Reprint of: Fibrinolytic and Non-fibrinolytic Roles of Tissue-type Plasminogen Activator in the Ischemic Brain.

The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by perivascular astrocytes (PVA), which in turn are in contact with synapses. Cerebral ischemia induces the rapid release of the serine proteinase tissue-type plasminogen activator (tPA) from endothelial cells, perivascular astrocytes, microglia and neurons. Owning to its ability to catalyze the conversion of plasminogen into plasmin, in the intravascular space tPA functions as a fibrinolytic enzyme. In contrast, the release of astrocytic, microglial and neuronal tPA have a plethora of effects that not always require the generation of plasmin. In the ischemic brain tPA increases the permeability of the NVU, induces microglial activation, participates in the recycling of glutamate, and has various effects on neuronal survival. These effects are mediated by different receptors, notably subunits of the N-methyl-D-aspartate receptor (NMDAR) and the low-density lipoprotein receptor-related protein-1 (LRP-1). Here we review data on the role of tPA in the NVU under non-ischemic and ischemic conditions, and analyze how this knowledge may lead to the development of potential strategies for the treatment of acute ischemic stroke patients.

Targeting PAK1 is effective against cutaneous squamous cell carcinoma in a syngenic mouse model.

By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS-PAK1-1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA-induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS-PAK1-1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA-sequencing analysis on the engrafted tumors indicates that NVS-PAK1-1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan-keratin-positive regions and potentially elevated infiltration of CD8-positive immune cells in NVS-PAK1-1-treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC.

Enhancing Gluten-Free Bread Production: Impact of Hydroxypropyl Methylcellulose, Psyllium Husk Fiber, and Xanthan Gum on Dough Characteristics and Bread Quality.

The demand for gluten-free products has increased due to improved diagnoses and awareness of gluten-related issues. This study investigated the effect of HPMC, psyllium, and xanthan gum in gluten-free bread formulations. Three tests were conducted, varying the amount of these ingredients: in the first formulation, the amount of HPMC was increased to 4.4 g/100 g of flour and starch; in the second, psyllium husk fiber was increased to 13.2 g/100 g of flour and starch; and in the third formulation, xanthan gum was removed. Differences were observed among the formulations: increasing HPMC reduced extrusion force without affecting bread quality; adding psyllium increased dough elasticity but also crumb gumminess and crust hardness. Eliminating xanthan gum altered dough rheology, resulting in a softer and less gummy crumb, and a less reddish color in the final bread.

Mechanisms of QiShenYiQi in Inhibiting Blood-Brain Barrier Damage Following Stroke: A Network Pharmacology and Experimental Study.

BACKGROUND AND PURPOSE: QiShenYiQi (QSYQ) has shown promise in the treatment of blood-brain barrier (BBB) damage following stroke. However, the identification of its bioactive components and the underlying molecular mechanisms of action remain unknown. This study aimed to investigate the active ingredients and mechanisms involved in the inhibitory effects of QSYQ on BBB damage after ischemic stroke based on network pharmacology and experimental verification. MATERIALS AND METHODS: The chemical composition and target information of QSYQ were obtained from the Traditional Chinese Medicine Systems Pharmacology and Analysis Platform. BBB injury-related targets were identified by screening databases, and the overlapping targets with QSYQ were collected. Cytoscape software was utilized to construct protein-protein interaction (PPI) networks. Molecular docking analysis was conducted using AutoDock software. Animal experiments were carried out to verify the protective effect of QSYQ on BBB and explore potential molecular mechanisms. RESULTS: A total of 131 active ingredients in QSYQ and 154 common targets related to QSYQ and BBB damage were identified. Analysis of the PPI network revealed key targets including ALB, INS, ACTB, TP53, and CASP3 against BBB injury. Molecular docking analysis indicated favorable binding interactions between dihydrotanshinlactone, tanshinone IIA, salviolone, and their respective target proteins, such as FOS, INS, CASP3, and JUN. In animal experiments, QSYQ demonstrated effective inhibition of BBB damage, and this effect may be attributed to the regulation of ALB, INS, TP53, and CASP3. CONCLUSION: This study provides intriguing insights into the mechanisms by which QSYQ protects against BBB injury following ischemic stroke. Key targets, including ALB, INS, TP53, and CASP3, could be potentially involved in the beneficial effects of QSYQ.

Treatment Delays for Patients With Acute Ischemic Stroke in a Rural Arkansas Emergency Department: A Retrospective Chart Review.

Objective The goal of this study is to evaluate treatment times regarding acute ischemic stroke and identify barriers to implementing stroke care at the Ouachita County Medical Center Emergency Department. Methods A retrospective review of medical records was conducted of patients who presented with acute ischemic stroke to the Ouachita County Medical Center Emergency Department between 2020 and 2023 and received intravenous (IV) r-tPA. The primary focus of this study was to analyze door-to-needle time with IV r-tPA. To determine areas of improvement, this study examined door-to-initial physician evaluation, door-to-CT, door-to-tele neurologist evaluation, and door-to-IV r-tPA administration. Results A total of 26 patients who received treatment with IV r-tPA for acute ischemic stroke were included in this study. Twenty-three patients (88%; n=26) received IV- r-tPA within the recommended 60-minute window with a mean treatment time of 44.5 minutes. The mean door-to-physician evaluation time for patients presenting with acute ischemic stroke was 1.81 minutes. All patients received CT scans within 28 minutes of arrival with the mean time being 5.08 minutes. Teleneurologist evaluation was initiated within 59 minutes of presentation with a mean time of 25.19 minutes. Conclusion Evaluation of treatment times at the Ouachita County Medical Center Emergency Department confirms that stroke care received at this facility adheres to the recommendations outlined by the American Stroke Association. Nevertheless, clinicians should always strive for improvement. Through extensive evaluation of the treatment process, we were able to provide recommendations to further decrease treatment times and improve overall clinical outcomes.

14-3-3σ/Stratifin and p21 limit AKT-related malignant progression in skin carcinogenesis following MDM2-associated p53 loss.

To study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of 14-3-3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN-mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14-3-3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14-3-3σ expression in supra-basal keratinocytes, paralleled by supra-basal p-MDM2166 activation and sporadic p-AKT473 expression. In bi-genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal-layer 14-3-3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri-genic HK1.ras/fos-Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal-layer 14-3-3σ, suggesting attempts to maintain supra-basal p-MDM2166 and protect basal-layer p53. However, HK1.ras/fos-Δ5PTENflx/flx papillomas exhibited increasing basal-layer p-MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14-3-3σ expression persisted in well-differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p-AKT1473 expression; until 14-3-3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p-AKT1473. Analysis of TPA-promoted HK1.ras-Δ5PTENflx/flx mouse skin, demonstrated early loss of 14-3-3σ/p53/p21 in hyperplasia and papillomas, with increased p-MDM2166/p-AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14-3-3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v-fos SCC cells cultured in monolayers, but not invasive 3D-cells. Collectively, these data suggest 14-3-3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53-dependent mechanisms; while persistent p53-independent expression in early wdSCC may involve p21-mediated AKT1 inhibition to limit malignant progression.

Feline Aortic Thromboembolism: Recent advances and future prospects.

PRACTICAL RELEVANCE: Feline aortic thromboembolism (FATE) is commonly encountered in clinical medicine, especially in emergency situations. This often devastating syndrome usually develops secondarily to severe heart disease, and has short- and long-term consequences. CLINICAL FEATURES: The clinical presentation of FATE is consistent with peripheral ischemic neuropathy, usually in both pelvic limbs. Diagnosis is relatively straightforward, but can be assisted with Doppler ultrasound, point-of-care ultrasound or infrared thermal imaging. RECENT ADVANCES AND FUTURE PROSPECTS: Interpretation of survival rates in cats with FATE has been hampered by historically high admission euthanasia, but recent studies suggest a survival rate with supportive care of 30-40%. Moreover, with advances in post-FATE thromboprophylaxis, median survival times of over 1 year are being achieved. Future directions include use of thrombolytic agents and treatment of common FATE sequelae such as acute kidney injury and reperfusion injury. OUTLINE: This article, aimed at small animal veterinarians, including emergency practitioners, reviews key aspects of the clinical presentation, diagnosis and treatment options for FATE, with a view to guiding client and veterinarian decision-making. Three case studies are included to illustrate the practical application of information presented in the review. EVIDENCE BASE: There are limited prospective studies on FATE, although the recent literature reflects a resurgence in clinical research interest in the past few years. Advances in FATE treatment will benefit many cats and it is important that research efforts continue to identify appropriate treatment modalities.

Complex Karyotype Detection in Chronic Lymphocytic Leukemia: A Comparison of Parallel Cytogenetic Cultures Using TPA and IL2+DSP30 from a Single Center.

Current CLL guidelines recommend a two parallel cultures assessment using TPA and IL2+DSP30 mitogens for complex karyotype (CK) detection. Studies comparing both mitogens for CK identification in the same cohort are lacking. We analyzed the global performance, CK detection, and concordance in the complexity assessment of two cytogenetic cultures from 255 CLL patients. IL2+DSP30 identified more altered karyotypes than TPA (50 vs. 39%, p = 0.031). Moreover, in 71% of those abnormal by both, IL2+DSP30 identified more abnormalities and/or abnormal metaphases. CK detection was similar for TPA and IL2+DSP30 (10% vs. 11%). However, 11/33 CKs (33%) were discordant, mainly due to the detection of a normal karyotype or no metaphases in the other culture. Patients requiring treatment within 12 months after sampling (active CLL) displayed significantly more CKs than those showing a stable disease (55% vs. 12%, p < 0.001). Disease status did not impact cultures' concordance (κ index: 0.735 and 0.754 for stable and active). Although CK was associated with shorter time to first treatment (TTFT) using both methods, IL2+DSP30 displayed better accuracy than TPA for predicting TTFT (C-index: 0.605 vs. 0.580, respectively). In summary, the analysis of two parallel cultures is the best option to detect CKs in CLL. Nonetheless, IL2+DSP30 could be prioritized above TPA to optimize cytogenetic assessment in clinical practice.

How Effective Are the Nance Appliance and Transpalatal Arch at Reinforcing Anchorage in Extraction Cases?

OBJECTIVE: This narrative review aimed to evaluate, based on current evidence, whether the transpalatal arch (TPA) and Nance appliance can effectively reinforce anchorage during fixed orthodontic treatment while also offering a comprehensive and in-depth overview of the existing literature on this subject. MATERIALS AND METHODS: A thorough literature search was performed across multiple electronic databases to identify peer-reviewed articles relevant to the review. RESULTS: Evidence suggests that the Nance appliance does not provide absolute anchorage. Additionally, patients experienced discomfort and inflammation of the palatal tissues. The transpalatal arch is also insufficient for maximum anteroposterior anchorage, and existing studies on its effectiveness in vertical anchorage control are inconsistent with conflicting data. CONCLUSIONS: For patients with critical anchorage demand, mini-screws may be the method of choice, either solely or in combination with Nance or transpalatal arch, though they carry a risk of failure.

Efficient biodegradation of Polyethylene terephthalate (PET) plastic by Gordonia sp. CN2K isolated from plastic contaminated environment.

Since we rely entirely on plastics or their products in our daily lives, plastics are the invention of the hour. Polyester plastics, such as Polyethylene Terephthalate (PET), are among the most often used types of plastics. PET plastics have a high ratio of aromatic components, which makes them very resistant to microbial attack and highly persistent. As a result, massive amounts of plastic trash accumulate in the environment, where they eventually transform into microplastic (<5 mm). Rather than macroplastics, microplastics are starting to pose a serious hazard to the environment. It is imperative that these polymer microplastics be broken down. Through the use of enrichment culture, the PET microplastic-degrading bacterium was isolated from solid waste management yards. Bacterial strain was identified as Gordonia sp. CN2K by 16 S rDNA sequence analysis and biochemical characterization. It is able to use polyethylene terephthalate as its only energy and carbon source. In 45 days, 40.43 % of the PET microplastic was degraded. By using mass spectral analysis and HPLC to characterize the metabolites produced during PET breakdown, the degradation of PET is verified. The metabolites identified in the spent medium included dimer compound, bis (2-hydroxyethyl) terephthalate (BHET), mono (2-hydroxyethyl) terephthalate (MHET), and terephthalate. Furthermore, the PET sheet exposed to the culture showed considerable surface alterations in the scanning electron microscope images. This illustrates how new the current work is.

Temporal Trends of Sex Differences in Acute Reperfusion Therapy and Early Outcomes of Acute Ischemic Stroke in South Korea: 10-Year Analysis of the Nationwide Stroke Registry.

BACKGROUND: Sex differences in stroke outcomes are notable, with women experiencing higher incidence rates, greater disability-adjusted life years, and poorer recovery compared to men, even after adjusting for age and comorbidities. Despite the disproportionate burden in women, studies have reported that women are less likely to receive appropriate stroke treatment than men. AIM: This study investigated temporal trends of sex differences in acute reperfusion therapy and early outcomes in patients with acute ischemic stroke over 10 years in South Korea. METHODS: A retrospective analysis of Korean Stroke Registry included patients with acute ischemic stroke from 2012 to 2021. The study outcomes were the temporal trends of acute reperfusion therapy and early outcomes over 10 years in men and women, respectively. Additionally, this study analyzed the temporal trends of sex differences in these parameters during the same period. Early outcomes include the proportions of favorable functional outcomes at discharge, discharge patterns, and in-hospital mortality. RESULTS: A total of 93,692 patients (68.4 years, 40.1% women) with acute ischemic stroke were finally enrolled. Women had a higher age at stroke onset, a higher prevalence of atrial fibrillation, and more severe strokes than men. Women had lower proportion of favorable functional outcomes at discharge and higher proportion of in-hospital mortality compared to men each year. The proportion of patients who received intravenous thrombolysis was lower or similar in women compared to men in most years, and the proportion of patients who received endovascular thrombectomy did not significantly differ between sexes annually. Sex differences in acute reperfusion therapy remained unchanged over 10 years. CONCLUSION: Women have received acute reperfusion therapy at similar or lower rates than men and experienced poorer outcomes, despite having more stroke risk factors and often more severe strokes.

Exploration of Hypertension Following Traumatic Renal Hematoma Formation and Page Kidney Discussion.

Page kidney is defined as a rare cause of secondary hypertension due to a subcapsular hematoma externally compressing the kidney resulting in the activation of the renin-angiotensin-aldosterone system (RAAS). This phenomenon consists of numerous etiologies including acute or chronic traumatic or non-traumatic events. In this case, we report on an acute unilateral hematoma following blunt renal trauma as the result of a fall from standing height treated with tissue plasminogen activator (tPA) infusion and image-guided drainage. Qualities within this case and how they are paralleled in the diagnosis of a Page kidney are explored. A brief review of current etiologies and management plans per the literature review will also be discussed.

Number needed to treat with intravenous tenecteplase to reduce the need for mechanical thrombectomy in large vessel occlusion acute ischemic stroke patients: A retrospective look at real-world experience data.

OBJECTIVE: We sought to describe short term outcomes in patients with large vessel occlusion acute ischemic stroke (LVOAIS) who were treated with intravenous tenecteplase (TNK) as compared to alteplase (tPA), focusing on reduction in the need for mechanical thrombectomy (MT). BACKGROUND: In LVOAIS, TNK has shown improved reperfusion and outcomes with a similar safety profile to tPA. Ultra-early reperfusion has been described with TNK which would prevent the need for MT. We analyze the magnitude of this effect in a "real-world" setting. DESIGN/METHODS: In this retrospective study, demographic, clinical, and imaging information from patients with LVOAIS treated with intravenous thrombolysis was collected. Data was compared between the group treated with TNK and tPA. RESULTS: One hundred eighty-six patients met the criteria for the study. Of these,144patients received tPA and 42 received TNK. Nine had clinical improvement prior to groin puncture and did not require angiography. When combining the number of patients who had recanalization on angiography before MT and those who had clinical improvement prior to angiography, there were a total of 23 patients. This was noted in 9.7 % of patients who received tPA and 21.4 % of those who received TNK (p = 0.043). For patients treated with TNK we observed a rapid clinical improvement, improved NIHSS, improved functional outcomes and decreased length of stay compared to patients treated with tPA. For patients with spontaneous recanalization either angiographically or with clinical improvement from intravenous thrombolysis, MT may not be required. CONCLUSIONS: Intravenous TNK in patients with LVOAIS decreases the need for MT, and is associated with improved outcomes and reduced length of stay.

Impact of terephthalic acid emissions from intensive nocturnal biomass incineration on oxidative potential in Seoul, South Korea.

This study investigated the impact of large-scale incineration facilities on PM2.5 levels in Seoul during winter. Due to the challenge of obtaining accurate combustion data from external sources, heat supply records were used as a proxy for combustion activity. To assess health risks, dithiothreitol-oxidative potential (DTT-OP) was analyzed to identify potential hazards to human health. By comparing DTT-OP with PM2.5 sources related to combustion, the study aimed to understand the impact of local pollution sources on human health in Seoul. The diurnal analysis showed that oxidative potential (0.19 µM/m3) and the biomass burning factor (5.53 µg/m3) peaked between 4:00 and 8:00 AM, with lower levels observed from 12:00 to 20:00. A significant correlation was found between combustion sources and oxidative potential, with a high correlation coefficient (r2 = 0.92). The presence of terephthalic acid (TPA) in the Cellulose combustion source profile, which is produced by the pyrolysis of plastics like polyester fiber and polyethylene terephthalate (PET), further supported the link to emissions from incineration facilities. These findings suggest that the biomass burning source is strongly correlated with DTT-OP, indicating a significant association with health risks among various local sources of PM2.5 in Seoul.

Validation of the transcranial Doppler rescue criteria for mechanical thrombectomy.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) identifies acute stroke patients with arterial occlusion where treatment may not effectively open the blocked vessel. This study aimed to examine the clinical utility and prognostic value of TCD flow findings in patients enrolled in a multicenter prospective study (CLOTBUST-PRO). METHODS: Patients enrolled with intracranial occlusion on computed tomography angiography (CTA) who underwent urgent TCD evaluation before intravenous thrombolysis was included in this analysis. TCD findings were assessed using the mean flow velocity (MFV) ratio, comparing the reciprocal ratios of the middle cerebral artery (MCA) depths bilaterally (affected MCA-to-contralateral MCA MFV [aMCA/cMCA MFV ratio]). RESULTS: A total of 222 patients with intracranial occlusion on CTA were included in the study (mean age: 64 ± 14 years, 62% men). Eighty-eight patients had M1 MCA occlusions; baseline mean National Institutes of Health Stroke Scale (NIHSS) score was 16, and a 24-hour mean NIHSS score was 10 points. An aMCA/cMCA MFV ratio of <.6 had a sensitivity of 99%, specificity of 16%, positive predictive value (PV) of 60%, and negative PV of 94% for identifying large vessel occlusion (LVO) including M1 MCA, terminal internal carotid artery, or tandem ICA/MCA. Thrombolysis in Brain Ischemia scale, with (grade ≥1) compared to without flow (grade 0), showed a sensitivity of 17.1%, specificity of 86.9%, positive PV of 62%, and negative PV of 46% for identifying LVO. CONCLUSIONS: TCD is a valuable modality for evaluating arterial circulation in acute ischemic stroke patients, demonstrating significant potential as a screening tool for intravenous/intra-arterial lysis protocols.

Pneumatic displacement with intravitreal tPA injection versus vitrectomy with sub retinal tPA injection in small and medium sub macular hemorrhages- a multicenter comparative study.

PURPOSE: Comparing between the visual outcomes and post operative complications of two surgical treatments for sub macular hemorrhage, pars plana vitrectomy with tissue plasminogen activator (tPA) injection procedure, and pneumatic displacement of submacular hemorrhage with intravitreal tPA injection. METHODS: A retrospective chart review of patients with sub macular hemorrhage (SMH) was performed. Data was collected from 150 patients with sub macular hemorrhage. Patients were followed up from the day of admission and up to a year post surgery. Evaluation included visual acuity, optical coherence tomography (OCT), fundus examination and rates of complications. RESULTS: Pars plana vitrectomy procedure has showed a better visual outcome in small SMH. Comparing complications between the two treatment modalities, no significant difference has been found in the study. CONCLUSIONS: Pars plana vitrectomy and tPA showed a clear advantage with a trend of better visual acuity as well as a significant predictor to better visual acuity for small and medium sub macular hemorrhage.

Quantum Size-Driven Spectral Variations in Pillar[n]arene Systems: A Density Functional Theory and Wave Function Assessment.

This study explores the quantum size effects on the optical properties of pillar[n]arene (n = 5, 6, 7, 8) utilizing density functional theory (DFT) and wave function analysis. The mechanisms of electron transitions in one-photon absorption (OPA) and two-photon absorption (TPA) spectra are investigated, alongside the calculation of electron circular dichroism (ECD) for these systems. Transition Density Matrix (TDM) and electron-hole pair density maps are employed to study the electron excitation characteristics, unveiling a notable size dependency. Analysis of the transition electric dipole moment (TEDM) and the transition magnetic dipole moment (TMDM) reveals the electromagnetic interaction mechanism within pillar[n]arene. Raman spectra computations further elucidate vibrational modes, while interactions with external environments are studied using electrostatic potential (ESP) analysis, and electron delocalization is assessed under an external magnetic field, providing insights into the magnetically induced current phenomena within these supramolecular structures. The thermal stability of pillar[n]arene was investigated by ab initio molecular dynamics (AIMD).

Sex-dependent behavioral effects of chronic nicotine during adolescence evaluated in young adult rats tested in Hole-Board.

As one of the leading causes of death and serious illnesses, tobacco smoking remains a significant issue in modern societies. Many individuals smoke during adolescence, a trend that has been exacerbated by the prevalence of vaping among young people. In this context, studying the behavioral effects induced by nicotine administration in male and female rats, during the adolescent period, assumes great importance because it can help to better understand the dynamics underlying tobacco use in the two sexes. For this purpose, we employed 4 groups of rats, 2 male and 2 female groups, chronically treated with saline or nicotine 3 mg/kg i.p. for 30 days, spanning from postnatal day 30 to postnatal day 60. Utilizing quantitative analyses and T-pattern detection and analysis, our findings revealed a complex and multifaceted behavioral reorganization in adolescent rats subjected to chronic nicotine administration. Specifically, we observed an increase of anxiety in males and a reduction in females. The distinctive structural changes, induced by chronic nicotine in both sexes, have significant implications, from a translational perspective, for studies on nicotine dependence disorders.