Nature Reviews Disease Primers最新文献

Intervertebral disc (IVD) degeneration is a naturally occurring process that is a consequence of biological ageing and exposure to normal physiological loading over a lifetime and is characterized by loss of IVD tissue structural integrity. The nucleus pulposus changes with loss of pressurization, decreased collagen concentration and loss of distinction from annulus fibrosus. The annulus fibrosus and cartilaginous endplate suffer delamination, tears, fractures and clefts of their respective extracellular matrix at both microscopic and macroscopic scales. This loss of structural integrity generally follows a predictable pattern of degeneration, and it predisposes the IVD to pathological states. As the disc degenerates, the likelihood of functional failure to protect the neural elements and/or to provide stable spine motion and support increases. Functional failure takes the degenerated IVD to a state of disc pathology that has various phenotypes: the most common forms are disc herniation, mechanical instability, spinal stenosis, degenerative spondylolisthesis and degenerative scoliosis. IVD pathology is commonly self-limited and non-operative treatment remains the mainstay of treatment in most patients. For patients with refractory disease, surgical intervention focuses on neural decompression and, when indicated, motion segment stabilization. Future therapies for prevention of disc degeneration, targeted disc regeneration and biological modification of the degenerative cascade might prevent or reverse pathological changes across all spinal regions.

This PrimeView summarizes the clinical manifestations and diagnosis of Charcot-Marie-Tooth disease, and accompanies the Primer article by Burns and colleagues.

Charcot-Marie-Tooth disease (CMT) subsumes many different inherited neuropathies. CMT and related neuropathies are among the most common inherited neurological disorders, affecting ~1 in 2,500 people globally and including both sexes. Mutations in genes that cause demyelinating forms of CMT often affect the proteins of the myelin sheath, the unfolded protein response, endosomal signalling and recycling, or key transcription factors. Mutations in genes that cause axonal forms often affect mitochondrial biology, aminoacyl-tRNA synthetases, molecular chaperones or the axonal cytoskeleton. All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits. Compared with the general population, children and adults with CMT have reduced quality of life across physical, emotional and social domains, with the physical domain being the most disabling. Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications. The investigation of genetically authentic cellular, organoid and animal models will enable the development of rational therapies. Natural history studies and biomarkers will enable potential therapies to be critically evaluated.

Cytokine storm describes a spectrum of clinical manifestations that feature increased cytokine levels in circulation owing to overactivated immune responses. These increased concentrations of cytokines can cause tissue and organ damage, potentially leading to lethality. Cytokine storm can be induced by a variety of underlying clinical conditions, including infection, auto-inflammatory and autoimmune conditions, monogenic causes, or therapeutic intervention, which often makes diagnosis and treatment difficult. However, studies have identified conserved molecular mechanisms that inform therapeutic strategies. Cytokine storm is initiated by cytokine production and exacerbated by a self-amplifying positive feedback loop between cytokines and inflammatory cell death (PANoptosis). The process begins when cells detect triggers and undergo inflammatory signalling to produce and release cytokines via canonical secretion pathways or through lytic cell death such as pyroptosis and PANoptosis. This release of inflammatory cytokines, and potentially of other damage-associated molecules, can then drive inflammation and cell death in neighbouring cells through paracrine PANoptosis, resulting in further cytokine release and the amplification of the cycle. Improved understanding of the molecular and cellular mechanisms driving cytokine storm is critical for developing effective therapeutic strategies and improving clinical outcomes.

Long COVID is an infection-associated chronic condition that typically occurs within 3 months of acute COVID-19 infection in which symptoms are intermittently or continuously present for at least 3 months. Long COVID is estimated to affect between 80 and 400 million people globally, with an incidence of 5-20% in the community and up to 50% among hospitalized patients following acute SARS-CoV-2 infection. Common neuropsychiatric and mental health symptoms of long COVID include memory deficits, executive dysfunction, anxiety, depression, recurring headaches, sleep disturbances, neuropathies, problems with taste and smell, and dizziness that accompanies erratic heart rates and severe post-exertional malaise. Underlying pathophysiological mechanisms includes SARS-CoV-2 viral persistence, herpesvirus reactivation, microbiota dysbiosis, autoimmunity, clotting and endothelial abnormalities, and chronic immune activation. Owing to the variability in the clinical presentation, management must be tailored based on a patient's presenting symptoms.

Buruli ulcer is a slowly progressive necrotizing disease of the skin caused by Mycobacterium ulcerans, recognized by WHO as a neglected tropical disease. Around 2,000 cases are reported annually, but underdiagnosis and under-reporting probably obscure the true burden. A major advance in the understanding of Buruli ulcer pathogenesis was the discovery that mycolactone, a lipid-like exotoxin secreted by M. ulcerans, inhibits the Sec61 translocon, driving tissue destruction and immune suppression. M. ulcerans is an opportunistic environmental pathogen; however, its mechanisms of transmission remain unclear in most regions. PCR is the current gold standard for diagnosis, but its cost and technical demands limit use in resource-limited settings. Treatment is available with an oral regimen of rifampicin plus clarithromycin for 8 weeks, but further research is in progress to explore alternative drugs, optimized dosing and duration, and improved affordability. Adjunctive wound care, management of paradoxical reactions and rehabilitation, including physiotherapy and psychosocial support, are essential components of Buruli ulcer management. Future efforts should focus on elucidating transmission pathways to inform prevention, developing rapid diagnostics, refining and adapting drug regimens for diverse clinical presentations and patient groups, and advancing wound care. Strengthening healthcare worker training and integrating Buruli ulcer control with that of other skin diseases will enhance accessibility to early diagnosis and treatment, prevent disabilities and deformities, and reduce stigma, ultimately ensuring better quality of life for affected individuals worldwide.