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1.
Front Vet Sci ; 11: 1406928, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38915886

RESUMO

The objective of this research was to compare two previously described stereotactic brain biopsy (SBB) techniques, three-dimensional skull contoured guides (3D-SCGs) and neuronavigation with Brainsight, to a novel SBB technique using Brainsight combined with a 3D-printed headframe (BS3D-HF) to improve the workflow of SBB in dogs. This was a prospective methods comparison with five canine cadavers of different breeds and size. Initial helical CT was performed on cadavers with fiducial markers in place. Ten different target points were randomly selected for each method. The headframe for the BS3D-HF was designed and printed. Trajectories were planned for each method. Steinmann pins (SPs) were placed into the target points using the planned trajectories for each method, and CT was repeated (post CT). Accuracy was assessed by overlaying the initial CT onto the post CT and measuring the difference of the planned target point to the SP placement. For 3D-SCG, the median deviation was 2.48 mm (0.64-4.04). With neuronavigation, the median deviation was 3.28 mm (1.04-4.64). For BS3D-HF, the median deviation was 14.8 mm (8.87-22.1). There was no significant difference between 3D-SCG and neuronavigation for the median deviation (p = 0.42). When comparing BS3D-HF to 3D-SCG, there was a significant difference in the median deviation (p < 0.0001). Additionally, when comparing BS3D-HF to neuronavigation, there was a significant difference for the median deviation (p < 0.0001). Our findings concluded that both 3D-SCGs and neuronavigation were accurate for SBB, however BS3D-HF was not. Although feasible, the current BS3D-HF technique requires further refinement before it can be recommended for use for SBB in dogs.

2.
Sci Adv ; 6(25): eaba2502, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32596454

RESUMO

Cryptococcal meningoencephalitis (CM) is the major cause of infection-related neurological death, typically seen in immunocompromised patients. However, T cell-driven inflammatory response has been increasingly implicated in lethal central nervous system (CNS) immunopathology in human patients and murine models. Here, we report marked up-regulation of the chemokine receptor CXCR3 axis in human patients and mice with CM. CXCR3 deletion in mice improves survival, diminishes neurological deficits, and limits neuronal damage without suppressing fungal clearance. CD4+ T cell accumulation and TH1 skewing are reduced in the CNS but not spleens of infected CXCR3-/- mice. Adoptive transfer of WT, but not CXCR3-/- CD4+ T cells, into CXCR3-/- mice phenocopies the pathology of infected WT mice. Collectively, we found that CXCR3+CD4+ T cells drive lethal CNS pathology but are not required for fungal clearance during CM. The CXCR3 pathway shows potential as a therapeutic target or for biomarker discovery to limit CNS inflammatory damages.


Assuntos
Criptococose , Meningoencefalite , Receptores CXCR3 , Transferência Adotiva , Animais , Encéfalo/patologia , Sistema Nervoso Central , Criptococose/patologia , Cryptococcus , Humanos , Meningoencefalite/microbiologia , Meningoencefalite/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR3/genética
3.
mBio ; 9(6)2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30563896

RESUMO

Human infection with Cryptococcus causes up to a quarter of a million AIDS-related deaths annually and is the most common cause of nonviral meningitis in the United States. As an opportunistic fungal pathogen, Cryptococcus neoformans is distinguished by its ability to adapt to diverse host environments, including plants, amoebae, and mammals. In the present study, comparative transcriptomics of the fungus within human cerebrospinal fluid identified expression profiles representative of low-nutrient adaptive responses. Transcriptomics of fungal isolates from a cohort of HIV/AIDS patients identified high expression levels of an alternative carbon nutrient transporter gene, STL1, to be associated with poor early fungicidal activity, an important clinical prognostic marker. Mouse modeling and pathway analysis demonstrated a role for STL1 in mammalian pathogenesis and revealed that STL1 expression is regulated by a novel multigene regulatory mechanism involving the CAC2 subunit of the chromatin assembly complex 1, CAF-1. In this pathway, the global regulator of virulence gene VAD1 was found to transcriptionally regulate a cryptococcal homolog of a cytosolic protein, Ecm15, in turn required for nuclear transport of the Cac2 protein. Derepression of STL1 by the CAC2-containing CAF-1 complex was mediated by Cac2 and modulated binding and suppression of the STL1 enhancer element. Derepression of STL1 resulted in enhanced survival and growth of the fungus in the presence of low-nutrient, alternative carbon sources, facilitating virulence in mice. This study underscores the utility of ex vivo expression profiling of fungal clinical isolates and provides fundamental genetic understanding of saprophyte adaption to the human host.IMPORTANCECryptococcus is a fungal pathogen that kills an estimated quarter of a million individuals yearly and is the most common cause of nonviral meningitis in the United States. The fungus is carried in about 10% of the adult population and, after reactivation, causes disease in a wide variety of immunosuppressed individuals, including the HIV infected and patients receiving transplant conditioning, cancer therapy, or corticosteroid therapy for autoimmune diseases. The fungus is widely carried in the soil but can also cause infections in plants and mammals. However, the mechanisms for this widespread ability to infect a variety of hosts are poorly understood. The present study identified adaptation to low nutrients as a key property that allows the fungus to inhabit these diverse environments. Further studies identified a nutrient transporter gene, STL1, to be upregulated under low nutrients and to be associated with early fungicidal activity, a marker of poor clinical outcome in a cohort of HIV/AIDS patients. Understanding molecular mechanisms involved in adaptation to the human host may help to design better methods of control and treatment of widely dispersed fungal pathogens such as Cryptococcus.


Assuntos
Cryptococcus neoformans/genética , Cryptococcus neoformans/patogenicidade , Redes e Vias Metabólicas/genética , Serina-Treonina Quinases TOR/genética , Fatores de Virulência/genética , Adulto , Animais , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Genes Reguladores , Infecções por HIV/microbiologia , Interações Hospedeiro-Patógeno/genética , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Meningite Criptocócica/líquido cefalorraquidiano , Camundongos , Camundongos Endogâmicos CBA , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Virulência , Adulto Jovem
4.
PLoS One ; 9(8): e103386, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25106033

RESUMO

Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intruder paradigm at adulthood. These outcomes were complemented by assays of urine scent marking and ultrasonic vocalizations as indices of social communication. We provide evidence of sociosexual deficits after brain injury at p21, which manifest as reduced mounting behavior and scent marking towards an unfamiliar female at adulthood. In contrast, with the exception of the loss of social recognition in a three-chamber social approach task, mice that received TBI at adolescence were remarkably resilient to social deficits at adulthood. Increased emission of ultrasonic vocalizations (USVs) as well as preferential emission of high frequency USVs after injury was dependent upon both the stimulus and prior social experience. Contrary to the hypothesis that changes in white matter volume may underlie social dysfunction, injury at both p21 and p35 resulted in a similar degree of atrophy of the corpus callosum by adulthood. However, loss of hippocampal tissue was greater after p21 compared to p35 injury, suggesting that a longer period of lesion progression or differences in the kinetics of secondary pathogenesis after p21 injury may contribute to observed behavioral differences. Together, these findings indicate vulnerability of the developing brain to social dysfunction, and suggest that a younger age-at-insult results in poorer social and sociosexual outcomes.


Assuntos
Lesões Encefálicas/complicações , Encéfalo/crescimento & desenvolvimento , Transtornos da Comunicação/etiologia , Comportamento Sexual/fisiologia , Comportamento Social , Fatores Etários , Análise de Variância , Animais , Lesões Encefálicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vocalização Animal/fisiologia
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