Ischemic Damage Research Articles

Carpal tunnel syndrome related to rheumatic disease (Review).

Carpal tunnel syndrome (CTS) is the most commonly occurring type of entrapment neuropathy in the world. Several conditions may contribute to the development of CTS, such as obesity, repetitive wrist movements, pregnancy, genetic predisposition and rheumatoid arthritis (RA) inflammation. CTS is characterized by a wide range of pathophysiological factors, including increased pressure, mechanical trauma and ischemic damage to the median nerve that runs through the wrist tunnel. In the present narrative literature review, the way rheumatic diseases (RDs) contribute to CTS occurrence is investigated. The epidemiological, clinical, paraclinical and pathogenesis aspects of the relationship are examined. CTS is the most common neurological finding in RA, and incidences of RA, psoriatic arthritis and CTS are closely related. The association of CTS with systemic lupus erythematosus, Sjögren's syndrome, Behcet's disease and systemic sclerosis is weaker. In these cases, the prevalence of CTS is similar to that in the general population. As the occurrence of CTS is increasing, understanding the common mechanism and making an early diagnosis are required to limit pain and costs. When patients with RD present with symptoms such as wrist pain, tingling sensations or numbness in their fingers, CTS should be suspected. This suspicion should not be interpreted in terms of RD. To accurately evaluate patients with RD, a detailed electrophysiological examination should be included in the evaluation process. A diagnostic algorithm should include neuromuscular ultrasound or magnetic resonance imaging for patients with RD.

Abstract We073: CLEC4E Signaling in Myocardial Ischemia-Reperfusion Injury

Background: The innate immune receptor CLEC4E (C-type lectin domain family 4 member E) in cardiac resident cells and circulating leukocytes contributes to ischemic myocardial damage and adverse LV remodeling following ischemia reperfusion injury (I/R). Mice with loss of CLEC4E gene function show reduced cardiac injury and better LV remodeling but the mechanisms of this cardioprotection remain unknown. Aims: We investigated whether Clec4e gene function in cardiac resident cells vs infiltrating immune cells mediates cardioprotection during myocardial ischemia-reperfusion injury. Methods: We generated chimeric mice by IV infusion of 5 x 10 6 bone marrow cells originating from C57Bl6/J CLEC4E -/- and C57Bl6/J wild-type (WT) donor mice in 8w-old lethally irradiated (9.5 Gy) WT (n=36) and CLEC4E -/- (n=50) receptor mice, respectively. After 4 w, mice were subjected to ischemia reperfusion injury (I/R) by 60 min LAD occlusion. Troponin levels (TnI) were measured at 90 min post I/R and 7T-magnetic resonance imaging with late gadolinium enhancement (LGE) for infarct size evaluation was performed at 24 h and 28 d post I/R. Mice were euthanized at 28 days for immunohistochemistry and analysis of BM chimerism. Results: Immunohistochemistry for CLEC4E expression on bone marrow smears confirmed successful BM chimerism. At 24h post I/R, TnI levels and LGE-assessed infarct size on MRI were not significantly different between groups (42.1 vs 48.4 ng/ml, and 25.2% vs 31.5% of LVmass in CLEC4E -/- & WT BM versus in WT & CLEC4E -/- BM, respectively) suggesting similar myocardial damage . After 28 d, LV end-diastolic volumes (43µL vs 55µL), and end-systolic volumes (13µL vs 25µL) were significantly smaller in CLEC4E -/- & WT BM than in WT & CLEC4E -/- BM mice (P<0.05 for both), resulting in better preserved global LV function (LVEF 62% vs 47%, P<0.05) . Infarct size, semiquantitatively assessed using planimetry on Sirius red stains, was smaller in CLEC4E -/- & WT BM than in WT & CLEC4E -/- BM (6.9% vs 19.8%, P<0.01). Conclusion: CLEC4E gene deletion in cardiac resident cells, but not in infiltrating hematopoietic immune cells is associated with better functional and structural remodelling after myocardial I/R. Inhibition of CLEC4E signaling via blocking antibodies or small molecule inhibitors in cardiac myocytes might be a promising cardioprotective strategy.

A novel neuroprotective method against ischemic stroke by accelerating the drainage of brain interstitial fluid.

Ischemic stroke is a leading cause of death and disability worldwide. Inflammatory response after stroke determines the outcome of ischemic injury. A recent study has reported an efficient method, epidural arterial implantation (EAI), for accelerating interstitial fluid (ISF) drainage, which provides a promising strategy to clear pro-inflammatory cytokines in the brain extracellular space (ECS). In this study, the method of EAI was modified (m-EAI) to control its function of accelerating the ISF drainage at different time points following ischemic attack. The neuroprotective effect of m-EAI on ischemic stroke was evaluated with the transient middle cerebral artery occlusion (tMCAO) rat model. The results demonstrated the accumulation of IL-1β, IL-6, and TNF-α was significantly decreased by activating m-EAI at 7 d before and immediately after ischemic attack in tMCAO rats, accompanied with decreased infarct volume and improved neurological function. This study consolidates the hypothesis of exacerbated ischemic damage by inflammatory response and provides a new perspective to treat encephalopathy via brain ECS. Further research is essential to investigate whether m-EAI combined with neuroprotective drugs could enhance the therapeutic effect on ischemic stroke.

Clec7a Worsens Long-Term Outcomes after Ischemic Stroke by Aggravating Microglia-Mediated Synapse Elimination.

Ischemic stroke (IS) is a leading cause of morbidity and mortality globally and triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia in the central nervous systemplay dual roles in neuroprotection and responding to ischemic brain damage. Here, an IS model is employed to determine the involvement of microglia in phagocytosis at excitatory synapses. Additionally, the effects of pharmacological depletion of microglia are investigated on improving neurobehavioral outcomes and mitigating brain injury. RNA sequencing of microglia reveals an increase in phagocytosis-associated pathway activity and gene expression, and C-type lectin domain family 7 member A (Clec7a) is identified as a key regulator of this process. Manipulating microglial Clec7a expression can potentially regulate microglial phagocytosis of synapses, thereby preventing synaptic loss and improving neurobehavioral outcomes after IS. It is further demonstrat that microglial Clec7a interacts with neuronal myeloid differentiation protein 2 (MD2), a key molecule mediating poststroke neurological injury, and propose the novel hypothesis that MD2 is a ligand for microglial Clec7a. These findings suggest that microglial Clec7a plays a critical role in mediating synaptic phagocytosis in a mouse model of IS, suggesting that Clec7a may be a therapeutic target for IS.

ПЕРФУЗИОННАЯ КОМПЬЮТЕРНАЯ ТОМОГРАФИЯ – НОВЫЕ ГОРИЗОНТЫ В ДИАГНОСТИКЕ ЗАБОЛЕВАНИЙ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ

Abstract. Introduction. According to the World Health Organization, the most common disease of the pancreas is acute pancreatitis, which can lead to the development of pancreatic necrosis. In this regard, early diagnosis and assessment of the pancreatic necrosis risk development are of paramount importance for choosing adequate treatment approaches and improving outcomes for patients. Radiological research methods have become the “gold” standard in clinical practice for the primary diagnosis of pancreatic diseases. Contrast-enhanced computed tomography has traditionally been used to visualize the pancreas and assess the extent of inflammation and necrotic changes. However, standard computed tomography has limitations in assessing tissue perfusion, which is an important aspect of the pathophysiology of acute pancreatitis. Perfusion computed tomography of the pancreas has become a colossal breakthrough in radiation imaging, has become widespread as a method that allows the quantitative assessment of blood supply to the pancreas, including information about microcirculation, and it can be used for the early detection of ischemic changes that precede tissue necrosis in the pancreas. Aim. To study the capabilities of perfusion computed tomography and computed tomography angiography of the pancreas for evaluating the area of pancreatic necrosis in acute pancreatitis, with the aim of improving diagnosis and planning treatment measures to minimize the consequences and increase patient survival. Materials and Methods. A single-center examination was carried out on 42 patients (18 women, 24 men, mean age 38±2 years) with suspected acute pancreatitis. All patients underwent perfusion computed tomography within the first 3 days; over the next 3-5 days, computed tomography angiography of the pancreas was performed with bolus intravenous contrast to confirm the development of necrotic changes. Results and Discussion. After performing perfusion computed tomography within the first 3 days from the onset of symptoms, areas of ischemic damage to the pancreas tissue were identified in 16 (38.1%) out of 42 patients. After computed tomography angiography, the development of necrotic changes was confirmed in 7 patients (16.7%). The localization of the necrosis zone detected in computed tomography coincided with the ischemic zones on the color hemodynamic maps of perfusion computed tomography.

Morphological characteristics of the cerebral cortex of a mini-pig under conditions of gene therapy after experimental stroke

Aim. To study the effectiveness of preventive gene therapy (within 2 days) and gene therapy in the acute phase (after 4 hours) of ischemic stroke in mini-pigs using an autologous leucoconcentrate (AutoLeuc) enriched with recombinant genes of vascular endothelial growth factor (VEGF165), glial cell line-derived neurotrophic factor (GDNF) and neural cell adhesion molecule 1 (NCAM1), as well as the migration of leukocytes transduced with a chimeric adenoviral vector serotype 5 with fiber 35 serotype (Ad5/F35) and the green fluorescent protein (GFP) genome into immune defense organs.Materials and methods. The experiment was conducted on 8-month-old Vietnamese lop-bellied mini-pigs (n=16). An ischemic stroke was created by occlusion of the distal branches of the left middle cerebral artery and the right common carotid artery. Genetically modified AutoLeuc was administered preventively intravenously 2 days before or in the acute phase 4 hours after stroke modelling; the control group was injected with 30 ml of saline solution. The morphology of the cerebral cortex was assessed using histological methods in the areas bordering the infarction and peri-infarction after 21 days. The migration of genetically modified Ad5/F35-GFP leukocytes into the brain, spleen, and submandibular lymph nodes was studied a week after stroke modelling.Results. In the peri-infarction zone, the content of pyknotic neurons in control animals was higher, while the number of capillaries was lower than in the gene therapy groups. In the latter, neurons had a typical morphology with preserved outgrowths; in the control group, the outgrowths were tortuous and fragmented. Fluorescence microscopy after injection of AutoLeuc with Ad5/F35-GFP revealed GFP-positive cells in the spleen and submandibular lymph nodes.Conclusion. 21 days after modeling a stroke in mini-pigs against the background of preventive gene therapy or gene therapy in the acute phase using VEGF165/GDNF/NCAM1 AutoLeuc, greater preservation of neurons and a higher density of capillaries in the peri-infarction zone of ischemic brain damage were established. Leukocytes with Ad5/ F35-GFP were found in the spleen and submandibular lymph nodes.

The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity.

Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms are not well understood. Here, it is reported that SWELL1, the essential subunit of the volume-regulated anion channel (VRAC), plays a dual role in ischemic injury by promoting neuronal swelling and glutamate excitotoxicity. SWELL1 expression is upregulated in neurons and astrocytes after experimental stroke in mice. The neuronal SWELL1 channel is activated by intracellular hypertonicity, leading to Cl- influx-dependent cytotoxic neuronal swelling and subsequent cell death. Additionally, the SWELL1 channel in astrocytes mediates pathological glutamate release, indicated by increases in neuronal slow inward current frequency and tonic NMDAR current. Pharmacologically, targeting VRAC with a new inhibitor, an FDA-approved drug Dicumarol, attenuated cytotoxic neuronal swelling and cell death, reduced astrocytic glutamate release, and provided significant neuroprotection in mice when administered either before or after ischemia. Therefore, these findings uncover the pleiotropic effects of the SWELL1 channel in neurons and astrocytes in the pathogenesis of ischemic stroke and provide proof of concept for therapeutically targeting it in this disease.

Raynaud's Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment.

Raynaud's phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. This leads to a distinctive sequence of color changes in the digits. Pallor indicates reduced blood flow due to oxygen deprivation, while erythema appears as reperfusion. RP can be primary, with no identifiable underlying cause, or secondary, associated with other conditions. These conditions include autoimmune diseases, most commonly systemic sclerosis, vascular diseases; and neurological conditions. While the exact cause of RP remains unclear, genetic and hormonal (estrogen) factors are likely contributors. The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. This explains why digital tissue damage frequently occurs in secondary RP but not primary RP. Diagnosis of RP is primarily clinical. Recent advancements in imaging techniques have aided in diagnosis and monitoring, but nail fold capillaroscopy remains the gold standard for distinguishing between primary and secondary RP. If there are signs of acute ischemic injury, vascular imaging, particularly preoperatively, is crucial to rule out other vaso-occlusive conditions. Management of RP focuses on alleviating symptoms and preventing tissue damage. Vasodilator medications are the first-line treatment when general measures like warmth and stress management are not sufficient. Dihydropyridine calcium channel blockers (CCBs), such as nifedipine, are commonly used for vasodilation. Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. Bosentan, an endothelin-1 receptor antagonist, has shown effectiveness in treating and preventing digital ulcers, especially in patients with multiple ulcers. For severe cases, botulinum toxin injections or sympathectomy surgery can be used to control RP symptoms. However, botulinum toxin injections require repeated administration, and sympathectomy's long-term effectiveness is uncertain. Fat grafting is a promising surgical therapy for promoting healing and preventing tissue injury.

Technological innovations in cardiac rehabilitation: effectiveness and impact on patient's quality of life

Introduction: Today, the issue of effective rehabilitation of patients after ischemic damage to the heart muscle is relevant in connection with the annual increase in the number of patients with chronic cardiovascular pathology. The aim of our study was to establish modern effective methods of cardiorehabilitation through a literature search. Methods: A review of the literature on the topic of innovations in cardiorehabilitation using databases: GoogleScholar, PubMed, Web of Science, Scopus was carried out using the survey and system analysis method. These methods provide the possibility of remote monitoring of patients with chronic cardiovascular diseases using telemonitoring, which encourages patients to monitor the state of the cardiovascular system based on ECG, blood pressure, and oximetry. Telecardiorehabilitation is a modern method that has been widely implemented in the last 10 years, and especially during the outbreak of the COVID-19 pandemic. Taking into account that after discharge from the hospital , elderly people sometimes find it difficult to get to rehabilitation centers or work in groups. Development: As an alternative, specialists found the possibility of physical rehabilitation with a set of exercises at home and constant monitoring with the help of smart technologies. The introduction of modern techniques increased the percentage of patients who were involved in cardiorehabilitation, which reduced mortality rates and positively affected the quality of life of patients. Conclusions: The implementation of telemonitoring and telecardiorehabilitation in the conditions of aging population and increasing share of patients with chronic course is a very promising direction of modern rehabilitation

An Endocellulase-Triggered NO Targeted-Release Enzyme-Prodrug Therapy System and Its Application in Ischemia Injury.

Nitric oxide (NO) is a crucial gaseous signaling molecules in regulating cardiovascular, immune, and nervous systems. Controlled and targeted NO delivery is imperative for treating cancer, inflammation, and cardiovascular diseases. Despite various enzyme-prodrug therapy (EPT) systems facilitating controlled NO release, their clinical utility is hindered by nonspecific NO release and undesired metabolic consequence. In this study, a novel EPT system is presented utilizing a cellobioside-diazeniumdiolate (Cel2-NO) prodrug, activated by an endocellulase (Cel5A-h38) derived from the rumen uncultured bacterium of Hu sheep. This system demonstrates nearly complete orthogonality, wherein Cel2-NO prodrug maintains excellent stability under endogenous enzymes. Importantly, Cel5A-h38 efficiently processes the prodrug without recognizing endogenous glycosides. The targeted drug release capability of the system is vividly illustrated through an in vivo near-infrared imaging assay. The precise NO release by this EPT system exhibits significant therapeutic potential in a mouse hindlimb ischemia model, showcasing reductions in ischemic damage, ambulatory impairment, and modulation of inflammatory responses. Concurrently, the system enhances tissue repair and promotes function recovery efficacy. The novel EPT system holds broad applicability for the controlled and targeted delivery of essential drug molecules, providing a potent tool for treating cardiovascular diseases, tumors, and inflammation-related disorders.

Proanthocyanidin alleviates testicular torsion/detorsion-induced ischemia/reperfusion injury in rats

Testicular torsion is an urological emergency and can lead to ischemia damage and testicular loss if not diagnosed in time. Proanthocyanidin is reported to have anti-inflammatory and antioxidant properties. The current study aimed to examine the possible effects of proanthocyanidin (P) on the testis in torsion/detorsion (T/D)-induced testicular ischemia/reperfusion (I/R) injury in rats. Forty rats were divided into four groups (n=10 for each): sham-operated (sham), I/R, I/R + P100 (100 mg/kg, 30 min before torsion), and I/R + P200 (200 mg/kg, 30 min before torsion). Testicular T/D was performed on the left testicle by 3 hours of torsion at 720° clockwise, followed by 3 hours of detorsion. In the I/R group, an increase in malondialdehyde (MDA) levels and a decrease in glutathione (GSH), vitamin C (Vit C), glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD) values were determined compared to the sham group (p<0.001). Moreover, an increase in the expression of cleaved caspase-3 and Bcl2-associated X protein (Bax), a decrease in the expression of B-cell lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were detected in the I/R group (p<0.001). Histopathologically, it was determined that the Johnsen and Cosentino scores of the testicles were irregular in the I/R group (p<0.001). Proanthocyanidin treatment caused a decrease in MDA, cleaved caspase-3 and Bax levels and an increase in GSH, Vit C, GPx, G6PD, Bcl-2 and PCNA values. Additionally, Johnsen and Cosentino rearranged the scores. The present findings revealed the protective and curative effects of proanthocyanidin in organ damage due to testicular torsion/detorsion-induced ischemia/reperfusion with their antioxidative and antiapoptotic properties.

Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

BIOCHEMICAL IMBALANCE IN ISCHEMIC HEART DAMAGE COMBINED WITH STEATOHEPATOSIS

The development of steatohepatosis in most cases is the primary process and consequence of the metabolic syndrome. This disease has a long asymptomatic course. The connection of steatohepatosis with the development and progression of coronary heart disease occurs when steatohepatosis is associated with metabolic syndrome and obesity. Patients with steatohepatosis usually have signs of metabolic syndrome: arterial hypertension, abdominal obesity, impaired glucose tolerance, atherogenic dyslipidemia, which are considered risk factors for cardiovascular diseases. Biochemical parameters were determined in coronary artery disease complicated by steatohepatosis. 101 people were examined. When examining the serum level of brain natriuretic peptide in patients with ischemic heart disease in combination with steatohepatosis, a higher level was found than in uncomplicated coronary heart disease, which indicates a deeper violation of the functional state of the myocardium in ischemic heart disease in combination with steatohepatosis. When examining the cytolytic syndrome markers LDH, AST and ALT, a probable increase in their activity is observed. The detected activation of LDH is associated with damage, tissue necrosis, which is observed in the case of damage to the myocardium and hepatocytes in the examined groups, which indicates an inflammatory type of pathogenesis. Apparently, activation of transaminases is associated with cytolytic syndrome in myocardial damage and increased energy expenditure of hepatocytes in fatty hepatosis. Signs of impaired glucose tolerance were found in the examined subjects: the fasting glucose level and the postprandial glucose level probably exceeded normal values, the HbA1c level was 1.5 times higher than the control in myocardial ischemia, and 1.7 times higher in coronary heart disease and steatohepatosis (p&lt; 0.05). Disruption of hormonal regulation of carbohydrate metabolism was detected in both examined groups. An elevated level of total cholesterol and dyslipoproteinemia were also found in both groups of examined patients, however, the most pronounced changes are observed in the case of complications of steatohepatosis. The obtained results indicate complex disorders of lipid metabolism in myocardial ischemia and ischemic heart damage in combination with steatohepatosis, which confirms the development of metabolic syndrome.

Pyruvate Kinase M2: A Potential Regulator of Cardiac Injury Through Glycolytic and Non-glycolytic Pathways.

Adult animals are unable to regenerate heart cells due to postnatal cardiomyocyte cycle arrest, leading to higher mortality rates in cardiomyopathy. However, reprogramming of energy metabolism in cardiomyocytes provides a new perspective on the contribution of glycolysis to repair, regeneration, and fibrosis after cardiac injury. Pyruvate kinase (PK) is a key enzyme in the glycolysis process. This review focuses on the glycolysis function of PKM2, although PKM1 and PKM2 both play significant roles in the process after cardiac injury. PKM2 exists in both low-activity dimer and high-activity tetramer forms. PKM2 dimers promote aerobic glycolysis but have low catalytic activity, leading to the accumulation of glycolytic intermediates. These intermediates enter the pentose phosphate pathway to promote cardiomyocyte proliferation and heart regeneration. Additionally, they activate adenosine triphosphate (ATP)-sensitive K + (K ATP ) channels, protecting the heart against ischemic damage. PKM2 tetramers function similar to PKM1 in glycolysis, promoting pyruvate oxidation and subsequently ATP generation to protect the heart from ischemic damage. They also activate KDM5 through the accumulation of αKG, thereby promoting cardiomyocyte proliferation and cardiac regeneration. Apart from glycolysis, PKM2 interacts with transcription factors like Jmjd4, RAC1, β-catenin, and hypoxia-inducible factor (HIF)-1α, playing various roles in homeostasis maintenance, remodeling, survival regulation, and neovascularization promotion. However, PKM2 has also been implicated in promoting cardiac fibrosis through mechanisms like sirtuin (SIRT) 3 deletion, TG2 expression enhancement, and activation of transforming growth factor-β1 (TGF-β1)/Smad2/3 and Jak2/Stat3 signals. Overall, PKM2 shows promising potential as a therapeutic target for promoting cardiomyocyte proliferation and cardiac regeneration and addressing cardiac fibrosis after injury.

Microglial repopulation induced by PLX3397 protects against ischemic brain injury by suppressing neuroinflammation in aged mice

As the resident immune cells in the central nervous system, microglia exhibit a ‘sensitized’ or ‘primed’ phenotype with dystrophic morphology and dysregulated functions in aged brains. Although studies have demonstrated the inflammatory profile of aged microglia in several neurological diseases, this issue is largely uncertain in stroke. Consequently, this study investigated the effects of primed and repopulated microglia on post-ischemic brain injury in aged mice. We replaced primed microglia with newly repopulated microglia through pharmacological administration and withdrawal of the colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX3397. Further, we performed a series of behavioral tests and flow cytometry in mouse models of middle cerebral artery occlusion (MCAO) to study the effects of microglial replacement on ischemic injury in the aged brain. With depletion and subsequent repopulation of microglia in MCAO mice, microglial replacement in aged mice improved neurological function and decreased brain infarction. This protective effect was accompanied by the reduction of peripheral immune cells infiltrating into brains. We showed that the repopulated microglia expressed elevated neuroprotective factors (including Cluster of Differentiation 206, transforming growth factor-β, and interleukin-10) and diminished expression of inflammatory markers (including Cluster of Differentiation 86, interleukin-6, and tumor necrosis factor α). Moreover, microglial replacement protected the blood–brain barrier and relieved neuronal death in aged mice subjected to 60 min of MCAO. These results imply that the replacement of microglia in the aged brain may alleviate brain damage and neuroinflammation, and therefore, ischemic brain damage. Thus, targeting microglia could be a promising therapeutic strategy for ischemic stroke.

Transcriptome Study in Sicilian Patients with Autism Spectrum Disorder.

ASD is a complex condition primarily rooted in genetics, although influenced by environmental, prenatal, and perinatal risk factors, ultimately leading to genetic and epigenetic alterations. These mechanisms may manifest as inflammatory, oxidative stress, hypoxic, or ischemic damage. To elucidate potential variances in gene expression in ASD, a transcriptome analysis of peripheral blood mononuclear cells was conducted via RNA-seq on 12 ASD patients and 13 healthy controls, all of Sicilian ancestry to minimize environmental confounds. A total of 733 different statistically significant genes were identified between the two cohorts. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) terms were employed to explore the pathways influenced by differentially expressed mRNAs. GSEA revealed GO pathways strongly associated with ASD, namely the GO Biological Process term "Response to Oxygen-Containing Compound". Additionally, the GO Cellular Component pathway "Mitochondrion" stood out among other pathways, with differentially expressed genes predominantly affiliated with this specific pathway, implicating the involvement of different mitochondrial functions in ASD. Among the differentially expressed genes, FPR2 was particularly highlighted, belonging to three GO pathways. FPR2 can modulate pro-inflammatory responses, with its intracellular cascades triggering the activation of several kinases, thus suggesting its potential utility as a biomarker of pro-inflammatory processes in ASD.

Amide proton transfer MRI at 9.4 T for differentiating tissue acidosis in a rodent model ofischemic stroke.

Differentiating ischemic brain damage is critical for decision making in acute stroke treatment for better outcomes. We examined the sensitivity of amide proton transfer (APT) MRI, a pH-weighted imaging technique, to achieve this differentiation. In a rat stroke model, the ischemic core, oligemia, and the infarct-growth region (IGR) were identified by tracking the progression of the lesions. APT MRI signals were measured alongside ADC, T1, and T2 maps to evaluate their sensitivity in distinguishing ischemic tissues. Additionally, stroke under hyperglycemic conditions was studied. The APT signal in the IGR decreased by about 10% shortly after stroke onset, and further decreased to 35% at 5 h, indicating a progression from mild to severe acidosis as the lesion evolved into infarction. Although ADC, T1, and T2 contrasts can only detect significant differences between the IGR and oligemia for a portion of the stroke duration, APT contrast consistently differentiates between them at all time points. However, the contrast to variation ratio at 1 h is only about 20% of the contrast to variation ratio between the core and normal tissues, indicating limited sensitivity. In the ischemic core, the APT signal decreases to about 45% and 33% of normal tissue level at 1 h for the normoglycemic and hyperglycemic groups, respectively, confirming more severe acidosis under hyperglycemia. The sensitivity of APT MRI is high in detecting severe acidosis of the ischemic core but is much lower in detecting mild acidosis, which may affect the accuracy of differentiation between the IGR and oligemia.

Targeting TNF-α: The therapeutic potential of certolizumab pegol in the early period of cerebral ischemia reperfusion injury in mice

The neuroinflammatory response triggered by cerebral ischemia–reperfusion injury (CIRI) is characterized by the upsurge of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, which promote leukocyte infiltration and subsequent accumulation in the ischemic zone. This accumulation further intensifies inflammation and aggravates ischemic damage. Certolizumab pegol (CZP), a monoclonal antibody targeting TNF-α, is widely used in treating various inflammatory diseases. This study explored the therapeutic potential of CZP in a mouse model of CIRI, induced by middle cerebral artery occlusion (MCAO), focusing on its influence on the microglial inflammatory response. In vitro analyses revealed that CZP markedly inhibits TNF-α-stimulated inflammation in primary microglia with an EC50 of 1.743 ng/mL. In vivo, MCAO mice treated with CZP (10 μg/mouse, i.p.) for 3 days showed reduced infarct volume, partially improved neurological function, and diminished blood–brain barrierdisruption. Additionally, CZP treatment curtailed microglial activation and the release of pro-inflammatory mediators in the early stages of stroke. It also favorably modulated microglial M1/M2 polarization, rebalanced Th17/Treg cells dynamics, and inhibited Caspase-8-mediated GSDMD cleavage, preventing microglial pyroptosis. Collectively, this study described that the treatment with CZP reversed damaging process caused by CIRI, offering a promising therapeutic strategy for the treatment of ischemic stroke.

The Use of Hematopoietic Stem Cells for Heart Failure: A Systematic Review.

The purpose of this review is to summarize the current understanding of the therapeutic effect of stem cell-based therapies, including hematopoietic stem cells, for the treatment of ischemic heart damage. Following PRISMA guidelines, we conducted electronic searches in MEDLINE, and EMBASE. We screened 592 studies, and included RCTs, observational studies, and cohort studies that examined the effect of hematopoietic stem cell therapy in adult patients with heart failure. Studies that involved pediatric patients, mesenchymal stem cell therapy, and non-heart failure (HF) studies were excluded from our review. Out of the 592 studies, 7 studies met our inclusion criteria. Overall, administration of hematopoietic stem cells (via intracoronary or myocardial infarct) led to positive cardiac outcomes such as improvements in pathological left-ventricular remodeling, perfusion following acute myocardial infarction, and NYHA symptom class. Additionally, combined death, rehospitalization for heart failure, and infarction were significantly lower in patients treated with bone marrow-derived hematopoietic stem cells. Our review demonstrates that hematopoietic stem cell administration can lead to positive cardiac outcomes for HF patients. Future studies should aim to increase female representation and non-ischemic HF patients.

Idiopathic Atypical Hemolytic Uremic Syndrome: A Case Report

Thrombotic microangiopathies (TMAs) are a spectrum of disorders characterized by hemolytic anemia, thrombocytopenia, and formation of microthrombi in blood vessels, resulting in tissue injury due to compromised blood flow. This classical presentation of TMA is characterized by varying degrees of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and ischemic damage to the brain, kidneys, heart, lungs and GI tract. TMA can be classified into different types based upon the etiology and pathogenesis like thrombotic thrombocytopenic purpura (TTP), Complement mediated TMA (atypical Hemolytic uremic syndrome [aHUS]), infection associated TMA (shiga toxin producing E.coli, streptococcus pneumoniae) secondary to systemic causes like malignancy, autoimmune diseases and medications. In this article, we discuss a case of a female diagnosed with aHUS with acute kidney injury complicated by hypertension and severe anemia. As aHUS is known to be associated with high mortality and morbidity, prompt recognition of aHUS is crucial for efficient treatment. Here we have discussed the clinical presentation, histopathological hallmarks, and the diagnostic approach for TMA.