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Journal of Virology Jun 2024Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in substantial morbidity and mortality. The...
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in substantial morbidity and mortality. The basis of severe disease in humans is difficult to determine without the use of experimental animal models. Mice are resistant to infection with ancestral strains of SARS-CoV-2, although many variants that arose later in the pandemic were able to directly infect mice. In almost all cases, viruses that naturally infected mice or were engineered to enable mouse infection required mouse passage to become virulent. In most cases, changes in structural and nonstructural changes occurred during mouse adaptation. However, the mechanism of increased virulence in mice is not understood. Here, using a recently described strain of mouse-adapted SARS-CoV-2 (rSARS2-MA30), we engineered a series of recombinant viruses that expressed a subset of the mutations present in rSARS2-MA30. Mutations were detected in the spike protein and in three nonstructural proteins (nsp4, nsp8, and nsp9). We found that infection of mice with recombinant SARS-CoV-2 expressing only the S protein mutations caused very mild infection. Addition of the mutations in nsp4 and nsp8 was required for complete virulence. Of note, all these recombinant viruses replicated equivalently in cultured cells. The innate immune response was delayed after infection with virulent compared to attenuated viruses. Further, using a lineage tracking system, we found that attenuated virus was highly inhibited in the ability to infect the parenchyma, but not the airway after infection. Together, these results indicate that mutations in both the S protein and nonstructural proteins are required for maximal virulence during mouse adaptation.IMPORTANCEUnderstanding the pathogenesis of coronavirus disease 2019 (COVID-19) requires the study of experimental animals after infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). For this purpose, several mouse-adapted SARS-CoV-2 strains have been developed. Here, using a strain of mouse-adapted virus that causes a range of diseases ranging from mild to severe, we show that mutations in both a structural protein [spike (S) protein] and nonstructural proteins are required for maximal virulence. Thus, changes in the S protein, the most widely studied viral protein, while required for mouse adaptation, are not sufficient to result in a virulent virus.
PubMed: 38888344
DOI: 10.1128/jvi.00584-24 -
Journal of Minimally Invasive Surgery Jun 2024Robotic liver surgery is emerging as a minimally invasive surgery to overcome the disadvantages of laparoscopy. The two biggest barriers to the uptake of robotic...
Robotic liver surgery is emerging as a minimally invasive surgery to overcome the disadvantages of laparoscopy. The two biggest barriers to the uptake of robotic hepatectomy are the high cost and instrument limitations. Transection of the liver parenchyma is the main issue in robotic hepatectomy. Nonetheless, with adequate experience and the aid of reliable and enhanced three-dimensional visualization, many robotic surgeons have successfully used robotic Harmonic ACE curved shears (Intuitive Surgical Inc.) for parenchymal transection of the liver. Herein, we share a method of using robotic Harmonic ACE curved shears for parenchymal transection using a video clip.
PubMed: 38887003
DOI: 10.7602/jmis.2024.27.2.114 -
Neural Regeneration Research Mar 2025Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not...
Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.
PubMed: 38886941
DOI: 10.4103/NRR.NRR-D-23-01595 -
Insights Into Imaging Jun 2024Chronic liver disease is responsible for significant morbidity and mortality worldwide. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) can fully... (Review)
Review
Chronic liver disease is responsible for significant morbidity and mortality worldwide. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) can fully visualise the liver and adjacent structures in the upper abdomen providing a reproducible assessment of the liver and biliary system and can detect features of portal hypertension. Subjective interpretation of CT and MRI in the assessment of liver parenchyma for early and advanced stages of fibrosis (pre-cirrhosis), as well as severity of portal hypertension, is limited. Quantitative and reproducible measurements of hepatic and splenic volumes have been shown to correlate with fibrosis staging, clinical outcomes, and mortality. In this review, we will explore the role of volumetric measurements in relation to diagnosis, assessment of severity and prediction of outcomes in chronic liver disease patients. We conclude that volumetric analysis of the liver and spleen can provide important information in such patients, has the potential to stratify patients' stage of hepatic fibrosis and disease severity, and can provide critical prognostic information. CRITICAL RELEVANCE STATEMENT: This review highlights the role of volumetric measurements of the liver and spleen using CT and MRI in relation to diagnosis, assessment of severity, and prediction of outcomes in chronic liver disease patients. KEY POINTS: Volumetry of the liver and spleen using CT and MRI correlates with hepatic fibrosis stages and cirrhosis. Volumetric measurements correlate with chronic liver disease outcomes. Fully automated methods for volumetry are required for implementation into routine clinical practice.
PubMed: 38886297
DOI: 10.1186/s13244-024-01727-3 -
Cureus May 2024Cerebral arteriovenous malformations (cAVMs) are developmental pathologic lesions of the blood vessels of the brain in which multiple arteries shunt blood directly into...
Cerebral arteriovenous malformations (cAVMs) are developmental pathologic lesions of the blood vessels of the brain in which multiple arteries shunt blood directly into the venous drainage network. They are lesions with an unclear etiology and, if left untreated, can bear significant risks of complications such as migraines, seizures, neurological deficits, and intracranial hemorrhages. The diagnosis is based on several imaging methods, with angiography being the primary method. Treatment modalities include microsurgery, radiosurgery, embolization with the intent of obliteration, and various multidisciplinary approaches. We aim to introduce the case of an adult female patient with symptomatic cAVM who underwent partial endovascular embolization of the lesion and evaluate her recovery and the overall reliability of her treatment modality. A 22-year-old female patient has presented to the Neurosurgery Clinic with clinical manifestations with photosensitive seizures, migraines, and a history of sleep disturbances persisting for a period of one year. An appointed MRI and angiography revealed the presence of a glomerular cAVM of the anterior parietal branch of the middle cerebral artery located within the intraparietal sulcus of the left cerebral hemisphere (Spetzler-Martin grade 2). The venous drainage of the malformation led to a loss of nutrients in the surrounding brain parenchyma (a steal phenomenon), causing the seizures. The patient successfully underwent transarterial endovascular embolization with Onyx, which proved to be partial on a postoperative angiography, and refused further embolization procedures. There were no postoperative complications to be mentioned. The patient reported no seizures or sleep disturbances at the 12-month follow-up, with sporadic weak headaches remaining. cAVMs remain a pathology with significant morbidity and mortality when undiagnosed. Symptomatic cAVMs leading to a steal phenomenon and seizures can be reliably managed via endovascular embolization alone when the malformation has an appropriate angioarchitecture, location, size, and a low Spetzler-Martin score. However, further inquiry is required into the use of partial embolization in cases where further multiple-stage embolization procedures are declined and/or complete occlusion of the lesion is unfeasible. This case report emphasizes that partial endovascular embolization can be successfully utilized as a treatment modality for the symptoms caused by a steal phenomenon of the venous drainage of a cAVM, such as seizure disorders and migraines, in the rare instance when multiple-stage embolization is declined by the patient and occlusion of the lesion remains subtotal.
PubMed: 38883140
DOI: 10.7759/cureus.60499 -
Translational Cancer Research May 2024The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still...
BACKGROUND
The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still unknown. Therefore, we investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastases from SCLC to explore the tumor microenvironment of SCLC brain metastases.
METHODS
A retrospective analysis was performed on 12 surgical specimens of brain metastases from patients with SCLC treated in the Department of Neurosurgery of The First Affiliated Hospital of Anhui Medical University from June 2017 to June 2022. The inclusion criteria for this study were the following: (I) a pathologically confirmed diagnosis of SCLC brain metastases; (II) surgical resection of brain metastases; (III) age >18 years; (IV) and complete clinical data. Patient-related data were retrieved from the inpatient medical record system, telephone follow-up of patients date of death, and overall survival (OS). The immunofluorescence-based tissue microenvironment analysis panel (MAP) was utilized for the detection of TILs, including CD3, CD8, programmed cell death 1 (PD-1), and PD-L1, in formalin-fixed and paraffin-embedded archival specimens of brain metastases. The expression levels of PD-L1 in tumor cells were detected by immunohistochemistry. The correlation between the OS and the above-mentioned markers was analyzed in the 12 patients.
RESULTS
Twelve patients were included in the study. The patients' ages ranged from 51-78 years with a median of 68 years, with 1 female and 11 males. Among 12 patients with SCLC brain metastases: positive rates of CD3 TILs in the tumor parenchyma tumor stroma were 0.60%±0.94% 1.76%±2.72% (P=0.01), respectively; positive rates of CD8 TILs in the tumor parenchyma tumor stroma were 0.80%±0.78% 2.46%±3.72% (P=0.02), respectively. There was no co-expression of CD8 and PD-1 TILs in the tumor parenchyma of 11 cases, and the infiltration density of coexpressed CD3 and PD-1 TILs was more than 10/mm in only 1 case. There was no coexpression of CD3 and PD-1 TIL in the stroma of 10 cases, and the infiltration density of CD8 and PD-1 TILs was more than 10/mm in 2 cases. Immunohistochemistry was used to detect the expression of PD-L1 in 12 cases of SCLC metastatic lesions, and 3 cases (25%) were positive. Survival analysis showed that patients with positive intraepithelial CD3 TILs had significantly longer OS [hazard ratio 3.383, 95% confidence interval (CI): 0.959-11.940; P=0.04].
CONCLUSIONS
Our study further demonstrated the immune microenvironment of SCLC brain metastases. The distribution of TILs in SCLC brain metastases is low and mainly distributed in the stroma, with the expression of PD-L1 in these tumor tissues being low. Further exploration of the immune microenvironment of SCLC brain metastases is of great significance for potential treatment.
PubMed: 38881925
DOI: 10.21037/tcr-24-552 -
Immunity & Ageing : I & A Jun 2024Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and... (Review)
Review
Alzheimer's disease (AD) is a serious brain disorder characterized by the presence of beta-amyloid plaques, tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. The presence of chronic neuroinflammation, breaches in the blood-brain barrier (BBB), and increased levels of inflammatory mediators are central to the pathogenesis of AD. These factors promote the penetration of immune cells into the brain, potentially exacerbating clinical symptoms and neuronal death in AD patients. While microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD, recent evidence suggests the infiltration of cerebral vessels and parenchyma by peripheral immune cells, including neutrophils, T lymphocytes, B lymphocytes, NK cells, and monocytes in AD. These cells participate in the regulation of immunity and inflammation, which is expected to play a huge role in future immunotherapy. Given the crucial role of peripheral immune cells in AD, this article seeks to offer a comprehensive overview of their contributions to neuroinflammation in the disease. Understanding the role of these cells in the neuroinflammatory response is vital for developing new diagnostic markers and therapeutic targets to enhance the diagnosis and treatment of AD patients.
PubMed: 38877498
DOI: 10.1186/s12979-024-00445-0 -
Microbiology Spectrum Jun 2024The human polyomavirus, JCPyV, establishes a lifelong persistent infection in the peripheral organs of a majority of the human population worldwide. Patients who are...
JCPyV infection of primary choroid plexus epithelial cells reduces expression of critical junctional proteins and increases expression of barrier disrupting inflammatory cytokines.
UNLABELLED
The human polyomavirus, JCPyV, establishes a lifelong persistent infection in the peripheral organs of a majority of the human population worldwide. Patients who are immunocompromised due to underlying infections, cancer, or to immunomodulatory treatments for autoimmune disease are at risk for developing progressive multifocal leukoencephalopathy (PML) when the virus invades the CNS and infects macroglial cells in the brain parenchyma. It is not yet known how the virus enters the CNS to cause disease. The blood-choroid plexus barrier is a potential site of virus invasion as the cells that make up this barrier are known to be infected with virus both and . To understand the effects of virus infection on these cells we challenged primary human choroid plexus epithelial cells with JCPyV and profiled changes in host gene expression. We found that viral infection induced the expression of proinflammatory chemokines and downregulated junctional proteins essential for maintaining blood-CSF and blood-brain barrier function. These data contribute to our understanding of how JCPyV infection of the choroid plexus can modulate the host cell response to neuroinvasive pathogens.
IMPORTANCE
The human polyomavirus, JCPyV, causes a rapidly progressing demyelinating disease in the CNS of patients whose immune systems are compromised. JCPyV infection has been demonstrated in the choroid plexus both and and this highly vascularized organ may be important in viral invasion of brain parenchyma. Our data show that infection of primary choroid plexus epithelial cells results in increased expression of pro-inflammatory chemokines and downregulation of critical junctional proteins that maintain the blood-CSF barrier. These data have direct implications for mechanisms used by JCPyV to invade the CNS and cause neurological disease.
PubMed: 38874395
DOI: 10.1128/spectrum.00628-24 -
ESC Heart Failure Jun 2024Cognitive impairment (CI) is a common, yet frequently unrecognized co-morbidity in chronic heart failure (HF). We quantified trajectories of cognitive performance, brain...
AIMS
Cognitive impairment (CI) is a common, yet frequently unrecognized co-morbidity in chronic heart failure (HF). We quantified trajectories of cognitive performance, brain volume, and related clinical outcome over a time course of 6 years.
METHODS AND RESULTS
The Cognition.Matters-HF cohort study recruited patients with stable HF of any aetiology and severity. Beyond cardiological assessment, the workup included cognitive testing and brain magnetic resonance imaging (MRI). Of 148 recruited patients, 70% exhibited CI at baseline. During the median follow-up time of 69 months (quartiles: 68, 70), indicators of HF severity remained essentially unaltered. CI was also stable, with the exception of intensity of attention, where age-adjusted t-scores decreased from 42 (38, 46) to 38 (34, 44; P < 0.001). Complete sets of four serial brain MRI scans were available in 47 patients (32% of total sample). Total brain volume shrank by 0.4% per year, from 1103 (1060, 1143) cm to 1078 (1027, 1117) cm, which was within limits observed in non-diseased ageing individuals. During follow-up, 29 study participants (20%) died, and 26 (18%) were at least once hospitalized due to worsening HF. The presence of CI was not associated with overall (P = 0.290) or hospitalization-free (P = 0.450) survival.
CONCLUSIONS
In patients with stable HF patients receiving guideline-directed pharmacologic treatment and regular medical care, the presence of CI did not affect overall and hospitalization-free 6-year survival. The loss of brain parenchyma observed in patients with stable HF did not exceed that of normal ageing.
PubMed: 38873878
DOI: 10.1002/ehf2.14909 -
Respiratory Medicine Case Reports 2024Metastatic pulmonary calcification (MPC) is a metabolic disorder characterized by an ectopic deposition of calcium in the lung parenchyma, prevalent in patients with...
Metastatic pulmonary calcification (MPC) is a metabolic disorder characterized by an ectopic deposition of calcium in the lung parenchyma, prevalent in patients with chronic kidney disease. A combination of parenchymal lung abnormalities on high resolution chest computed tomography (CT) and pulmonary radiotracer uptake in Tc-methyl diphosphate (MDP) bone scintigraphy can establish diagnosis of MPC. We herein present a case of MPC with documented stability of chest CT abnormalities after renal transplant. We also describe novel findings of diffuse pulmonary uptake of F-sodium fluoride, a calcium-avid radiotracer, in positron emission tomography (PET)/CT performed in the same patient.
PubMed: 38872935
DOI: 10.1016/j.rmcr.2024.102043