Search

We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.

Chylopericardium is a rare entity in veterinary medicine. In this report we document the development of chylopericardium in two dogs undergoing chronic hemodialysis. An 11-year-old female spayed Labrador retriever (Case 1) presented with acute coughing and lethargy 2 months following initial dialysis catheter placement and initiation of dialysis therapy for severe azotemia. Echocardiography demonstrated severe pericardial effusion and cardiac tamponade. Pericardial fluid analysis was consistent with chylous effusion. The dog underwent a subtotal pericardiectomy with thoracic duct ligation, and a PleuralPort™ was placed. The patient continued to receive outpatient hemodialysis therapy after pericardiectomy for several months until she died acutely at home. A 4-year-old male neutered Doberman (Case 2) was being treated for 2 months with outpatient hemodialysis for management of chronic kidney disease. On presentation for the 17th hemodialysis treatment, the patient had increased respiratory rate. Echocardiography demonstrated pleural and pericardial effusions, and fluid analysis in both cavities was consistent with chylous effusion. Use of tissue plasminogen activator (TPA), clot removal and replacement of the catheter was attempted; however pleural and pericardial effusion continued. The patient was euthanized after 25 hemodialysis sessions as owners elected not to pursue more procedures. In both cases, the cause of the chylopericardium was suspected to be secondary to catheter-associated thrombosis and/or stenosis based on multiple imaging modalities. Despite use of rivaroxaban and clopidogrel concurrently in each case, the chylous effusion persisted. This case report describes clinical details of a rare complication of long-term indwelling dialysis catheters in two dogs.

Ischemic stroke (IS) is the leading cause of disability and the second most common cause of death in adults globally. Unfortunately, the recombinant tissue plasminogen activator (rt-PA), the only thrombolytic drug approved by the Food and Drug Administration (FDA), has numerous side effects such as hemorrhage risk and narrow therapeutic windows, which limits its clinical application. Butylphthalide (NBP) from celery seeds was approved against IS, and its derivative 6-amino-3-n-butylphthalide has been demonstrated to offer better neuroprotective effects against IS-induced injury. In this study, a series of 6-amino-3-n-butylphthalide (ABP) derivatives were designed and synthesized in order to obtain novel powerful compounds against IS. Permanent middle cerebral artery occlusion (pMCAO)-operated mice and oxygen and glucose deprivation (OGD)-treated primary cortical neurons and HT22 cell lines were used to evaluate the activity of these derivatives in protecting against ischemic injury. The results showed that the effect of compound ABP18 (ABP connecting with memantine) on alleviating OGD-induced cell death was better than that of NBP both in primary cortical neurons and HT22 cells, and the safety of ABP18 is comparable to that of NBP. In addition, ABP18 significantly reduced the brain infarct volume and improved neurological function in mice at 24 h after pMCAO. The acute toxicity test showed that ABP18 had high safety. Therefore, the present study identified that ABP18 is a potential candidate for the treatment of IS. [ABSTRACT FROM AUTHOR]

Background: Pulmonary intravascular thrombus formation has been widely observed in patients with respiratory failure, for example, in patients with SARS-CoV-2 infection (COVID-19). The aim of this study was to evaluate the efficacy/safety of alteplase thrombolysis in COVID-19 severe hypoxemic respiratory failure. In this multicenter, open-label study, patients were randomized to receive alteplase (low- or high-dose) over 5 days plus standard of care (SOC), or SOC alone. The primary endpoint was time to clinical improvement (≥ 2-point decrease on WHO Clinical Progression Scale, or hospital discharge) up to Day 28. Secondary endpoints included all-cause mortality at Day 28, treatment failure at Day 28 and change in arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) ratio at Day 6 versus baseline. Results: Sixty-nine patients were randomized to alteplase (low- or high-dose) and 35 to SOC; 65% were on high-flow oxygen or non-invasive ventilation at baseline. Median time to clinical improvement was 25 days in the alteplase group and > 28 days (median not reached) in the SOC group. All-cause mortality was 8/69 (12%) versus 10/35 (29%) in the alteplase versus SOC groups, respectively (unadjusted risk difference [RD], − 17% [95% confidence interval (CI) − 34 to 0], p = 0.047; adjusted RD, − 16% [95% CI − 31 to 1], p = 0.058). The PaO2/FiO2 ratio (mean [standard deviation]) increased by + 30 (84) mmHg in the alteplase group and decreased by − 12 (59) mmHg in the SOC group (adjusted mean difference vs. SOC, p = 0.052). Differences were greater in patients receiving high-dose alteplase, and in those not receiving invasive ventilation. Eighteen patients (26.1%) in the alteplase group discontinued treatment due to adverse events. Major bleeding was more frequent with alteplase than with SOC (9 vs. 0 patients); no bleeding was fatal. The study closed early due to insufficient patient recruitment. Conclusion: Alteplase was not associated with faster clinical recovery from COVID-19 severe hypoxemic respiratory failure. A numerical difference in survival and PaO2/FiO2 ratio was observed, particularly in patients not receiving invasive ventilation. These exploratory findings merit further investigation in larger patient cohorts that are adequately powered to confirm the hypotheses generated in this study regarding the impact of alteplase on treatment outcomes. Trial registration ClinicalTrials.gov: NCT04640194 (November 23, 2020); https://clinicaltrials.gov/study/NCT04640194 (early discontinuation due to insufficient patient recruitment). [ABSTRACT FROM AUTHOR]

Accessory middle cerebral arteries (AMCAs) are found in 0.3–4.0% of cases, and ipsilateral dual AMCAs are rare. A seventy-three-year-old man presented with right hemiplegia and total aphasia. Magnetic resonance angiography showed left carotid artery occlusion. We infused him with tissue plasminogen activator. Digital subtraction angiogram showed revascularization of the left internal carotid artery. However, the left proximal anterior cerebral artery was occluded. We performed mechanical thrombectomy and achieved partial reperfusion. CT angiography on the tenth day showed ipsilateral dual AMCAs. Due to middle cerebral artery anomalies, we performed mechanical thrombectomy using contact aspiration which is safer than other techniques. [ABSTRACT FROM AUTHOR]

Background: Stroke is a true medical emergency condition with thrombolytic treatment with recombinant tissue plasminogen activator as the standard treatment. In Thailand, including the Northeast region (Health region 7 to 10), stroke incidence and mortality rate have increased. However, there is no study of stroke incidence, recombinant tissue plasminogen activator (rtPA) access rate, and mortality rate by district in Northeastern Thailand. Objective: This study aimed to present stroke incidence, access rate of thrombolytic treatment, and acute stroke mortality rates for each district in Northeast Thailand for the 5 years, 2017 to 2022. Materials and Methods: The study drew from the Thai National Health Security Office's (NHSO) database for 2017 to 2022 and reported using rates per 100,000 population and percentage statistics. Results: The overall incidence of acute stroke and acute ischemic stroke patients aged over 15 years in Northeastern Thailand were 264.19 to 331.70/100,000 population and 184.57 to 232.82/100,000 population respectively. The rtPA access rate was 6.09 to 8.01% (Main Universal Coverage Scheme) and 6.01 to 7.92% (Referral Universal Coverage Scheme). The mortality rate of acute ischemic stroke patients within 30 days and post-rtPA were 8.80 to 10.43% and 3.65 to 5.67% respectively. Conclusion: In Northeastern Thailand, stroke incidence has shown an upward trend over the past 5 years. The number of acute ischemic stroke patients receiving rtPA has also been on the rise. The mortality rate in patients with acute ischemic stroke within 30 days declined from 2017 to 2019, then increased from 2020 to 2022. Particularly notable was the increase in the mortality rate among patients with acute ischemic stroke post-intravenous thrombolysis. [ABSTRACT FROM AUTHOR]

Background: Acute ischemic stroke (AIS) is a major public health issue, and women have a disproportionate share of stroke-related disability and mortality, which is poorly understood. This study aimed to determine the effect of sex differences on AIS treated by thrombolysis using recombinant tissue plasminogen activator (rTPA). The study included 134 AIS patients eligible for rTPA. Risk factors, clinical presentation, thrombolysis response, complications, and outcomes were recorded. The outcomes were measured using the National Institute of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) 3 months after stroke. The incidence of intracranial haemorrhage was also determined. Results: Among 134 AIS patients treated with rTPA (59% male, 41% female), females had higher rates of hypertension (67.3% versus 49.4%, p = 0.040) and atrial fibrillation (AF) (12.7% versus 2.5%, p = 0.020), while smoking was more prevalent in males (31.6% versus 0%, p < 0.0001). Cardioembolism was more frequent in females than in males (23.6% versus 6.3%, p = 0.004). Females also had shorter onset-to-door (110.7 ± 63 versus 131.1 ± 50.2 min, p = 0.035) and onset-to-needle times (151.6 ± 66.5 versus 173.7 ± 50.6 min, p = 0.046). Both sexes showed significant improvements in NIHSS (males: 11.58 ± 3.7 to 6.05 ± 5.6; females: 11.64 ± 4.7 to 6.9 ± 5.9; p < 0.0001) and mRS scores (males: 3.34 ± 1.05 to 2.03 ± 2; females: 3.53 ± 1 to 2.02 ± 2; p < 0.0001) over 3 months, with no significant differences between sexes. Predictors of poor outcome (mRS 3–6) differed: diabetes mellitus (DM) (OR 7.79, p = 0.002) and longer door-to-needle time (OR 1.04, p = 0.008) for males, and hemorrhage (OR 9.41, p = 0.048) for females. Hemorrhage predicted mortality in males (OR 27.08, p < 0.0001), while AF was associated with increased mortality in females (OR 8.06, p = 0.024). Conclusions: This study revealed sex-specific differences in AIS risk factors, aetiology, and rTPA treatment timelines, although post-treatment improvements were comparable between sexes. Notably, outcome predictors and mortality factors differed by sex. These findings emphasize the need for sex-specific considerations in AIS management and risk assessment. [ABSTRACT FROM AUTHOR]

Stroke remains a leading cause of mortality and disability, with ischemic stroke being the most common type. It occurs due to reduced cerebral blood flow, leading to a cascade of events initiated by oxygen and nutrient deprivation, triggering excitotoxicity, oxidative stress, and inflammation and finally culminating in neuronal injury and death. Key molecular players in ischemic stroke include glutamate receptors, acid-sensing ion channels, and purinergic receptors, exacerbating cellular damage through calcium influx, oxidative stress, and mitochondrial dysfunction. Understanding these mechanisms has shaped therapeutic strategies, such as neuroprotective agents and stem cell therapies. Current treatments such as tissue plasminogen activator (tPA) emphasize timely intervention, yet challenges persist in patient-specific variability and accessibility. This review provides an overview of ischemic stroke pathophysiology, emphasizing cellular responses to ischemia and current and future therapeutic approaches including stem cell therapies aimed at mitigating stroke-induced disabilities and improving long-term outcomes. [ABSTRACT FROM AUTHOR]

Background: Congenital agenesis of internal carotid artery (ICA) is a rare cerebrovascular variation entity. Most cases of congenital ICA agenesis are asymptomatic and discovered incidentally. Congenital ICA agenesis presenting as ischemic stroke is even rare. Case presentation: An 80-year-old male patient was admitted to our hospital due to sudden dysarthria and left limb weakness for 3.5 h. Based on emergency physical examination and head computed tomography (CT) scan results, acute ischemic stroke (AIS) of right cerebral hemisphere was suspected. Following intravenous thrombolysis with recombinant tissue plasminogen activator, right congenital agenesis of ICA was confirmed by CT and digital subtraction angiography. Additionally, there was a severe right vertebral artery ostial (VAO) stenosis. After ruling out common causes of AIS such as haematological diseases, arterial dissection, organic heart disease, immunological abnormality and underlying possible malignancies, we hypothesize that the severe stenosis of the right VAO may have contributed to the development of AIS in this case. Conclusions: We present a case of right congenital ICA agenesis in which severe stenosis of the right VAO may have played a role in the development of AIS. This case underscores a rare scenario where a lesion in the posterior circulation leads to an infarction in the anterior circulation in the setting of congenital ICA agenesis. [ABSTRACT FROM AUTHOR]

Background: With the launch of mechanical thrombectomy (MT), the prognosis of patients with cerebral infarction associated with large-vessel occlusion has improved. However, good outcomes are still not achieved in a few patients because of technical difficulties. Case presentation: A 79-year-old Japanese woman was admitted with sudden-onset left hemiplegia. Tissue plasminogen activator was administered and MT was performed for internal carotid artery occlusion distal to a large paraclinoid aneurysm. Some technical difficulties were unique, including contrast agent retention, difficulty in guiding the system, and avoidance of rupture of the aneurysm. Here, we discuss the technical issues and solutions of the MT procedure employed in this case. Conclusions: The procedure used in flow-diverter devices should be referenced and a stent-retrieving into an aspiration catheter with proximal balloon technique may be the most appropriate method. [ABSTRACT FROM AUTHOR]

The article discusses the importance of improving stroke care in Australia, highlighting the need for faster access to stroke units and reperfusion treatments. Despite having a national clinical care standard and registry, Australia lags behind other countries in stroke unit admissions and treatment speed. The article introduces the 30/60/90 National Stroke Targets, aiming to improve stroke care by setting specific goals for stroke unit admission rates and reperfusion treatment times. The targets have been endorsed by various Australian stroke organizations and are seen as a crucial step towards enhancing stroke outcomes and establishing a template for quality improvement initiatives in healthcare. [Extracted from the article]

The article presents supplementary material from the journal "Frontiers in Neurology" related to datasets on Barthel Index assessments and EQ-5D-3L scores of patients with ischemic stroke. The datasets include demographic information, stroke subtypes, diagnostic details, and follow-up information at different time points post-stroke. The data provides insights into gender distribution, marital status, stroke types, NIHSS scores, and functional outcomes such as mobility, self-care, and usual activities. The study aims to train models to predict health outcomes and quality of life for stroke patients at different time intervals post-stroke. [Extracted from the article]

Objectives: To evaluate the safety and efficacy of catheter-directed thrombolysis (CDT) with the recombinant tissue plasminogen activator (rt-PA) in all patients with symptomatic peripheral artery disease in real world practice. Methods: Consecutive patients treated with CDT between January 2013 and December 2020 were included in this retrospective analysis. The primary endpoint was the rate of serious adverse events (SAEs) until discharge. Secondary endpoints included interventional success, predictors for SAEs, bleeding and reperfusion edema/compartment syndrome, limb salvage, and clinical outcomes including target lesion revascularization rate (TLR). Results: Overall, 1238 patients were treated with CDT. SAEs occurred in 511 (41.3%) of the patients, 314 (25.4%) being bleeding complications. There were 95 cases of reperfusion edema/compartment syndrome. Forty-two patients underwent amputation and 33 patients (2.7%) died. CDT was successful in 1177 cases (95.1%). Multivariate logistic regression analysis identified age, abciximab and alprostadil usage, and lysis duration as predictors for SAEs and the use of abciximab as a predictor of reperfusion edema/compartment syndrome. Predictors for bleeding were age, alprostadil usage, and lysis duration. At 12 and 24 months, the limb salvage rate was 91.6% and 88.8%, and TLR rate was 46% and 57.2%, respectively. Conclusions: CDT is an effective endovascular method for the treatment of thrombotic peripheral artery occlusions but is associated with a high complication rate. For SAEs in general and bleeding specifically, increasing age, alprostadil use, and lysis duration were independent risk factors. [ABSTRACT FROM AUTHOR]

As an essential thrombolytic agent, the tissue plasminogen activator receives increasing attention due to its longer half-life, lower immunogenicity, and easier administration, which are superior to other thrombolytic agents. In this study, the isolated and purified plasminogen activator from the sandworm (Perinereis aibuhitensis) was expressed in E. coli (Escherichia coli) to investigate its potential for simplifying the development process. The sandworm plasminogen activator was previously successfully cloned and expressed in E. coli with low yield and activity in the culture supernatant. This low yield and activity prompted us to optimize its DNA sequence. Furthermore, to raise the efficiency in the separation of the target protein, the protein's solubility was enhanced by fusing it with maltose-binding protein (MBP) tags. Eventually, the fibrinolytic activity was successfully restored after digestion with tobacco etch virus (TEV) protease. This study provides an innovative method of efficiently expressing and purifying plasminogen activators from sandworm in E. coli and broadens its applications in therapeutic treatment of cardiovascular diseases, including thrombosis, stroke, and coronary atherosclerotic heart disease. [ABSTRACT FROM AUTHOR]