Enhancing multiplex detection capabilities of the Cas12a/blocker DNA system.

In the field of molecular diagnostics, the demand for multiplex detection, aimed at reducing overall analysis costs and streamlining procedures, is on the rise, prompting ongoing developments in various technologies. In this study, we developed a novel system, the split T7 promoter-based three-way junction-transcription, coupled with Cas12a/Blocker DNA (T3-CaB), for the multiplex detection of target nucleic acids. The T3-CaB system builds upon the foundation of the T3 system, generating numerous RNA transcripts upon encountering target nucleic acids. Subsequently, these RNA transcripts displace the blocker DNA from reporter DNA, allowing active Cas12a to engage in efficient trans-cleavage reaction on the reporter DNA, resulting in a strong fluorescence signal. Importantly, the proposed system operates at the isothermal condition (37 °C), with the entire analysis completed within 90 min. Further, the detection performance of the proposed system surpasses that of the preceding Cas12a/Blocker DNA system. Model targets, namely the 16S rRNA of Staphylococcus aureus and Escherichia coli, were selected, and a successful demonstration of multiplex detection was achieved. This technology holds promise for broadening the applicability of CRISPR/Cas-based diagnostics, especially in settings necessitating multiplex detection capabilities.

Preventive and therapeutic effects of a super-multivalent sialylated filamentous bacteriophage against the influenza virus.

The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.

Endoscopic findings and outcomes of gastric mucosal changes relating to potassium-competitive acid blocker and proton pump inhibitor therapy.

Gastric mucosal changes associated with long-term potassium-competitive acid blocker and proton pump inhibitor (PPI) therapy may raise concern. In contrast to that for PPIs, the evidence concerning the safety of long-term potassium-competitive acid blocker use is scant. Vonoprazan (VPZ) is a representative potassium-competitive acid blocker released in Japan in 2015. In order to shed some comparative light regarding the outcomes of gastric mucosal lesions associated with a long-term acid blockade, we have reviewed six representative gastric mucosal lesions: fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like gastric mucosal changes, gastric black spots, and stardust gastric mucosal changes. For these mucosal lesions, we have evaluated the association with the type of acid blockade, patient gender, Helicobacter pylori infection status, the degree of gastric atrophy, and serum gastrin levels. There is no concrete evidence to support a significant relationship between VPZ/PPI use and the development of neuroendocrine tumors. Current data also shows that the risk of gastric mucosal changes is similar for long-term VPZ and PPI use. Serum hypergastrinemia is not correlated with the development of some gastric mucosal lesions. Therefore, serum gastrin level is unhelpful for risk estimation and for decision-making relating to the cessation of these drugs in routine clinical practice. Given the confounding potential neoplastic risk relating to H. pylori infection, this should be eradicated before VPZ/PPI therapy is commenced. The evidence to date does not support the cessation of clinically appropriate VPZ/PPI therapy solely because of the presence of these associated gastric mucosal lesions.

The sympathetic nervous system shapes the tumor microenvironment to impair chemotherapy response.

The tumor microenvironment influences cancer progression and response to treatments, which ultimately impacts the survival of patients with cancer. The sympathetic nervous system (SNS) is a core component of solid tumors that arise in the body. In addition to influencing cancer progression, a role for the SNS in the effectiveness of cancer treatments is beginning to emerge. This review explores evidence that the SNS impairs chemotherapy efficacy. We review findings of studies that evaluated the impact of neural ablation on chemotherapy outcomes and discuss plausible mechanisms for the impact of neural signaling on chemotherapy efficacy. We then discuss implications for clinical practice, including opportunities to block neural signaling to improve response to chemotherapy.

Efficacy and Safety of Esmolol in Neonatal Cardiac Surgery with Cardiopulmonary Bypass (CPB) for d-Transposition of the Great Arteries (d-TGA).

OBJECTIVE: D-Transposition of the great arteries (d-TGA) is the most common congenital heart disease requiring surgical correction within the neonatal period. Sinus tachycardia often persists postoperatively, potentially affecting cardiac function. This study aimed to investigate the efficacy and safety of the short-acting beta-1-selective beta-blocker esmolol in controlling heart rate in neonatal cardiac surgery with cardiopulmonary bypass (CPB). METHODS: A retrospective cohort study was conducted on neonates undergoing surgery for d-TGA. The study cohort included 112 patients, divided into an esmolol intervention group (n = 57) and a control group (n = 55). Baseline characteristics, hemodynamic parameters and outcome measures were assessed. RESULTS: In the esmolol group, median heart rate at ICU admission was significantly higher compared to the control group (155 vs. 147 bpm, p = 0.018). After a median time of 11 h, heart rate was lower among the esmolol patients (135 vs. 144 bpm, p < 0.001). There were no differences in other hemodynamic parameters between the two groups. Patients treated with esmolol required longer catecholamine support while no difference regarding survival, duration of invasive ventilation and ICU stay were noticed. CONCLUSION: No relevant hemodynamic difference was seen between neonates treated with perioperative esmolol and the control group and outcome did not differ. This indicates non-inferiority of perioperative betablocker therapy in young age. Prospective and placebo-controlled assessment of perioperative esmolol therapy in neonates is needed.

Impact of Angiotensin Receptor Blockers (ARB) versus Other Antihypertensive Medication on Blood Pressure in Patients on Dialysis: A Meta-Analysis.

Introduction: Hypertension is an important factor driving mortality among dialysis patients. Angiotensin-II receptor blocker (ARB) has been effective similarly to angiotensin-converting enzymes (ACEs) but with a low incidence of side effects. Methodology: The meta-analysis included all published studies that investigated the effect of ARB on the hypertension in adult dialysis patients (≥18 years). Data extraction was guided by a predetermined checklist. Data sources of the retrieved studies were PubMed, MEDLINE, ScienceDirect, SCOPUS, Cochrane, Web of knowledge, and Google Scholar were systematically searched until February 2023. Using the RevMan 5 software, the mean difference for systolic and diastolic BP (SBP and DBP) and the risk ratio (RR) of the adverse events (AEs) were pooled from the selected studies. The random-effects model was used to compare the difference in the pre-and post-dialysis of the SBP and DBP. Data analyses were performed from December 2022 to February 2023. The primary outcome was the reduction in SBP and DBP in dialysis hypertensive patients who were on anti-hypertensive agents, and the secondary outcome was assessment of AE associated with the drug after dialysis (PROSPERO Registration: CRD42022355369). Results: The initial search yielded 1,679 records, of which 84 studies underwent full-text evaluation, which identified 13 studies and 1,462 patients. The pooled standard MD for losartan with other anti-hypertensive agents, where the pre-dialysis SBP was 0.17 (95% confidence interval [CI]: -0.21-0.55) and the post-dialysis was 0.35 (95% CI: -0.17-1.02); yet, both are statistically non-significant, implies that there was no difference between Losartan and ARB drugs regarding the effect on the SBP. Diastolic BP for predialysis was -0.01 (95% CI: -0.65-0.63) and post-dialysis was 0.03 (95% CI: -0.24-0.30) and statistically non-significant. AEs by the ARB agents were lower compared to other anti-antihypertensive agents (relative risk [RR]: 1.01; 95% CI: 0.59-1.75) and statistically non-significant. Conclusion: This systematic review and meta-analysis of RCT demonstrated that ARB and other anti-hypertensive medications had similar impacts on the treatment of hypertension.

Left lateral-aortic paraganglioma in an adolescent: A rare case report.

INTRODUCTION: Paraganglioma is a rare neuroendocrine tumor arising outside the adrenal gland from the primitive neural crest cells. The pediatric form is an exceptional entity. CASE REPORT: Here we report a case of a 15-year-old boy presenting with hypertensive crisis. Computed tomography scan revealed a left lateral-aortic paraganglioma, with significantly elevated plasmatic catecholamine levels. Preoperative management was conducted in our patient with selective alpha-1 blockers, then complete resection of the tumor was achieved without complications. The histological and immunohistochemical examination confirmed the diagnosis of a paraganglioma. DISCUSSION: Paranganglioma management should be started as soon as possible to prevent high blood pressure complications. It is based on preoperative medication with alpha-blocker to prevent adrenegeric discharge, followed by a complete and safe surgical removal of the tumor. CONCLUSION: Functional paraganglioma remains a rare entity among pediatric population. Preoperative management is mandatory to avoid postoperative morbidity.

Safety of beta-blocker discontinuation after acute coronary syndromes with preserved or mildly reduced left ventricular ejection fraction: a target trial emulation from a real-world cohort.

AIMS: The benefit of long-term beta-blocker therapy after acute coronary syndromes (ACS) without heart failure in the reperfusion era is uncertain. Two recent randomized trials found conflicting results. The present study assessed the safety of beta-blocker discontinuation within 12 months following ACS with LVEF ≥40%. METHODS: In a multicentre prospective real-world cohort (N=3,762) of patients hospitalized for ACS, patients with LVEF ≥40% and beta-blockers at discharge were included. Patients who continued beta-blockers at one year were compared with those who discontinued beta-blockers within 12 months post-ACS using target trial emulation and inverse probability weighting over an additional four-year follow-up. The primary endpoint was major adverse cardiovascular events (MACE), a composite of four-year cardiovascular death, myocardial infarction, stroke, transient ischemic attack, unplanned coronary revascularization, or unstable angina hospitalization. RESULTS: Of 2,077 patients, 1,758 (85%) continued beta-blockers and 319 (15%) had discontinued beta-blockers at one year. The risk of primary endpoint was similar in both groups (14.1% versus 14.3% with beta-blocker discontinuation versus continuation; adjusted hazard ratio [aHR]=0.98; 95% confidence interval, 0.72-1.34, P=0.91). Subgroup analysis suggested a higher risk of primary endpoint with beta-blocker discontinuation after STEMI (aHR=1.46 [0.99-2.16]) compared to NSTEMI (aHR=0.70 [0.40-1.22], Pinteraction=0.033), whereas there was no interaction with LVEF (Pinteraction=0.68). CONCLUSIONS: Beta-blocker discontinuation within 12 months following ACS with LVEF ≥40% was not associated with an increased risk of MACE compared to long-term beta-blocker therapy. Subgroup analysis suggested potential risk in STEMI patients. Discontinuing beta-blockers 12 months after ACS appears safe in patients with LVEF ≥40%, particularly after NSTEMI.

Beta-blockers are part of the standard drug therapy prescribed to prevent adverse health events in patients who suffered from myocardial infarction. However, the studies that established their benefit were conducted before the advent of modern therapies, that have since then dramatically changed the prognosis. The benefit of long-term beta-blockers in the contemporary era has therefore been questioned. The present study assessed the safety of beta-blocker discontinuation within 12 months after myocardial infarction in patients who did not have severely impaired heart function. Beta-blocker discontinuation within 12 months after myocardial infarction was safe, as it was not associated with a higher risk of major adverse cardiovascular events or death, compared to long-term beta-blocker continuation. Patients who presented with acute occlusion of a coronary artery ­ a severe type of myocardial infarction referred to as "ST-elevation myocardial infarction" ­ may still benefit from long-term beta-blocker therapy based on subgroup analysis.

The role of eprosartan in the management of essential hypertension: literature review and expert opinion.

INTRODUCTION: Eprosartan is an angiotensin receptor blocker (ARB) used for management of essential hypertension. With unique pharmacological characteristics, dual action mechanism, and clinical effectiveness, eprosartan offers additional advantages over other ARBs in specific patient populations. AREAS COVERED: A comprehensive review of the literature was performed across publicly available databases, with no time limitations, to ensure the inclusion of all relevant studies. The review focuses on presenting the efficacy and safety profile of eprosartan, alone or in combination with other agents. Additionally, it explores the etiology of hypertension concerning the structure and function of angiotensin II type 1 receptors. Further, the efficacy of eprosartan in special populations and its additional benefits are also discussed. EXPERT OPINION: Eprosartan effectively reduces blood pressure (BP), with a 24-hour BP-lowering effect at 600 mg/day. Eprosartan demonstrates similar or better efficacy than other ARBs, such as telmisartan and losartan, particularly in managing coagulation-related abnormalities and peripheral resistance. In combination therapy, eprosartan with hydrochlorothiazide significantly enhances BP reduction. Eprosartan is well-tolerated, with a low incidence of adverse events, making it a reliable choice for long-term hypertension management across various patient populations, such as those with comorbid diabetes and renal disease and older adults.

Challenges in Lung Isolation in a Tracheostomized Patient: A Case Report.

Tracheostomized patients who require one-lung ventilation represent a unique challenge for the anaesthesiologist: on the one hand, the need to protect the airway safely and, on the other, provide optimal lung isolation for surgery. A 65-year-old tracheostomized patient scheduled for an esophagectomy requiring one-lung ventilation raised a challenge in lung isolation using a bronchial blocker. The authors describe the strategies applied to overcome the obstacle and review lung isolation techniques in this type of patient.

[Translated article] Real-world effectiveness and safety of nivolumab in patients with relapsed or refractory classical Hodgkin lymphoma.

OBJECTIVE: The primary objective is to describe the real-life effectiveness and safety of nivolumab treatment in patients with relapsed or refractory classical Hodgkin's lymphoma. The secondary objective is to describe the therapeutic management after nivolumab monotherapy. METHOD: Observational, retrospective, multidisciplinary study including all patients with relapsed or refractory classical Hodgkin's lymphoma treated with nivolumab monotherapy from November 2015 to March 2023. Patient and treatment-related variables were collected. Effectiveness was measured as overall response rate, progression-free survival, and overall survival. Safety was measured as percentage of patients with adverse effects and severity. RESULTS: Thirteen patients were included, median age 37.5 years (RIQ: 25.3-54.7), 84.6% male. The median number of previous lines of therapy was 3 (RIQ: 2-4.5), including autologous haematopoietic stem cell transplantation (84.6%) and brentuximab vedotin (100%). All received nivolumab 3 mg/kg/14 days, with a median of 11 cycles (RIQ: 6.5-20.5) per patient. Median time on treatment was 4.9 months (RIQ: 3-9.6) and median follow-up time was 9.2 months (RIQ: 5.6-32.3). Complete response was achieved by 3 patients (23.1%), partial response by 3 (23.1%), stable disease by 3 (23.1%), and progression by 4 (30.8%). The objective response rate was 46.2%. Median progression-free survival was 23.9 months (95% CI: 0-49.1), median overall survival was not reached. At the study cut-off date, 5 patients had died (38.5%), 4 were in complete remission without active treatment (30.8%), and 4 were continuing treatment (30.8%). Adverse events occurred in 76.9% of patients, 44% of severity ≥3, the most frequent being hypothyroidism and hepatotoxicity. One patient discontinued treatment due to pneumonitis, 2 suffered treatment delays (thrombocytopenia and hypertransaminemia), and 1 changed the regimen to monthly (pulmonary toxicity). CONCLUSIONS: Nivolumab in the treatment of relapsed or refractory classical Hodgkin's lymphoma has confirmed favourable effectiveness data in the study sample, expressed as objective response rate of 46.2% and a clinical benefit rate of 69.2%. Safety was acceptable, manageable, and consistent with that described in the literature.

Betablockers and clinical outcome after surgical aortic valve replacement: a report from the SWEDEHEART registry.

OBJECTIVES: Previous reports suggest that betablockers appear non-beneficial after surgical aortic valve replacement (SAVR). This study aims to clarify the associations between betablockers and long-term outcome after SAVR. METHODS: All patients with isolated SAVR due to aortic stenosis in Sweden between 2006 and 2020, alive at 6 months after surgery, were included. Patients were identified in the SWEDEHEART registry, and records were merged with data from 3 other mandatory national registries. Association between dispensed betablockers and major adverse cardiovascular events (MACE) (all-cause mortality, myocardial infarction and stroke) was analyzed using Cox proportional hazards models, with time-updated data on medication and adjusted for age, sex and comorbidities at baseline. RESULTS: In total, 11 849 patients were included [median follow-up 5.4 years (range 0-13.5)]. Betablockers were prescribed to 79.7% of patients at baseline, decreasing to 62.2% after 5 years. Continuing treatment was associated with higher risk of MACE [adjusted hazard ratio 1.14 (95% confidence interval, CI 1.05-1.23)]. The association was consistent over subgroups based on age, sex and comorbidities except atrial fibrillation [hazard ratio (HR) 1.05 (95% CI 0.93-1.19)]. A sensitivity analysis including time-updated data on comorbidites attenuated the difference between the groups [HR 1.04 (95% CI 0.95-1.14, P = 0.33)]. CONCLUSIONS: Treatment with betablockers did not appear to be associated with inferior long-term outcome after SAVR, when adjusting for new concomitant diseases. Thus, it is likely that it is the underlying cardiac diseases that are associated with MACE rather than betablocker treatment.

Comparison of the Role of Anticholinergics and α-1 Adrenergic Blockers in Bladder Management in Posterior Urethral Valves: A Pilot Randomized Control Trial.

INTRODUCTION: Posterior urethral valve (PUV) is a major cause of congenital bladder dysfunction, often persisting despite treatment. Emerging therapies, including anticholinergics and α-1 blockers, offer potential but lack clear guidelines. This study evaluates their effectiveness in improving bladder function after valve fulguration. METHODS: Twenty PUV patients, aged ≥3 years, were randomized into anticholinergic (group A, n = 11) and α-1 adrenergic blocker (group B, n = 9) groups post-fulguration. Follow-up included clinical, radiological, and urodynamic assessments 6 months posttreatment initiation. RESULTS: In group A, the mean maximum detrusor pressure (Pdet) decreased from 30.17 to 23.45 cm H2O (p = 0.033). Two patients normalized from high detrusor pressure (>40 cm H2O). In group B, 1 patient retained high detrusor pressure posttreatment. Group B improved in average urinary flow (Q avg) and maximum flow rate (Q max), with all patients having initially low Q avg (<10 mL/s). Two group B patients showed improved average flow rates posttreatment (p = 0.016); three in group A showed improvement but were not statistically significant (p = 0.197). Q max/flow time ratio was abnormal in all group B patients pretreatment. Two of the nine improved posttreatment, while only one in group A did. CONCLUSIONS: Anticholinergic medications positively impact cystometric parameters and are effective for detrusor instability and low compliance bladder. α-Adrenergic blockers influence uroflow parameters and can help treat bladder outflow obstruction. Consideration for a larger study with extended follow-up is warranted.

Association Between Alpha-1 Adrenoreceptor Antagonist Use and Cognitive Impairment: A Systematic Review.

Alpha-1 adrenergic receptor (α1-AR) antagonists are commonly used for management of benign prostatic hyperplasia or hypertension. Some studies have shown a potential link between α1-AR antagonist use and cognitive impairment. Given the conflicting data surrounding α1-AR antagonists association with cognitive dysfunction, we aim to systematically review the association of cognitive dysfunction with α1-AR antagonist use to aid clinician decision both with medication initiation and continuation. A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We searched Ovid Cochrane, Ovid Embase, Ovid MEDLINE, Scopus, and Web of Science on March 7, 2023, with an update run on January 22, 2024. The primary outcome was cognitive dysfunction. We used Cochrane risk of bias for randomized controlled trials (RCTs) and MINORS (Methodological Index for Non-Randomized Studies) criteria for non-RCTs to evaluate study quality. This study was registered with PROSPERO (CRD42024505751). We identified 7 studies for our systematic review (3 RCTs, 4 non-RCTs). Tamsulosin was the most studied medication (6 of 7 studies). Tamsulosin was associated with no cognitive dysfunction in 2 RCTs, increased risk for dementia in 2 non-RCTs, no change in cognition in 1 non-RCT, and decreased risk for dementia in 1 non-RCT. Among 3 non-RCTs analyzing alfuzosin, it was associated with decreased risk of or no association with dementia in 2 studies and increased risk for dementia in 1 study. Doxazosin, prazosin, and terazosin were neutral or showed a negative risk for dementia. Our systematic review did not show a convincing causal association between α1-AR antagonists, including tamsulosin, and cognitive dysfunction. Considering the existing literature, it is appropriate to use α1-AR antagonists without concern for cognitive dysfunction. Future research, through robust study designs considering the multifactorial nature of cognitive dysfunction, is required to further evaluate this association.

Phase III randomized clinical trial of efficacy and safety of amlodipine and candesartan cilexetil combination for hypertension treatment.

Effective antihypertensive therapy is essential for achieving optimal blood pressure (BP) control and reducing cardiovascular events. This double-blind, multicenter, randomized trial aimed to compare the antihypertensive efficacy and safety of a combination of amlodipine (AML) and candesartan cilexetil (CC) versus AML monotherapy in patients with essential hypertension (HTN). After a 4-week run-in period with AML 5 mg, patients whose HTN remained uncontrolled (diastolic BP [DBP]) ≥ 90 mmHg and < 120 mmHg) were randomized to receive either AML + CC or AML alone for 8 weeks. Efficacy was assessed by measuring changes in DBP and systolic BP (SBP). The primary safety measure was the incidence of adverse events (AEs). A total of 174 participants were included in the efficacy analysis. After 8 weeks, DBP decreased by -9.92 ± 0.86 mmHg in the AML + CC arm and - 2.08 ± 0.86 mmHg in the AML arm (p < 0.0001). SBP decreased by -14.27 ± 1.39 mmHg in the AML + CC arm versus - 2.77 ± 1.39 mmHg in the AML arm (p < 0.0001). AEs occurred in 11.24% of the AML + CC group and 5.62% of the AML group (p = 0.1773). AML + CC combination therapy demonstrated superior efficacy with good tolerance, making it a promising option for patients with inadequately controlled hypertension on amlodipine alone.

Evaluation of ß-Blocker-Induced Bradyarrhythmia Using an Analysis of the Japanese Adverse Drug Event Report Database.

ß-Adrenergic receptor blockers (ß-blockers) are used to treat hypertension, ischemic heart disease, chronic heart failure, and tachyarrhythmia. The main side effects of treatment include bradycardia, atrioventricular block, and hypotension. Bradycardia may result in pacemaker implantation as well as the discontinuation of ß-blockers. Bradycardia is difficult to confirm at a single institution because it diagnosed only by symptoms when electrocardiogram (ECG) are not routinely performed. Previous studies reported an increase in bradycardia in heart failure patients treated with ß-blockers; however, limited information is currently available for non-heart failure patients. Bradycardia induced by ß-blockers has not yet been comprehensively examined. Therefore, the present study investigated data on the incidence and duration of bradyarrhythmia caused by ß-blockers using the Japanese Adverse Drug Event Report database (JADER). Cases of adverse effects associated with this medication were extracted from JADER and Fisher's exact test was performed to assess whether each ß-blocker caused bradyarrhythmia. In addition, only data from patients who reported bradyarrhythmia after ß-blocker treatment were extracted, and the Weibull distribution was used to analyze the time-to-onset of bradyarrhythmia. Thirteen ß-blockers caused bradyarrhythmia and signals were observed for 12 drugs, except nadolol. Bradyarrhythmia induced by oral ß-blockers was more likely to be of the early failure type, and developed within 2 months of treatment initiation with most ß-blockers. A comprehensive analysis of bradyarrhythmia with ß-blockers suggests that careful monitoring is needed, particularly early in the initiation of treatment.

Monoamine Oxidase Contributes to Valvular Oxidative Stress: A Prospective Observational Pilot Study in Patients with Severe Mitral Regurgitation.

Monoamine oxidases (MAOs), mitochondrial enzymes that constantly produce hydrogen peroxide (H2O2) as a byproduct of their activity, have been recently acknowledged as contributors to oxidative stress in cardiometabolic pathologies. The present study aimed to assess whether MAOs are mediators of valvular oxidative stress and interact in vitro with angiotensin 2 (ANG2) to mimic the activation of the renin-angiotensin system. To this aim, valvular tissue samples were harvested from 30 patients diagnosed with severe primary mitral regurgitation and indication for surgical repair. Their reactive oxygen species (ROS) levels were assessed by means of a ferrous oxidation xylenol orange (FOX) assay, while MAO expression was assessed by immune fluorescence (protein) and qRT-PCR (mRNA). The experiments were performed using native valvular tissue acutely incubated or not with angiotensin 2 (ANG2), MAO inhibitors (MAOI) and the angiotensin receptor blocker, irbesartan (Irb). Correlations between oxidative stress and echocardiographic parameters were also analyzed. Ex vivo incubation with ANG2 increased MAO-A and -B expression and ROS generation. The level of valvular oxidative stress was negatively correlated with the left ventricular ejection fraction. MAOI and Irb reduced valvular H2O2. production. In conclusion, both MAO isoforms are expressed in pathological human mitral valves and contribute to local oxidative stress and ventricular functional impairment and can be modulated by the local renin-angiotensin system.

Effective Treatment of Refractory Cluster Headache With Propranolol.

Cluster headache (CH) is a debilitating neurological condition characterized by excruciating unilateral pain, often accompanied by autonomic symptoms. We present a compelling case report detailing the experience of a 22-year-old male who suffered from refractory CH and exhibited a remarkable response to propranolol. This unique case highlights the potential effectiveness of propranolol in alleviating CH symptoms that are resistant to conventional therapies. Moreover, the absence of reported side effects on such a low dose further underscores its appeal as a treatment option. This case report sheds light on a potential avenue for managing refractory CH, offering hope for individuals who struggle with this debilitating condition.

Changes in motor unit firing pattern are associated with post-exercise blood pressure response in older untreated but not treated hypertensive adults.

This study aimed to determine the difference in motor unit (MU) firing pattern between hypertensive and normotensive individuals, and the relationship between MU firing pattern and post-exercise blood pressure (BP) response in older individuals. Fourteen older untreated (systolic/diastolic BP (SBP/DBP) ≥ 130/80 mmHg, 76 (5) years), 11 treated hypertensive (78 (4) years) and 14 normotensive (SBP/DBP < 130/80 mmHg, 71 (4) years) individuals were studied. Participants performed ramp-up exercises until 50% of maximal voluntary contraction (MVC) of knee extension and five MVCs. During the ramp-up exercise, high-density surface electromyography signals were recorded and each MU firing rate (FR) and recruitment threshold was assessed. The slope of the linear regression between MUFRs and recruitment thresholds was calculated to assess the MU firing pattern. Pre- and post-exercise blood pressure was measured. Change in (∆)SBP from pre- to post-exercise was greater in treated hypertensive than untreated hypertensive individuals (P = 0.026). MUFR was lower in treated hypertensive than untreated hypertensive and normotensive individuals (P < 0.001). Although the slope was not significantly different between groups (P = 0.294), FRs of larger MUs were lower than those of smaller MUs in treated hypertensive and normotensive individuals (P < 0.05) but sustained in untreated hypertensive individuals. The FRs of larger MUs and slope were positively correlated with the ∆SBP only in hypertensive individuals (r = 0.768 and 0.715; P = 0.044 and 0.020). MUFR was lower in treated hypertensive than untreated hypertensive and normotensive individuals. Furthermore, MU firing patterns were associated with the ∆SBP after exercise in older untreated hypertensive individuals, but this relationship was not observed in treated hypertensive and normotensive individuals.

Real-world efficacy of fimasartan vs. other angiotensin receptor blockers in combination with calcium channel blockers: a nationwide cohort study.

BACKGROUND: The antihypertensive efficacy of fimasartan was assessed based on the transition rate from a combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) to three-drug combination therapy, as compared to other ARBs. METHODS: This nationwide cohort study used data obtained from the Korean National Health Insurance Service database. Patients who had received national health checkups within 2 years prior to January 1, 2017, and were concurrently prescribed ARBs and CCBs for > 30 days during the 6 months from January 1, 2017, to June 30, 2017 were included in the study. Patients were categorized into the 'fimasartan group' (those prescribed fimasartan) and the 'non-fimasartan group' (those prescribed ARBs other than fimasartan). The index date was set as the last day of a 30-day prescription period for ARBs and CCBs, with a subsequent 2.5-year follow-up to observe the potential addition of a third drug, such as beta-blockers or diuretics. RESULTS: The study included 34,422 patients with a mean age of 60.3 years and 58.3% being male. The fimasartan group constituted 2.7% (n = 928) of the total, and the non-fimasartan group, 97.3% (n = 33,494). During the follow-up period, 38 patients in the fimasartan group (14.3 per 1,000 person-years) and 3,557 patients in the non-fimasartan group (42.8 per 1,000 person-years) required additional antihypertensive medications. After multivariate adjustment for age, sex, diabetes mellitus, dyslipidemia, cancer, heart failure, systolic blood pressure, and diastolic blood pressure, the fimasartan group showed a significantly lower rate of adding a third medication (hazard ratio 2.68, 95% confidence interval 1.95-3.69) compared to that of the non-fimasartan group. CONCLUSIONS: Fimasartan is associated with a lower need for additional antihypertensive drugs compared to other ARBs. This implies its greater effectiveness in hypertension management, potentially enhancing cardiovascular outcomes, and minimizing polypharmacy.