Yale Journal of Biology and Medicine最新文献

Monkeypox (Mpox) has once again been designated a Public Health Emergency of International Concern (PHEIC) as of August, 2024. The severity of the disease is underscored by its significant mortality rate, and unfortunately, there are no targeted therapeutics currently available for this viral infection. Management relies on preventive measures and the use of existing smallpox vaccines due to their genetic similarity to the Mpox virus. Diagnosing a disease is a critical aspect of managing any health condition, and for a highly contagious viral infection like Mpox, it is essential to employ a specific and sensitive diagnostic approach. The lack of adequate diagnostic facilities in laboratories poses a significant challenge, hindering accurate diagnoses and the identification of underlying etiologies, particularly in low-resource settings. Current serology-based diagnostic tests lack specificity for the Mpox virus, leading to cross-reactivity with other orthopoxviruses. With the emergence of new viral variants, molecular and genomic diagnostic methods are far more reliable for accurately confirming Mpox infections. This review focuses on current diagnostic methods approved worldwide and the future challenges that need to be addressed to effectively control and mitigate the spread of Mpox.

Chikungunya virus infection (CHIKV) increases the risk of persistent arthralgia; however, there is no consistent evidence regarding prognostic biomarkers of progression to chronic arthropathy. This systematic review provides an overview of currently available literature about the potential role of the acute immunologic response in predicting long-term joint pain in patients with a diagnosis of CHIKV. We searched for observational studies using the terms "chikungunya," "cytokines," "biomarkers," and "joint pain" in PubMed/MEDLINE, LILACS, Cochrane Library Plus, and SCOPUS databases, restricting to articles published in English and up to April 2024. PROSPERO registration number: CRD42021279400. Thirty-eight studies were selected for qualitative synthesis with a maximum duration from diagnosis to clinical evaluation of 60 months. The sample sizes ranged from 8 to 346 participants (age range: 0-90 years). We identified an immunologic profile during the acute phase of CHIKV that includes increased levels of proinflammatory cytokines (IFN-α, IFN-γ, IL-2R, IL-6, IL-7, and IL-8), anti-inflammatory cytokines (IL-1Ra and IL-4), chemokines (MCP-1, MIG, and IP-10) and growth factors (VEGF and G-CSF). Only one out of two studies reported differences in cytokine levels during the acute phase, predicting persistent joint pain at 20 months of follow-up. Also, persistence of anti-CHIKV IgG seemed to be a potential prognostic marker. The evidence suggests the existence of an inflammatory response in the acute phase of CHIKV that persists during its chronic phase; however, there is no unequivocal candidate set of biomarkers of progression toward long-term articular sequelae.

Purpose: To report a case of cystoid macular edema (CME) secondary to immune recovery uveitis (IRU) in a patient with previous history of cytomegalovirus (CMV) retinitis and leukemia, which was successfully treated with tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist. Method: The clinical records of the case were reviewed, focusing on demographics, image findings, and clinical course. Results: A 17-year-old female with a past medical history of T-cell acute lymphoblastic leukemia (T-ALL) undergoing chemotherapy for two years presented with active CMV retinitis. She was successfully treated with intravitreal foscarnet injections and systemic ganciclovir. After 5 months of systemic valganciclovir maintenance and following cessation of chemotherapy, the patient developed bilateral CME and vasculitis, and was diagnosed with IRU. CME management was challenging due to a history of bilateral avascular necrosis of the femoral head resulting from prolonged systemic corticosteroid use. Two cycles of monthly TCZ infusions were administered at the dosage of 8mg/kg. Subsequently, the CME and retinal vasculitis resolved significantly without any evidence of inflammation in the anterior chamber and vitreous. Conclusion: The index case report demonstrated the safety and efficacy of the IL-6 receptor antagonist TCZ in treating CME associated with IRU in a non-HIV CMV retinitis patient.

Alkhumra fever is a viral disease caused by the Alkhumra hemorrhagic fever virus (AHFV). It belongs to family Flaviviridae, genus Flavivirus. AHFV is primarily transmitted to humans through the bite of infected ticks, for example, Hyalomma. This disease was first identified in the Kingdom of Saudi Arabia (KSA) in 1995 and then reported in other countries of the Arabian Peninsula and the Middle East. The AHFV genome consists of a positive-sense, single-stranded RNA molecule of approximately 10.2 kilobases (kb) in length. The Open Reading Frame (ORF) encodes a polyprotein precursor that is processed by viral and host proteases to yield individual viral proteins. The polyprotein precursor is cleaved by viral proteases and host signal peptidases into three structural and seven non-structural proteins. AHFV can cause a range of clinical manifestations, from mild flu-like symptoms to severe hemorrhagic fever. In this review, we focus on insightful understanding of molecular biology, pathogenesis, and their potential therapeutic targets for AHFV.

Patients with prior SARS-CoV-2 infections can develop chronic symptoms; this clinical presentation has been called post-acute sequelae of SARS-CoV-2 infection, post-COVID condition, and long COVID. It can develop in both outpatient cases and in hospital cases; the frequency depends on the severity of infection and comorbidity. Many of these patients have exercise limitation when tested using cardiopulmonary exercise tests. The potential explanations for reduced exercise capacity include cardiac limitations, respiratory limitations, skeletal muscle weakness, deconditioning, and limiting symptoms out of proportion to any measured physiological limitation, and many patients have more than one explanation for the exercise limitation. Since these patients may have required prolonged hospitalization, deconditioning has been considered a potential explanation for their post-hospitalization limitations. Patients with deconditioning have a low oxygen uptake per minute (VO₂) maximum with no obvious cardiac or respiratory limitation, but some do have measurable muscle weakness. One complex study reported that these patients had a high proportion of high-fatigable glycolytic fibers, reduced mitochondrial function, atrophic fibers, and focal necrosis in skeletal muscle. Some post-COVID patients have chronic fatigue and post-exertional malaise and meet the clinical criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Most patients with post-COVID syndrome do improve with conventional cardiopulmonary rehabilitation. However, patients with post-exertional malaise need special attention to their exercise programs and careful monitoring for adverse effects. In summary, patients with long COVID can have complex presentations with a broad range of symptoms and several possible exercise limitations. Their rehabilitation program should be based on their physical capacity and their symptom profile.

Chikungunya fever (CHIKF) is an acute viral disease caused by the chikungunya virus (CHIKV) transmitted by Aedes mosquitoes. The acute phase presents with limited symptoms and low mortality, but approximately half of cases progress to more chronic illness with persistent and disabling joint symptoms. To better characterize the burden of chronic disease, we analyzed the relationship between pain intensity, the Disease Activity Index by DAS28-ESR, rheumatoid factor (RF) positivity, sex, and age in a retrospective cohort of 133 patients with chikungunya arthritis (CHIKA). We assessed all subjects by clinical evaluations, and laboratory testing, including the Pain Visual Analog Scale (VAS), the Disease Activity Score (DAS28-ESR), and RF measurement. We observed that pain intensity increased significantly with disease activity (ρ = 0.416 and p-value < 0.05) and with age (ρ = 0.259 and p-value = 0.003). Despite a predominance of women in our cohort, sex/gender was not associated with increased pain risk. Our study demonstrated a strong correlation between pain and disease activity, but assessment of these variables in a larger, prospective cohort should be undertaken to further characterize risk variables and improve therapy for patients with CHIKA.

Viral myocarditis is associated with the development of dilated cardiomyopathy (DCM), left ventricular dysfunction, and heart failure. This review addresses the mechanisms of viral myocarditis and its treatment.

Post-Acute Sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, represents a significant and complex health challenge with a wide range of symptoms affecting multiple organ systems. This review examines the emerging evidence suggesting a critical role of the gut and gut-brain axis in the pathophysiology of Long COVID. It explores how changes in the gut microbiome, disruption of gut barrier integrity, and the persistence of SARS-CoV-2 antigens within the gastrointestinal tract may contribute to the prolonged and varied symptoms seen in Long COVID, including chronic inflammation and neuropsychiatric disturbances. The review also summarizes key insights gained about Long COVID, highlighting its multifactorial nature, which involves immune dysregulation, microvascular damage, and autonomic nervous system dysfunction, with the gut playing a central role in these processes. While progress has been made in understanding these mechanisms, current evidence remains inconclusive. The challenges of establishing causality, standardizing research methodologies, and addressing individual variations in the microbiome are discussed, emphasizing the need for further longitudinal studies and more comprehensive approaches to enhance our understanding of these complex interactions. This review underscores the importance of personalized approaches in developing effective diagnostic and therapeutic strategies for Long COVID, while also acknowledging the significant gaps in our current understanding. Future research should aim to further unravel the complex interplay between the gut and Long COVID, ultimately improving outcomes for those affected by this condition.

In relation to ancient infections, a substantial number of retroviral sequences with persistent immunogenic potential were integrated within the human genome (HERVs). Under physiological conditions, coding sequences from HERVs can participate in cell/tissue homeostasis and physiological functions in an epigenetically controlled manner. However, HERV expression is susceptible to contribute to various pathologies, including autoinflammatory and autoimmune disorders, when reprogrammed by exogenous stimuli such as drugs or microbial infections. Both innate and adaptive components of the immune system can be mobilized in response to deregulated/de-repressed expression of HERV determinants and thereby, modify immune tolerance to tissue antigens. Self-directed immune responses induced/worsened by HERV expression are suspected to participate in both tissue-specific and systemic disorders. A substantial level of mechanistic investigation is needed to better delineate the impact of HERV expression in diseases in general, and in inflammation and autoimmunity in particular.

Ocular gene therapy has rapidly advanced from proof-of-concept studies to clinical trials by exploiting the unique advantages of the eye, including its easy accessibility, relative immune privilege, and the ability to use the contralateral eye as a control. An important step forward was achieved with the Food and Drug Administration (FDA) approval of voretigene neparvovec (Luxturna) for the treatment of biallelic RPE65-mutation-associated retinal dystrophies in 2017. Gene therapy is a promising field aimed at treating various inherited and acquired eye diseases. Viral vectors such as adeno-associated virus (AAV) are mainly used to efficiently deliver genes. Despite the immune-privileged status of the eye, viral vector-based therapies can induce immune responses, potentially leading to gene therapy-associated uveitis. Future directions include developing strategies to reduce immune responses while maintaining therapeutic efficacy, optimizing vector selection, and improving delivery techniques. Continued advances in the field of viral vectors, particularly AAV, are expanding the potential applications of gene therapy to treat a variety of ocular diseases. To fully realize the potential of ocular gene therapy, more research and clinical trials are needed to improve these methods, ensure safe and efficient treatments, and ultimately overcome existing obstacles.