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Antimicrobial Agents and Chemotherapy Oct 2023() is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is...
() is an encapsulated neurotropic fungal pathogen and the causative agent of cryptococcal meningoencephalitis (CME) in humans. Recommended treatment for CME is Amphotericin B (AmpB) and 5-fluorocytosine (5-FC). Though effective, AmpB has displayed numerous adverse side effects due to its potency and nephrotoxicity, prompting investigation into alternative treatments. Palmitoylethanolamide (PEA) is an immunomodulatory compound capable of promoting neuroprotection and reducing inflammation. To investigate the efficacy of PEA as a therapeutic alternative for CME, we intracerebrally infected mice with and treated them with PEA or AmpB alone or in combination. Our results demonstrate that PEA alone does not significantly prolong survival nor reduce fungal burden, but when combined with AmpB, PEA exerts an additive effect and promotes both survivability and fungal clearance. However, we compared this combination to traditional AmpB and 5-FC treatment in a survivability study and observed lower efficacy. Overall, our study revealed that PEA alone is not effective as an antifungal agent in the treatment of CME. Importantly, we describe the therapeutic capability of PEA in the context of infection and show that its immunomodulatory properties may confer limited protection when combined with an effective fungicidal agent.
Topics: Humans; Mice; Animals; Meningitis, Cryptococcal; Antifungal Agents; Cryptococcus neoformans; Cryptococcosis; Amphotericin B; Flucytosine; Meningoencephalitis
PubMed: 37750714
DOI: 10.1128/aac.00459-23 -
Acta Medica Portuguesa Sep 2023Behçet's disease is a relapsing multisystemic inflammatory syndrome characterized by recurrent oral and/or genital ulcers, uveitis, arthritis, skin lesions, and... (Review)
Review
Behçet's disease is a relapsing multisystemic inflammatory syndrome characterized by recurrent oral and/or genital ulcers, uveitis, arthritis, skin lesions, and gastrointestinal and neurological involvement. Neuro-Behçet corresponds to nervous system involvement and is one of the most severe complications of Behçet disease. It occurs in 3% to 30% of cases and is categorized into parenchymal (most common) or non-parenchymal disease. The most common manifestation of parenchymal neuro-Behçet is meningoencephalitis with involvement of the brainstem, where patients present with cranial neuropathies, encephalopathy, sensory-motor syndromes, epilepsy, or myelitis. The main non-parenchymal manifestation is cerebral venous thrombosis. Neuro-Behçet has a predominantly subacute course, with remission within weeks, or clinical progression in one third of the cases. The diagnosis is essentially clinical and diagnostic tests help to corroborate the suspicion, distinguish from differential diagnoses, and exclude complications. Brain magnetic resonance imaging allows the identification of acute lesions (hypointense or isointense on T2-weighted and hypointense on T1-weighted sequences) contrast-enhanced, and chronic lesions characterized by non-contrast enhanced small lesions and brainstem atrophy. If non-parenchymal involvement is suspected, cerebral veno-magnetic resonance imaging /computed tomography should be performed. Cerebrospinal fluid shows elevated proteinorachia and pleocytosis in parenchymal and no changes in non-parenchymal neuro-Behçet (except increased opening pressure). Outbursts of parenchymal disease should be treated with high dose intravenous corticosteroid therapy, with subsequent switch to oral corticoids, followed by biologic therapy, usually an anti-TNF. The treatment of cerebral venous thrombosis is controversial and may consist of a combination of corticosteroids and anticoagulation.
Topics: Humans; Behcet Syndrome; Tumor Necrosis Factor Inhibitors; Brain; Magnetic Resonance Imaging; Diagnosis, Differential; Adrenal Cortex Hormones; Venous Thrombosis
PubMed: 37345389
DOI: 10.20344/amp.19734 -
Emerging Microbes & Infections Dec 2023Systemic infection with , a dangerous and contagious pathogen found throughout the world, frequently results in lethal cryptococcal pneumonia and meningoencephalitis,...
Systemic infection with , a dangerous and contagious pathogen found throughout the world, frequently results in lethal cryptococcal pneumonia and meningoencephalitis, and no effective treatments and vaccination of cryptococcosis are available. Here, we describe Prm1, a novel regulator of virulence cells exhibit extreme sensitivity to various environmental stress conditions. Furthermore, cells show deficiencies in the biosynthesis of chitosan and mannoprotein, which in turn result in impairment of cell wall integrity. Treatment of mice with heat-killed cells was found to facilitate the host immunological defence against infection with wild-type . Further investigation demonstrated that cells strongly promote pulmonary production of interferon-γ, leading to activation of macrophage M1 differentiation and inhibition of M2 polarization. Therefore, our findings suggest that Prm1 may be a viable target for the development of anti-cryptococcosis medications and, cells lacking Prm1 represent a promising candidate for a vaccine.
Topics: Animals; Mice; Hot Temperature; Cryptococcosis; Cryptococcus neoformans; Vaccination; Immunization
PubMed: 37526401
DOI: 10.1080/22221751.2023.2244087 -
Brain Sciences Sep 2023Autoinflammatory disorders encompass a wide range of conditions with systemic and neurological symptoms, which can be acquired or inherited. These diseases are... (Review)
Review
Autoinflammatory disorders encompass a wide range of conditions with systemic and neurological symptoms, which can be acquired or inherited. These diseases are characterized by an abnormal response of the innate immune system, leading to an excessive inflammatory reaction. On the other hand, autoimmune diseases result from dysregulation of the adaptive immune response. Disease flares are characterized by systemic inflammation affecting the skin, muscles, joints, serosa, and eyes, accompanied by unexplained fever and elevated acute phase reactants. Autoinflammatory syndromes can present with various neurological manifestations, such as aseptic meningitis, meningoencephalitis, sensorineural hearing loss, and others. Early recognition of these manifestations by general neurologists can have a significant impact on the prognosis of patients. Timely and targeted therapy can prevent long-term disability by reducing chronic inflammation. This review provides an overview of recently reported neuroinflammatory phenotypes, with a specific focus on genetic factors, clinical manifestations, and treatment options. General neurologists should have a good understanding of these important diseases.
PubMed: 37759952
DOI: 10.3390/brainsci13091351 -
Journal of Microbiology, Immunology,... May 2024Co-therapy with albendazole and steroid is commonly used in patients with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis infections. However,...
Curative effects and mechanisms of AG1296 and LY294002 co-therapy in Angiostrongylus cantonensis-induced neurovascular unit dysfunction and eosinophilic meningoencephalitis.
BACKGROUND
Co-therapy with albendazole and steroid is commonly used in patients with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis infections. However, anthelminthics often worsen symptoms, possibly due to the inflammatory reaction to antigens released by dying worms. Therefore, the present study was to investigate the curative effects and probable mechanisms of the platelet-derived growth factor receptor-beta (PDGFR-β) inhibitor AG1296 (AG) and the phosphoinositide 3-kinase inhibitor (PI3K) LY294002 (LY) in A. cantonensis-induced neurovascular unit dysfunction and eosinophilic meningoencephalitis.
METHODS
Western blots were used to detect matrix protein degradation and the expressions of PDGFR-β/PI3K signaling pathway. The co-localization of PDGFR-β and vascular smooth muscle cells (VSMCs), and metalloproteinase-9 (MMP-9) and VSMCs on the blood vessels were measured by confocal laser scanning immunofluorescence microscopy. Sandwich enzyme-linked immunosorbent assays were used to test S100B, interleukin (IL)-6, and transforming growth factor beta in the cerebrospinal fluid to determine their possible roles in mouse resistance to A. cantonensis.
RESULTS
The results showed that AG and LY cotherapy decreased the MMP-9 activity and inflammatory reaction. Furthermore, S100B, IL-6 and eosinophil counts were reduced by inhibitor treatment. The localization of PDGFR-β and MMP-9 was observed in VSMCs. Furthermore, we showed that the degradation of the neurovascular matrix and blood-brain barrier permeability were reduced in the mouse brain.
CONCLUSIONS
These findings demonstrate the potential of PDGFR-β inhibitor AG and PI3K inhibitor LY co-therapy as anti-A. cantonensis drug candidates through improved neurovascular unit dysfunction and reduced inflammatory response.
PubMed: 38839542
DOI: 10.1016/j.jmii.2024.05.012 -
Acta Neuropathologica Feb 2024Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease...
Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8/perforin/granzyme A/B cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.
Topics: Humans; Animals; Dogs; Glial Fibrillary Acidic Protein; Encephalomyelitis; Astrocytes; Autoimmune Diseases of the Nervous System; Meningoencephalitis; Autoantibodies
PubMed: 38310187
DOI: 10.1007/s00401-023-02678-7 -
Annals of Medicine Dec 2023Tuberculous meningitis is an infectious disease of the central nervous system caused by Mycobacterium tuberculosis (M. tuberculosis). It mainly involves the meninges... (Review)
Review
Tuberculous meningitis is an infectious disease of the central nervous system caused by Mycobacterium tuberculosis (M. tuberculosis). It mainly involves the meninges and brain parenchyma, as well as the spinal cord and meninges; Disability and mortality rates are high. In recent years, due to the increase of drug-resistant tuberculosis patients, population mobility and the prevalence of acquired immune deficiency syndrome, the incidence rate of tuberculosis has increased significantly, and tuberculous meningitis has also increased. At present, tuberculosis is still a worldwide infectious disease that seriously threatens human health, especially in underdeveloped and developing countries. China is the largest developing country in the world with a large population. The situation of tuberculosis prevention and control is grim. Its disability rate is the highest in tuberculosis infection. In addition to the common non-specific manifestations, tuberculous meningoencephalitis may also have rare manifestations of stroke, hearing loss and visual loss. Understanding and timely improvement of corresponding examinations and targeted treatment will help improve the prognosis of patients.
Topics: Humans; Tuberculosis, Meningeal; Mycobacterium tuberculosis; Brain; Meningoencephalitis; China
PubMed: 36598144
DOI: 10.1080/07853890.2022.2164348 -
Parasites & Vectors Jul 2023Toxoplasma gondii is an opportunistic protozoan that is ubiquitous in humans and animals. It can invade any human organ and cause severe diseases, including toxoplasma...
BACKGROUND
Toxoplasma gondii is an opportunistic protozoan that is ubiquitous in humans and animals. It can invade any human organ and cause severe diseases, including toxoplasma ophthalmopathy, meningoencephalitis, and liver necrosis. Porcine toxoplasmosis is prevalent in China. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and Cas (CRISPR-Associated Protein) systems are widely used for gene editing and pathogen detection. CRISPR-based diagnostics are molecular assays that have been developed to detect parasites with high sensitivity and specificity.
METHODS
This study aimed to establish a combined CRISPR/Cas12a and RPA rapid detection method for T. gondii by targeting the B1 gene and 529 bp repeat element (529 RE). The detection results could be visualized by the fluorescence or lateral flow strips (LFS). The sensitivity and specificity of the method were evaluated, and T. gondii-infected mouse blood was used for detection.
RESULTS
The results indicated that the established method for T. gondii detection was satisfactory, with a detection limit of 1.5 cp/μl for the two loci. Moreover, the B1 gene could detect 1 tachyzoite per reaction, and the 529 RE could detect 0.1 tachyzoite per reaction, consistently with the highly sensitive nested polymerase chain reaction (PCR) results. The method was suitable for strains, including RH, and did not cross-react with other protozoa DNA with similar habits. The T. gondii-infected mouse blood samples were all positive for T. gondii at 1, 3, and 5 days post infection (dpi).
CONCLUSIONS
This study established a rapid, sensitive, and time-saving DNA detection method for T. gondii that has the potential to be an alternative tool for T. gondii detection in the field.
Topics: Animals; Humans; Mice; Swine; CRISPR-Cas Systems; Toxoplasmosis; Toxoplasma; Polymerase Chain Reaction; Sensitivity and Specificity; DNA, Protozoan
PubMed: 37518013
DOI: 10.1186/s13071-023-05868-0 -
Neurology(R) Neuroimmunology &... Nov 2023Persistent impaired immunity is possible even years after B-cell depleting therapies. This may favor the occurrence of infections, including infectious meningitis and...
OBJECTIVES
Persistent impaired immunity is possible even years after B-cell depleting therapies. This may favor the occurrence of infections, including infectious meningitis and encephalitis. In this study, we report a case of chronic enterovirus meningoencephalitis in prolonged B-cell depletion years after rituximab therapy.
METHODS
This is a case report from a German academic hospital. In addition to repeated clinical examinations, repeated brain MRI and extended CSF and laboratory diagnostics were performed. We used the CARE checklist when writing our report.
RESULTS
A 38-year-old man presented with high fever (>40°C), severe headache, and progressive neurologic and cognitive deficits. As result of previous lymphoma therapy with rituximab years ago, prolonged B-cell aplasia was detected. To restore humoral immunity, the patient received repeated infusions of immunoglobulins. In the end, a complete restitution of the physical and mental condition was achieved with the established therapy.
DISCUSSION
This case report should emphasize the importance of assessing humoral immunity even years after B-cell depletion therapy, especially in case of opportunistic infections.
Topics: Male; Humans; Adult; Rituximab; Enterovirus; Enterovirus Infections; Meningoencephalitis; B-Lymphocytes
PubMed: 37813597
DOI: 10.1212/NXI.0000000000200171 -
Journal of Neuroimmunology Sep 2023Shikonin is an anti-inflammatory natural herbal drug extracted from Lithospermum erythrorhizon and its therapeutic effect on neuropsychiatric systemic lupus...
Shikonin is an anti-inflammatory natural herbal drug extracted from Lithospermum erythrorhizon and its therapeutic effect on neuropsychiatric systemic lupus erythematosus (NPSLE) is yet unknown. In our study, Shikonin significantly reversed the cognitive impairment and alleviated the brain tissue damage in NPSLE mice. The permeability of blood-brain barrier was also verified to be repaired in Shikonin-treated NPSLE mice. In particular, we found that Shikonin alleviated neuroinflammation through inhibiting β-catenin signaling pathway, thereby depressing the activation of microglia and the loss of neuronal synapses. Overall, Shikonin may be a promising candidate drug for NPSLE through diminishing neuroinflammation and repairing neuron damage.
Topics: Animals; Mice; Lupus Vasculitis, Central Nervous System; Lupus Erythematosus, Systemic; Neuroinflammatory Diseases; Cognitive Dysfunction; Neurons; Anti-Inflammatory Agents
PubMed: 37536051
DOI: 10.1016/j.jneuroim.2023.578166