The spleen in ischaemic heart disease
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The assessment and aetiology of drug-induced ischaemic priapism
Ischaemic priapism is a urological emergency characterised by a prolonged, painful erection unrelated to sexual stimulation. While several aetiological factors contribute to this condition, the pharmacological causes have gained significant attention in recent years. This narrative review aims to comprehensively assess ischaemic priapism, specifically focusing on its pharmacological aetiology. We propose an approach and assessment strategy to the numerous factors associated with pharmacologically induced ischaemic priapism. By enhancing our understanding of the pharmacological causes of this condition, healthcare professionals can improve patient management and reduce the long-term complications associated with ischaemic priapism.
PGRMC2 is a pressure-volume regulator critical for myocardial responses to stress in mice
Progesterone receptors are classified into nuclear and membrane-bound receptor families. Previous unbiased proteomic studies indicate a potential association between cardiac diseases and the progesterone receptor membrane-bound component-2 (PGRMC2); however, the role of PGRMC2 in the heart remains unknown. In this study, we use a heart-specific knockout (KO) mouse model (MyH6•Pgrmc2flox/flox) in which the Pgrmc2 gene was selectively deleted in cardiomyocytes. Here we show that PGRMC2 serves as a mediator of steroid hormones for rapid calcium signaling in cardiomyocytes to maintain cardiac contraction, sufficient stroke volume, and adequate cardiac output by regulating the cardiac pressure-volume relationship. The KO hearts from male and female mice exhibit an impairment in pressure-volume relationship. Under hypoxic conditions, this pressure-volume dysregulation progresses to congestive left and right ventricular failure in the KO hearts. Overall, we propose that PGRMC2 is a cardiac pressure-volume regulator to maintain normal cardiac physiology, especially during hypoxic stress.
A novel wearable device integrating ECG and PCG for cardiac health monitoring
The alarming prevalence and mortality rates associated with cardiovascular diseases have emphasized the urgency for innovative detection solutions. Traditional methods, often costly, bulky, and prone to subjectivity, fall short of meeting the need for daily monitoring. Digital and portable wearable monitoring devices have emerged as a promising research frontier. This study introduces a wearable system that integrates electrocardiogram (ECG) and phonocardiogram (PCG) detection. By ingeniously pairing a contact-type PZT heart sound sensing structure with ECG electrodes, the system achieves the acquisition of high-quality ECG and PCG signals. Notably, the signal-to-noise ratios (SNR) for ECG and PCG signals were measured at 44.13 dB and 30.04 dB, respectively, demonstrating the system’s remarkable stability across varying conditions. These collected signals were subsequently utilized to derive crucial feature values, including electromechanical delay (EMD), left ventricular ejection time (LVET), and pre-ejection period (PEP). Furthermore, we collected a dataset comprising 40 cases of ECG and PCG signals, enabling a comparative analysis of these three feature parameters between healthy individuals and coronary heart disease patients. This research endeavor presents a significant step forward in the realm of early, non-invasive, and intelligent monitoring of cardiovascular diseases, offering hope for earlier detection and more effective management of these life-threatening conditions.
Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial
Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib—a bromodomain and extraterminal domain (BET) inhibitor—plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50–175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD–25 mg BID permitted). Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response (≥50% reduction in TSS from baseline at week 24). The primary endpoint was met in 65.9% of patients randomized to pelabresib–ruxolitinib (n = 214) versus 35.2% to placebo–ruxolitinib (n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001). Absolute change in TSS was −15.99 versus −14.05 (difference, −1.94; 95% CI, −3.92, 0.04; P = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, −3.5, 15.5) with pelabresib–ruxolitinib versus placebo–ruxolitinib. Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination. Thrombocytopenia and anemia were the most common treatment-emergent adverse events, occurring in 52.8% (13.2% grade ≥3) versus 37.4% (6.1% grade ≥3) and 44.8% (23.1% grade ≥3) versus 55.1% (36.5% grade ≥3), respectively. Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy. ClinicalTrials.gov identifier: NCT04603495.
Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration
In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program. Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.
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