Irreversible Injury Research Articles

Prevalence of Venous Infarction in Patients With Cerebral Venous Thrombosis: Baseline Diffusion-Weighted MRI and Follow-Up MRI.

A venous pattern of infarction on neuroimaging is used as a clue to undiagnosed cerebral venous thrombosis (CVT); prevention of venous infarction is a goal of CVT management; and venous infarction is a factor used for clinical prognostication. Despite widespread use of the term venous infarct, the prevalence of true venous infarction is unclear. Our primary aim was to determine the prevalence of venous infarction in patients with CVT. We also measured the prevalence of diffusion abnormality without infarction, vasogenic edema, and intracranial hemorrhage. Single-center, retrospective cohort study using a registry of 110 consecutive patients admitted to hospital with cerebral venous thrombosis between 2004 and 2014. Inclusion criteria were brain magnetic resonance imaging (MRI) and contrast-enhanced venography at presentation, and repeat brain MRI ≥1 month later. Exclusion criteria were dural arteriovenous fistula, arteriovenous malformation, cavernous sinus thrombosis, or previous neurosurgical procedure. Main outcome was proportion of patients with venous infarction (irreversible ischemic injury) diagnosed using diffusion-weighted MRI at presentation, confirmed using T2-weighted fluid-attenuated inversion recovery MRI ≥1 month later, and reported with 95% CI using the Wilson score interval method. We also report the prevalence of transient diffusion MRI abnormality without infarction, vasogenic edema, and intracranial hemorrhage. Seventy-three patients met the inclusion criteria, and after exclusions, the final study population was 59 patients with median age 41 years (interquartile range, 32-57). Venous infarction occurred in 12% (7/59 [95% CI, 6%-23%]) of patients, and final infarct volume was >1 mL in only 5.1% (3/59) of patients. An additional 8% (5/59 [95% CI, 4%-18%]) of patients had a transient diffusion MRI abnormality without infarction. Prevalence of cerebral vasogenic edema and intracranial hemorrhage were 66% (39/59 [95% CI, 53%-77%]) and 54% (32/59 [95% CI, 41%-66%]), respectively. In patients with CVT, venous infarction is uncommon and venous infarcts are typically very small. Vasogenic edema and hemorrhage are more common consequences of CVT.

Mechanisms regulating vascular and lymphatic regeneration in the heart after myocardial infarction.

Myocardial infarction, caused by a thrombus or coronary vascular occlusion, leads to irreversible ischaemic injury. Advances in early reperfusion strategies have significantly reduced short-term mortality after myocardial infarction. However, survivors have an increased risk of developing heart failure, which confers a high risk of death at 1 year. The capacity of the injured neonatal mammalian heart to regenerate has stimulated extensive research into whether recapitulation of developmental regeneration programmes may be beneficial in adult cardiovascular disease. Restoration of functional blood and lymphatic vascular networks in the infarct and border regions via neovascularisation and lymphangiogenesis, respectively, is a key requirement to facilitate myocardial regeneration. An improved understanding of the endogenous mechanisms regulating coronary vascular and lymphatic expansion and function in development and in adult patients after myocardial infarction may inform future therapeutic strategies and improve translation from pre-clinical studies. In this review, we explore the underpinning research and key findings in the field of cardiovascular regeneration, with a focus on neovascularisation and lymphangiogenesis, and discuss the outcomes of therapeutic strategies employed to date. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Role of Iberin as an anti-apoptotic agent on renal ischemia-reperfusion injury in rats.

Ischemia-reperfusion injury (IRI) is a major contributor to acute and chronic kidney failure, heart failure, and ischemic stroke. This study aimed to investigate the therapeutic potential of Iberin, known for its anti-inflammatory, antioxidant, and antiapoptotic properties, in a rat model of renal IRI. Twenty-four adult male rats were randomly divided into four groups: Group I (Sham group) underwent laparotomy without IRI induction; Group II (Control group) underwent laparotomy followed by renal artery clamping for 30 minutes to induce ischemia, followed by 2 hours of reperfusion; Group III (Iberin treatment group) received a pre-injection of Iberin (15 mg/kg) and underwent 30 minutes of ischemia followed by 2 hours of reperfusion; and Group IV (Vehicle-treated group) received the vehicle (ethanol) 1 hour prior to ischemia and reperfusion induction. Iberin was diluted with ethanol. Biomarkers associated with inflammation, oxidative stress, and apoptosis were measured using enzyme-linked immunosorbent assay. Iberin treatment significantly reduced levels of inflammatory cytokines interleukin-1β (IL-1β) and IL-6, Bcl-2-associated X protein (BAX), tumor necrosis factor α (TNF-α), nuclear factor kappa p56, high mobility group B1, and neutrophil gelatinase-associated lipocalin. Moreover, Iberin increased levels of heat shock protein and Bcl2 compared to the control and vehicle groups. Iberin treatment prolonged the ischemic tolerance of renal tissue, potentially preventing or delaying irreversible injuries. These findings highlight the potential of Iberin as a promising candidate for mitigating renal injury caused by ischemia-reperfusion, due to its ability to modulate inflammatory markers.

Inflammatory Process on Knee Osteoarthritis in Cyclists.

Osteoarthritis is a disorder affecting the joints and is characterized by cellular stress and degradation of the extracellular matrix cartilage. It begins with the presence of micro- and macro-lesions that fail to repair properly, which can be initiated by multiple factors: genetic, developmental, metabolic, and traumatic. In the case of the knee, osteoarthritis affects the tissues of the diarthrodial joint, manifested by morphological, biochemical, and biomechanical modifications of the cells and the extracellular matrix. All this leads to remodeling, fissuring, ulceration, and loss of articular cartilage, as well as sclerosis of the subchondral bone with the production of osteophytes and subchondral cysts. The symptomatology appears at different time points and is accompanied by pain, deformation, disability, and varying degrees of local inflammation. Repetitive concentric movements, such as while cycling, can produce the microtrauma that leads to osteoarthritis. Aggravation of the gradual lesion in the cartilage matrix can evolve to an irreversible injury. The objective of the present review is to explain the evolution of knee osteoarthritis in cyclists, to show the scarce research performed in this particular field and extract recommendations to propose future therapeutic strategies.

Intraoperative Neuromonitoring during Peripheral Arteriovenous Malformation Embolization

PurposeTo evaluate whether intraoperative neuromonitoring (IONM), including pre-embolization lidocaine injection challenge (“provocative testing”) is associated with reduced risk of irreversible nerve injury during embolization of peripheral arteriovenous malformations (AVMs). Materials and MethodsMedical records of patients with peripheral AVMs who underwent embolotherapy with IONM with provocative testing between 2012 and 2021 were reviewed retrospectively. Data collected included patient demographic characteristics, AVM location and size, embolic agent used, IONM signal changes after lidocaine and embolic agent injections, postprocedural adverse events, and clinical outcomes. Decisions regarding whether embolization would proceed at specific locations were based on IONM findings after the lidocaine challenge and as embolization proceeded. ResultsA cohort of 17 patients (mean age, 27 years ± 19; 5 women) who underwent 59 image-guided embolization procedures with adequate IONM data was identified. No permanent neurologic deficits occurred. Transient neurologic deficits were observed in 3 patients (4 sessions), comprising skin numbness (2 patients), extremity weakness (1 patient), and extremity weakness and numbness (1 patient). All neurologic deficits resolved by postoperative day 4 without additional treatment. ConclusionsIONM, including provocative testing, during AVM embolization may minimize potential nerve injury.

Spontaneous reperfusion enhances succinate concentration in peripheral blood from stemi patients but its levels does not correlate with myocardial infarct size or area at risk

Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab. As succinate might be also increased in peripheral blood, we aimed to investigate whether peripheral plasma concentrations of succinate and other metabolites obtained during coronary revascularization correlate with edema volume or infarct size in STEMI patients. Plasma samples were obtained from peripheral blood within the first 10 min of revascularization in 102 STEMI patients included in the COMBAT-MI trial (initial TIMI 1) and from 9 additional patients with restituted coronary blood flow (TIMI 2). Metabolite concentrations were analyzed by 1H-NMR. Succinate concentration averaged 0.069 ± 0.0073 mmol/L in patients with TIMI flow ≤ 1 and was significantly increased in those with TIMI 2 at admission (0.141 ± 0.058 mmol/L, p < 0.05). However, regression analysis did not detect any significant correlation between most metabolite concentrations and infarct size, extent of edema or other cardiac magnetic resonance (CMR) variables. In conclusion, spontaneous reperfusion in TIMI 2 patients associates with enhanced succinate levels in peripheral blood, suggesting that succinate release increases overtime following reperfusion. However, early plasma levels of succinate and other metabolites obtained from peripheral blood does not correlate with the degree of irreversible injury or area at risk in STEMI patients, and cannot be considered as predictors of CMR variables.Trial registration: Registered at www.clinicaltrials.gov (NCT02404376) on 31/03/2015. EudraCT number: 2015-001000-58.

Severe Hypoglycemic Brain Injury Associated with Diffuse Restricted Diffusion on MRI Brain Sparing Cerebellar Lobes (P10-7.006)

<h3>Objective:</h3> Report a case of severe hypoglycemia-induced brain injury in an adult with MRI brain showing extensive diffusion restriction mimicking hypoxic brain injury. <h3>Background:</h3> Hypoglycemia is commonly seen in clinical practice, with most often benign outcome when appropriately treated. However, severe hypoglycemia may be associated with transient or permanent neurologic deficits. Irreversible diffuse brain injury is more often documented in the pediatric population, in particular neonatal, though devastating injury can also happen in adults. Energy deprivation and other chemical cascades lead to neuronal necrosis. Though some overlap exists and imaging shares some similarities, neurochemistry and brain lesion distribution of hypoglycemia differs markedly from ischemia. We present a case of severe, prolonged hypoglycemia leading to diffuse hypoglycemic brain injury. <h3>Design/Methods:</h3> Case report <h3>Results:</h3> 71-year-old male with history of insulin-dependent diabetes and depression with suicidal ideations who presented to the emergency room (ER) after being found unconscious with a serum glucose of 14 mg/dl. The patient was intubated for airway protection due to GCS at 9 but without significant hypoxia, saturating 93% on room air. Despite aggressive glucose replacement, he had several hypoglycemic episodes on a 27-hour span. Laboratory testing was remarkable only for elevated creatinine kinase of 3047 mg/dl, and presence of cannabis on urine drug screen. Patient remained comatose, with only preserved corneal reflexes after weaned off sedation. Non-epileptic myoclonus was also observed, confirmed by EEG. MRI brain revealed diffuse restricted diffusion, predominantly in the cerebral cortex and deep basal ganglia but sparing cerebellar lobes. Patient did not survive. <h3>Conclusions:</h3> Severe hypoglycemia leads to energy depletion and neuronal death with some overlap with ischemic brain injury though significant radiologic differences can help differentiate both pathophysiologic processes. Cerebellar involvement is uncommon compared to ischemic injury due to highly effective glucose transporter which can help differentiate both types of injury. <b>Disclosure:</b> Dr. Ribeiro has nothing to disclose. Dr. Gatchoff has nothing to disclose. Dr. Delpirou Nouh has nothing to disclose. Dr. Moon has nothing to disclose.

Testicular torsion diagnosis and injury assessment using photoacoustic oxygenation imaging

Testicular torsion (TT) is a medical emergency that requires immediate diagnostic evaluation. Photoacoustic imaging (PAI) has the potential to provide spatially resolved oxygen saturation (sO2), which can serve as a valuable marker in TT diagnosis. We investigated the potential of PAI as an alternative method for TT diagnosis and testicular injury assessment. We measured sO2 levels in different degrees of TT models using PAI at various time points. Based on histopathological results, we found that the averaged sO2 per pixel (sO2̅) and reduction of sO2̅ (rsO2) in twisted testicles had significant correlations with hypoxic conditions. Both sO2̅ and rsO2 exhibited excellent diagnostic abilities in detecting TT and identifying ischemia/hypoxia injury following TT. Furthermore, PAI-measured sO2 demonstrated favorable diagnostic capabilities in discriminating if the testicle had suffered irreversible injury. In summary, PAI presents a potentially promising novel approach in evaluating TT and warrants further clinical investigation.

UCP2 deficiency impairs podocyte autophagy in diabetic nephropathy

ObjectivePodocytes have been indicated to be a critical factor for the development of diabetic kidney disease. Podocyte loss leads to irreversible glomerular injury and proteinuria in animal models. As terminal differentiated cells, autophagy is crucial for maintaining podocyte homeostasis. Previous studies have shown that Uncoupling proteins 2 (UCP2) regulate fatty acid metabolism, mitochondrial calcium uptake and reactive oxygen species (ROS) production. This study aimed to investigate whether UCP2 promote autophagy in podocyte and further explore the regulation mechanism of UCP2. MethodsFor podocyte-specific UCP2-KO mice, we cross bred UCP2fl/fl mouse strain with the podocin-Cre mice. Diabetic mice were obtained by daily intraperitoneally injections of 40 mg/kg streptozotocin for 3 days. After 6 weeks, mice were scarified, and kidney tissues were analyzed by histological stain, Western blot, Immunofluorescence, and immunohistochemistry. Also, urine samples were collected for protein quantification. For in vitro study, podocytes were primary cultured from UCP2fl/fl mouse or transfected with adeno-associated virus (AAV)-UCP2. ResultsDiabetic kidney showed elevated expression of UCP2 and specific ablation of UCP2 in podocyte aggravates diabetes-induced albuminuria and glomerulopathy. UCP2 protects hyperglycemia-induced podocyte injury by promoting autophagy in vivo and in vitro. Rapamycin treatment significantly ameliorates streptozotocin (STZ)-induced podocyte injury in UCP2−/− mice. ConclusionUCP2 expression in podocyte increased under diabetic condition and appeared to be an initial compensatory response. UCP2 deficiency in podocyte impaired autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy.

Peptide Sodium Channels Modulator Mu-Agatoxin-Aa1a Prevents Ischemia-Reperfusion Injury of Cells

Ischemia-reperfusion injury (IRI) is an irreversible functional and structural injury. Restoration of normal oxygen concentration exacerbates the emergence and development of deadly cells. One of the possible moments of reperfusion damage to cells is an increase in the intracellular concentration of sodium ions. In this article, we study the mu-agatoxin-Aa1a, a modulator of sodium channels, on the processes of IRI cells damage. The toxin was synthesized using an automatic peptide synthesizer. Hypoxia was induced by reducing the content of serum and oxygen in the CHO-K1 culture. The influence of the toxin on the level of apoptosis; intracellular concentration of sodium, calcium, and potassium ions; intracellular pH; totality of reactive oxygen species (ROS), nitric oxide (NO), and ATP; and changes in the mitochondrial potential were studied. The experiments performed show that mu-agatoxin-Aa1a effectively prevents IRI of cells. Toxin reduces the level of apoptosis and prevents a decrease in the intracellular concentration of sodium and calcium ions during IRI. Mu-agatoxin-Aa1a contributes to the maintenance of elevated intracellular pH, reduces the intracellular concentration of ROS, and prevents the decrease in intracellular NO concentration and mitochondrial potential under conditions of reoxygenation/reperfusion. An analysis of experimental data shows that the mu-agatoxin-Aa1a peptide has adaptogenic properties. In the future, this peptide can be used to prevent ischemia/reperfusion tissue damage different genesis.

Biportal Endoscopic Posterior Thoracic Laminectomy for Thoracic Spondylotic Myelopathy Caused by Ossification of the Ligamentum Flavum: Technical Developments and Outcomes.

Advanced biportal endoscopic surgery techniques can be used to treat thoracic myelopathy secondary to ossification of the ligamentum flavum (OLF). This case series elaborates on a feasible biportal endoscopic technique for thoracic OLF removal and evaluates clinical and radiological outcomes. A biportal endoscopic posterior thoracic laminectomy was performed to remove the thoracic OLF. Surgical techniques have evolved from inside-out piecemeal removal methods to outside-in en bloc removal methods. Preoperative computed tomography was performed to analyze dural ossification and OLF types. Intraoperative videos were reviewed to observe dural ossification and to determine the surgical method. Neurological outcomes were assessed using the Japanese Orthopaedic Association (JOA) score. Clinical symptoms and neurological function improved markedly after surgery (JOA score, preoperative: 12.6 ± 1.0, final follow-up: 15.6 ± 1.2). The mean operation time per segment was not short (106.6 ± 38 minutes). At early experience stages, inside-out piecemeal decompression was used and it caused intraoperative spinal cord injury. However, outside-in en bloc decompression technique did not induce neural complications. Postoperative segmental instability and correlated mechanical back pain were not observed. The biportal endoscopic posterior thoracic approach is an attractive surgical option to treat thoracic spondylotic myelopathy secondary to OLF. Piecemeal inside-out decompression can induce irreversible spinal cord injury, especially in the early experience stages. Outside-in decompression is more efficient and safer than inside-out pattern procedures by minimizing dural manipulation. Nonetheless, this technique is technically demanding and should only be performed in selected patients after acquiring abundant experience with endoscopic spine surgeries.

Importance of Mitochondria in Cardiac Pathologies: Focus on Uncoupling Proteins and Monoamine Oxidases.

On the one hand, reactive oxygen species (ROS) are involved in the onset and progression of a wide array of diseases. On the other hand, these are a part of signaling pathways related to cell metabolism, growth and survival. While ROS are produced at various cellular sites, in cardiomyocytes the largest amount of ROS is generated by mitochondria. Apart from the electron transport chain and various other proteins, uncoupling protein (UCP) and monoamine oxidases (MAO) have been proposed to modify mitochondrial ROS formation. Here, we review the recent information on UCP and MAO in cardiac injuries induced by ischemia-reperfusion (I/R) as well as protection from I/R and heart failure secondary to I/R injury or pressure overload. The current data in the literature suggest that I/R will preferentially upregulate UCP2 in cardiac tissue but not UCP3. Studies addressing the consequences of such induction are currently inconclusive because the precise function of UCP2 in cardiac tissue is not well understood, and tissue- and species-specific aspects complicate the situation. In general, UCP2 may reduce oxidative stress by mild uncoupling and both UCP2 and UCP3 affect substrate utilization in cardiac tissue, thereby modifying post-ischemic remodeling. MAOs are important for the physiological regulation of substrate concentrations. Upon increased expression and or activity of MAOs, however, the increased production of ROS and reactive aldehydes contribute to cardiac alterations such as hypertrophy, inflammation, irreversible cardiomyocyte injury, and failure.

Assessment of increased knowledge about traffic accidents prevention, one month after a presentation included in the program “it can happen to you” of AESLEME

:Road traffic accidents are a real pandemic and incur expenses amounting to 1–2% of every country’s GDP. AESLEME (Association for the Study of Spinal Cord Injuries) has celebrated its 30th anniversary here in Spain. AESLEME’s instructors are health workers and people with spinal cord injuries caused by road accidents: their presentations—teaching road safety and sharing information on irreversible injuries—are enhanced by personal stories that help schoolchildren to acquire knowledge on this matter.Study designPre and post-quasi-experimental study.ObjectiveTo assess the increase in knowledge about road safety following a school-based road safety campaign.MethodsTwo multiple-choice tests were given to each of the 8106 students taking part, who were 12–14 years old. Of the four possible answers, only one of them was correct. The first multiple-choice test was taken before the presentation and the second was taken one month later.ResultsAfter assessing the answers, there was a change in the tendency of the number of correct before/after answers for the multiple-choice test, and the number of correct ones rose one month after the presentation. This increase is statistically significant (p < 0.01) and represents a national increase of 61% in the probability of correct answers, although this varies from 8% to 278% depending on the region.ConclusionsThe assessment, involving over 8000 people, showed that there has been an improvement in road safety knowledge thanks to education provided by AESLEME’s instructors, and a statistically significant increase was obtained throughout Spain and different regions.

Detection of surgical instruments based on Gaussian kernel

In minimally invasive laparoscopic surgery, it is of practical significance to quickly locate the location and category information of the surgical instrument. It can remind medical personnel of irreversible injury caused to patients due to leaving surgical instruments after the operation. In this paper, the Gaussian kernel is introduced into each ground truth, which is conducive to making full use of label information to allocate positive and negative samples and improve the accuracy of location and classification. Then, we introduce SIoU Loss and Harmonic Loss function into a total loss. The former uses relative coordinates to make the network converge more quickly, and the latter solves the problem of asynchronous optimization of the two branches of classification and regression. Our experiment proves that the strategy based on Gaussian kernel sample allocation is very effective on a pubic data set m2cai16-tool-locations, displaying our method possesses conspicuous accuracy of classification and regression than other work.

Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-β, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts.

In-situ tumor vaccination by percutaneous ablative therapy and its synergy with immunotherapeutics: An update on combination therapy.

Percutaneous tumor ablation is now a widely accepted minimally invasive local treatment option offered by interventional radiology and applied to various organs and tumor histology types. It utilizes extreme temperatures to achieve irreversible cellular injury, where ablated tumor interacts with surrounding tissue and host via tissue remodeling and inflammation, clinically manifesting as post-ablation syndrome. During this process, in-situ tumor vaccination occurs, in which tumor neoantigens are released from ablated tissue and can prime one's immune system which would favorably affect both local and remote site disease control. Although successful in priming the immune system, this rarely turns into clinical benefits for local and systemic tumor control due to intrinsic negative immune modulation of the tumor microenvironment. A combination of ablation and immunotherapy has been employed to overcome these and has shown promising preliminary results of synergistic effect without significantly increased risk profiles. The aim of this article is to review the evidence on post-ablation immune response and its synergy with systemic immunotherapies.

Nanoparticulate drug delivery systems for the treatment of rheumatoid arthritis: A comprehensive review

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects 1% of the world's population. It is a progressive condition that causes joint inflammation, polyarticular synovitis, bone and cartilage destruction, bone erosion, and deformation, resulting in impairments, morbidity, and a lower quality of life. There is no curative therapy for rheumatoid arthritis because the complete pathogenesis is unknown. The treatment aim is to give symptomatic relief while preventing irreversible joint injury. The standard treatment involves glucocorticoids alone or in combination with nonbiologic and biologic disease-modifying anti-rheumatoid drugs (DMARDs). Treatment of RA with conventional dosage forms has limitations such as non-specificity, dose-escalation, increased frequency of administration, toleration, and systemic side effects. Through its application to medicine, nanotechnology has been able to address the drawbacks of conventional treatment and the complexity of the disease, thus offering new possibilities for the treatment of RA by achieving specificity to joints through active and passive targeting strategies, overcoming dose escalation, increased frequency of administration, and the adverse effects associated with it. This review entails a thorough understanding of various Nanoparticulate drug delivery systems, including polymeric nanoparticles such as polymeric micelles, nanocapsules, and dendrimers; lipid-based nanoparticles such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, Transferosomes, exosomes, nanoemulsions, ethosomes; and metallic nanoparticles such as gold and silver nanoparticles, quantum dots, siRNA, and peptide-based nanoparticulate delivery systems. A comprehensive review of the merits and drawbacks of nanoparticulate drug delivery systems is provided, as well as an update on their application on the pharmacotherapy, toxicity, clinical trial of Nanoparticles on rheumatoid arthritis and patents granted in this field.

Introduction: Pushing the boundaries in liver transplantation

Liver disease is a major cause of mortality worldwide and liver transplantation remains the most effective therapeutic modality for the treatment of decompensated cirrhosis, acute liver failure, and small HCC. The field of liver transplantation has dramatically evolved over the past 50 years from an experimental endeavor to a highly successful life-saving procedure for patients with sustained irreversible liver injury. Advances in surgical technique, perioperative and postoperative management, and immunosuppression provided for increased application of liver transplantation with excellent 1-year survival rates reaching 90%. However, the ubiquity of liver transplantation has created its own unique challenges including determining patient eligibility and the shortage of deceased donor organs. The allocation of organs is predicated upon the fine balance between utility and justice. Applying these principles shapes public policy related to patient selection and organ allocation. Candidate selection is increasingly important when optimizing the selection of the recipients who would derive the most benefit from liver transplantation given the scarcity of organs. The trend toward viable organ donation scarcity continues while there has been exponential growth in the number of transplant candidates over the same period of time. The ever-expanding wait list registry reflects the rising tide of NAFLD, specifically the more advanced form, NASH, and alcohol-associated liver disease. Furthermore, ground-breaking success in liver transplantation for hepatic and biliary malignancies paved a path for reaching even more candidates. As perioperative and postoperative management continues to improve, those being considered for liver transplantation have more comorbidities including obesity, diabetes mellitus, and cardiovascular disease. Despite the growing number of potential recipients, the pool of donor organs is failing to keep pace and poses a highly challenging global problem. The mismatch between supply and demand requires the transplant community to ration already limited liver allografts and continually reassess allocation policies based on need versus survival benefit. Efforts were made to expand the pool of potential donors, including utilization of extended criteria donors and donation after cardiac death. Nevertheless, there remains a scarcity of organs. In recent years, the increasing application of living donor liver transplantation has helped mitigate the organ shortage. But this practice is still fraught with contentious elements that have hindered extensive implementation. We are in a new era of liver transplantation. As a transplant community, we must pioneer not only the rising obesity and alcohol epidemics but also successfully manage our aging population while minimizing waitlist mortality. The need for more innovative practices is upon us. In this Clinical Liver Disease series, “Pushing the Boundaries in Liver Transplantation,” the authors review select challenging indications for liver transplantation, the currently accepted practices, and innovative ways that endeavor to expand the reach of liver transplantation.

Tumor Necrosis Factor Family Members and Myocardial Ischemia-Reperfusion Injury: State of the Art and Therapeutic Implications.

Ischemic heart disease is the principal cause of death worldwide and clinically manifests as myocardial infarction (MI), stable angina, and ischemic cardiomyopathy. Myocardial infarction is defined as an irreversible injury due to severe and prolonged myocardial ischemia inducing myocardial cell death. Revascularization is helpful in reducing loss of contractile myocardium and improving clinical outcome. Reperfusion rescues myocardium from cell death but also induces an additional injury called ischemia-reperfusion injury. Multiple mechanisms are involved in ischemia-reperfusion injury, such as oxidative stress, intracellular calcium overload, apoptosis, necroptosis, pyroptosis, and inflammation. Various members of the tumor necrosis factor family play a key role in myocardial ischemia-reperfusion injury. In this article, the role of TNFα, CD95L/CD95, TRAIL, and the RANK/RANKL/OPG axis in the regulation of myocardial tissue damage is reviewed together with their potential use as a therapeutic target.

Machine learning segmentation of core and penumbra from acute stroke CT perfusion data.

Computed tomography perfusion (CTP) imaging is widely used in cases of suspected acute ischemic stroke to positively identify ischemia and assess suitability for treatment through identification of reversible and irreversible tissue injury. Traditionally, this has been done via setting single perfusion thresholds on two or four CTP parameter maps. We present an alternative model for the estimation of tissue fate using multiple perfusion measures simultaneously. We used machine learning (ML) models based on four different algorithms, combining four CTP measures (cerebral blood flow, cerebral blood volume, mean transit time and delay time) plus 3D-neighborhood (patch) analysis to predict the acute ischemic core and perfusion lesion volumes. The model was developed using 86 patient images, and then tested further on 22 images. XGBoost was the highest-performing algorithm. With standard threshold-based core and penumbra measures as the reference, the model demonstrated moderate agreement in segmenting core and penumbra on test images. Dice similarity coefficients for core and penumbra were 0.38 ± 0.26 and 0.50 ± 0.21, respectively, demonstrating moderate agreement. Skull-related image artefacts contributed to lower accuracy. Further development may enable us to move beyond the current overly simplistic core and penumbra definitions using single thresholds where a single error or artefact may lead to substantial error.