proven the therapeutic potential of SaIONPs in such anemias. The long-term follow-up showed that IV therapy resulted in higher HGB values. Proper use of the administration routes may modulate intrahepatic distribution and therapeutic effects of nanoparticles. These results may be beneficial in theragnosis of liver disease.

Phenotypic Switching of B16F10 Melanoma Cells as a Stress Adaptation Response to Fe3O4/Salicylic Acid Nanoparticle Therapy.

Melanoma is a melanocyte-derived skin cancer that has a high heterogeneity due to its phenotypic plasticity, a trait that may explain its ability to survive in the case of physical or molecular aggression and to develop resistance to therapy. Therefore, the therapy modulation of phenotypic switching in combination with other treatment modalities could become a common approach in any future therapeutic strategy. In this paper, we used the syngeneic model of B16F10 melanoma implanted in C57BL/6 mice to evaluate the phenotypic changes in melanoma induced by therapy with iron oxide nanoparticles functionalized with salicylic acid (SaIONs). The results of this study showed that the oral administration of the SaIONs aqueous dispersion was followed by phenotypic switching to highly pigmented cells in B16F10 melanoma through a cytotoxicity-induced cell selection mechanism. The hyperpigmentation of melanoma cells by the intra- or extracellular accumulation of melanic pigment deposits was another consequence of the SaIONs therapy. Additional studies are needed to assess the reversibility of SaIONs-induced phenotypic switching and the impact of tumor hyperpigmentation on B16F10 melanoma's progression and metastasis abilities.

Imaging of the Posttraumatic Knee in Pediatric Patients.

Owing to its continuous transformation, the musculoskeletal system of pediatric patients presents some unique features with respect to both anatomy and physiology. The lesional pattern of the knee in pediatric patients is both similar to and in many aspects different from the lesional pattern in adults with knee injuries. In the case of pediatric patients, meniscal, tendinous and ligamentous lesions occur most frequently as a consequence of traumatic episodes. The purpose of the present study is to emphasize the importance of MRI examinations in pediatric patients exhibiting symptoms of knee joint injury. The imaging assessment of the extent of the lesions, which can be either simple or complex alterations, can directly influence the clinical management of these cases by appreciating the growth potential of the specific segment of immature skeleton involved.

Cerebrolysin and Aquaporin 4 Inhibition Improve Pathological and Motor Recovery after Ischemic Stroke.

BACKGROUND: Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative. OBJECTIVE: New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke. METHODS: Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed. RESULTS: We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronalsurvival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals. CONCLUSION: Our data show that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region.

Long disease-free survival following total sternal resection and reconstruction of the sternum with acrylic cement for unique massive sternal metastasis after operated breast cancer.

Unique sternal metastasis is an uncommon finding in the follow-up of operated breast cancer. We present a case of massive sternal metastasis occurred few years after radical resection of a right mammary cancer, that we solved by total sternal resection and reconstruction of sternum with acrylic cement and Vicryl mesh. The patient is disease-free five years after the operation.

Magnetic nanoparticles-based therapy for malignant mesothelioma.

This work was aimed to analyze the versatility of the chick embryo chorioallantoic membrane (CAM) as in vivo model for the study of the malignant pleural mesothelioma (MPM) and the therapeutic potential of Fe3O4÷salicylic acid magnetic nanoparticles (SaMNPs) on MPM cells. The antitumor effects of SaMNPs were studied by in vitro and in vivo tests on CARM-L12 TG3 rat malignant mesothelioma cells and human MPM xenografts implanted on CAMs. In order to assess the human MPM xenograft growth characteristics, calretinin, HBME-1 (Hector Battifora mesothelial epitope-1), and cytokeratins immunohistochemical stainings were performed. The human MPM xenografts continue to develop on the CAMs and xenograft MPM cells showed highly metastatic features and a particular pattern of metastasis. The SaMNPs had a specific uptake by the MPM cells and an antiproliferative effect at therapeutic doses greater than 100 µg÷mL. The results confirmed the possibility to use the CAM as in vivo model to study the biology of MPM and to evaluate the antitumor potential of new therapeutic agents. They highlighted a strong antitumor effect of the SaMNPs on the rat and human MPM cells and open new perspectives in the treatment of MPM.

Basal cell carcinoma develops in contact with the epidermal basal cell layer - a three-dimensional morphological study.

Basal cell carcinoma is the most common malignant tumor of the skin, and it develops most frequently on the areas of the body that make its treatment and care extremely difficult, especially in cases of neglecting or aggressive growth and invasion. Both typical mild cases as well as locally aggressive tumor types do not tend to metastasize, and it has been postulated that they should share some common biological and morphological features that might explain this behavior. In this study, we have utilized a high-resolution three-dimensional reconstruction technique on pathological samples from 15 cases of common aggressive (fibrosing and adenoid types) and mild (superficial type) basal cell carcinomas, and showed that all these types shared contact points and bridges with the underlying basal cell layer of the epidermis or with the outmost layer of the hair follicle. The connections found had in fact the highest number for fibrosing type (100%), compared to the superficial (85.71%) and adenoid (55%) types. The morphology of the connection bridges was also different, adjacent moderate to abundant inflammatory infiltrate seeming to lead to a loss of basaloid features in these areas. For the adenoid type, tumor islands seemed to be connected also to each other more strongly, forming a common "tumor lace", and while it has been showed that superficial and fibrosing types have higher recurrence risks, all together these data might iterate a connection between the number of bridging points and the biological and clinical manifestation of this skin tumor.

The chick chorioallantoic membrane: a model of short-term study of Dupuytren's disease.

Dupuytren's disease is a progressive fibroproliferative disorder that impairs hand function by altering the normal structures of the palmar fascial bands. Nodules composed almost entirely of myofibroblasts and cords are pathognomonic of Dupuytren's disease. The myofibroblasts express alpha-smooth muscle actin that is especially involved in development of the disease. We aimed to evaluate whether the xenograft of Dupuytren's fibromatosis taken from operating room and transplanted on chick chorioallantoic membrane (CAM) survives with its histological and immunohistological features. Fresh samples obtained from eight patients with Dupuytren's disease were minced and immediately inoculated onto 24 CAMs of 8-day-old chick embryos. The implanted CAMs were examined daily by stereomicroscopy and finally the xenografts were examined and characterized in histological sections using a panel of antibodies. The xenografts were incorporated into the CAMs 6-7 days after transplantation, continued to grow and stimulated angiogenesis in the chick embryo CAMs. The CAMs vessels entered the xenografts and anastomosed with the newly formed xenografts vessels (CD34+ and CD105+) those containing nucleated chick erythrocytes. Myofibroblasts (α-SMA+) and macrophages (CD68+) were readily recognized in the xenograft thickness. We concluded that the xenografts of Dupuytren's fibromatosis transplanted onto chick embryo CAMs continued to develop and preserved the histological and immunohistological features.