The first few months after birth, when a child begins to interact with the environment, are critical to human brain development. The human frontal lobe is important for social behavior and executive function; it has increased in size and complexity relative to other species, but the processes that have contributed to this expansion are unknown. Our studies of postmortem infant human brains revealed a collection of neurons that migrate and integrate widely into the frontal lobe during infancy. Chains of young neurons move tangentially close to the walls of the lateral ventricles and along blood vessels. These cells then individually disperse long distances to reach cortical tissue, where they differentiate and contribute to inhibitory circuits. Late-arriving interneurons could contribute to developmental plasticity, and the disruption of their postnatal migration or differentiation may underlie neurodevelopmental disorders.
Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
BackgroundDespite its global recognition as a ruminant pathogen, cases of Chlamydia pecorum infection in Australian livestock are poorly documented. In this report, a C. pecorum specific Multi Locus Sequence Analysis scheme was used to characterise the C. pecorum strains implicated in two cases of sporadic bovine encephalomyelitis confirmed by necropsy, histopathology and immunohistochemistry. This report provides the first molecular evidence for the presence of mixed infections of C. pecorum strains in Australian cattle.Case presentationAffected animals were two markedly depressed, dehydrated and blind calves, 12 and 16 weeks old. The calves were euthanized and necropsied. In one calf, a severe fibrinous polyserositis was noted with excess joint fluid in all joints whereas in the other, no significant lesions were seen. No gross abnormalities were noted in the brain of either calf. Histopathological lesions seen in both calves included: multifocal, severe, subacute meningoencephalitis with vasculitis, fibrinocellular thrombosis and malacia; diffuse, mild, acute interstitial pneumonia; and diffuse, subacute epicarditis, severe in the calf with gross serositis. Immunohistochemical labelling of chlamydial antigen in brain, spleen and lung from the two affected calves and brain from two archived cases, localised the antigen to the cytoplasm of endothelium, mesothelium and macrophages. C. pecorum specific qPCR, showed dissemination of the pathogen to multiple organs. Phylogenetic comparisons with other C. pecorum bovine strains from Australia, Europe and the USA revealed the presence of two genetically distinct sequence types (ST). The predominant ST detected in the brain, heart, lung and liver of both calves was identical to the C. pecorum ST previously described in cases of SBE. A second ST detected in an ileal tissue sample from one of the calves, clustered with previously typed faecal bovine isolates.ConclusionThis report provides the first data to suggest that identical C. pecorum STs may be associated with SBE in geographically separated countries and that these may be distinct from those found in the gastrointestinal tract. This report provides a platform for further investigations into SBE and for understanding the genetic relationships that exist between C. pecorum strains detected in association with other infectious diseases in livestock.
Outcomes for children with high-grade gliomas (HGG) remain dismal despite aggressive treatment strategies. The use of targeted therapy for BRAFV600E mutated malignancies including HGG is being explored as a potentially well tolerated and effective therapeutic option. The results of adult melanoma studies demonstrating that combination therapy with BRAF inhibitors and MEK inhibitors results in prolonged survival led us to employ this treatment strategy in children with BRAFV600E mutated HGG. In this case series, we describe three pediatric patients with HGG with confirmed BRAFV600E mutation who demonstrated responses to combination therapy with dabrafenib and trametinib.
Objectives:To describe the clinical course and neuropathology at autopsy of a patient with neuromyelitis optica (NMO) treated with alemtuzumab.Methods:Case report.Results:A 61-year-old woman with aquaporin-4 immunoglobulin G antibody seropositive NMO had 10 clinical relapses in 4 years despite treatment with multiple immunosuppressive therapies. Alemtuzumab was administered and was redosed 15 months later. For the first 19 months after the initial alemtuzumab infusion, the patient did not experience discrete clinical relapses or have evidence of abnormally enhancing lesions on brain or spinal cord MRI. However, she experienced insidiously progressive nausea, vomiting, and vision loss, and her brain MRI revealed marked extension of cortical, subcortical, and brainstem T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. She died 20 months after the initial alemtuzumab infusion. Acute, subacute, and chronic demyelinating lesions were found at autopsy. Many of the lesions showed marked macrophage infiltration with a paucity of lymphocytes.Conclusions:Following alemtuzumab treatment, there appeared to be ongoing innate immune activation associated with tissue destruction that correlated with nonenhancing T2/FLAIR hyperintensities on MRI. We interpret the cessation of clinical relapses, absence of contrast-enhancing lesions, and scarcity of lymphocytes at autopsy to be indicative of suppression of adaptive immunity by alemtuzumab. This case illustrates that progressive worsening in NMO can occur as a consequence of tissue injury associated with monocytic infiltration. This observation may be relevant to multiple sclerosis (MS) as well as NMO and might explain why in previous studies of secondary progressive MS alemtuzumab did not seem to inhibit disability progression despite a dramatic decline in contrast-enhancing lesions.
Gliomas of the cranial nerve root entry zone are rare clinical entities. There have been 11 reported cases in the literature, including only 2 glioblastomas. The authors report the case of a 67-year-old man who presented with isolated facial numbness and was found to have a glioblastoma involving the trigeminal nerve root entry zone. After biopsy the patient completed treatment with conformal radiation and concomitant temozolomide, and at 23 weeks after surgery he demonstrated symptom progression despite the treatment described. This is the first reported case of a glioblastoma of the trigeminal nerve root entry zone.
Rates and characteristics of intracerebral cavernous malformations (ICMs) after cranial radiation therapy (CRT) remain poorly understood. Herein we report on ICMs detected on follow+up imaging in pediatric cancer patients who received CRT at age ≤ 18 years from 1980 to 2009. Through chart reviews (n=362) and phone interviews (n=104) of a retrospective cohort we identified 10 patients with ICMs. The median latency time for detection of ICMs after CRT was 12 years (range 1+24 years) at a median age of 21.4 years (IQR 15+28). The cumulative incidence was 3% (95% CI 1+8%) at 10 years post CRT and 14% (95% CI 7+26%) at 15 years. Three patients underwent surgical resection. Two surgical specimens were pathologically similar to sporadically occurring ICMs; one was consistent with capillary telangiectasia. ICMs are common after CRT and can show a spectrum of histological features.
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