Sympathetic hypoactivity leads to hypocontractility of the corpus cavernosum in sickle cell mice: a mechanism contributing to priapism
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Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head
Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.
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.
Effect of regional crosstalk between sympathetic nerves and sensory nerves on temporomandibular joint osteoarthritic pain
Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease often accompanied by pain, seriously affecting physical and mental health of patients. Abnormal innervation at the osteochondral junction has been considered as a predominant origin of arthralgia, while the specific mechanism mediating pain remains unclear. To investigate the underlying mechanism of TMJ-OA pain, an abnormal joint loading model was used to induce TMJ-OA pain. We found that during the development of TMJ-OA, the increased innervation of sympathetic nerve of subchondral bone precedes that of sensory nerves. Furthermore, these two types of nerves are spatially closely associated. Additionally, it was discovered that activation of sympathetic neural signals promotes osteoarthritic pain in mice, whereas blocking these signals effectively alleviates pain. In vitro experiments also confirmed that norepinephrine released by sympathetic neurons promotes the activation and axonal growth of sensory neurons. Moreover, we also discovered that through releasing norepinephrine, regional sympathetic nerves of subchondral bone were found to regulate growth and activation of local sensory nerves synergistically with other pain regulators. This study identified the role of regional sympathetic nerves in mediating pain in TMJ-OA. It sheds light on a new mechanism of abnormal innervation at the osteochondral junction and the regional crosstalk between peripheral nerves, providing a potential target for treating TMJ-OA pain.
The role of the urologist in managing high flow priapism
High-flow priapism (arterial) is a prolonged erection caused by irregular cavernous arterial flow, often resulting from blunt perineal or penile trauma, or iatrogenic needle injury. This condition leads to the formation of an arteriolacunar fistula, causing unregulated arterial blood flow into the sinusoidal spaces of the penis. Unlike low-flow priapism, high-flow priapism typically presents with a partially erect, non-painful penis. The diagnosis is confirmed through characteristic findings on color Doppler ultrasound, which reveals turbulent high-velocity flow pinpointing the fistula’s location. Blood gas analysis typically reflects arterial values, helping to differentiate high-flow priapism from its low-flow counterpart. Although high-flow priapism was historically considered non-urgent, recent evidence suggests that delayed treatment may increase the risk of erectile dysfunction. Therefore, prompt intervention by urologists is crucial. The primary goal is to close the fistula, and the treatment plan should be individualized based on the severity and duration of the condition. Urologists play a critical role in managing this condition, offering a range of therapeutic options. These include conservative approaches, such as observation and compression, medical therapy, arterial embolization, and, in some cases, surgical intervention. The choice of treatment depends on the patient’s condition, the fistula’s location, and the resources available. By ensuring timely and appropriate management, urologists can minimize complications and preserve erectile function.
A contemporary review of the management strategies for sickle cell disease related ischaemic and stuttering priapism
Sickle cell disease is one of the most common autosomal recessive genetic disorders with 23% and over 70% of men with this condition, experiencing episodes of ischaemic priapism and stuttering priapism, respectively, with potentially severe consequences. The effective prevention of sickle cell disease induced ischaemic priapism and stuttering priapism requires a multidisciplinary and multimodal approach. A search of the English literature was performed utilising Pubmed® and Google Scholar to identify publications on contemporary and novel treatment options, with their associated treatment outcomes if available, that are utilised to prevent stuttering priapism episodes and hence a fulminant ischaemic priapism. This narrative review focuses on three main aspects which include firstly, patient education and lifestyle modifications. Secondly, strategies aimed at preventing stuttering priapism episodes with traditional treatments such as alpha-adrenergic agonists and hormone manipulation strategies among others. Finally, we review treatments utilised to treat the underlying sickle cell disease with contemporary options such as hydroxyurea to more novel therapies such as crizanlizumab and voxelotor. The role of potentially curative techniques such as gene therapy and stem cell transplantation are also reviewed and summarised.
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