Lymphangiogenesis is supported by 2 homologous VEGFR3 ligands, VEGFC and VEGFD. VEGFC is required for lymphatic development, while VEGFD is not. VEGFC and VEGFD are proteolytically cleaved after cell ...secretion in vitro, and recent studies have implicated the protease a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the secreted factor collagen and calcium binding EGF domains 1 (CCBE1) in this process. It is not well understood how ligand proteolysis is controlled at the molecular level or how this process regulates lymphangiogenesis, because these complex molecular interactions have been difficult to follow ex vivo and test in vivo. Here, we have developed and used biochemical and cellular tools to demonstrate that an ADAMTS3-CCBE1 complex can form independently of VEGFR3 and is required to convert VEGFC, but not VEGFD, into an active ligand. Consistent with these ex vivo findings, mouse genetic studies revealed that ADAMTS3 is required for lymphatic development in a manner that is identical to the requirement of VEGFC and CCBE1 for lymphatic development. Moreover, CCBE1 was required for in vivo lymphangiogenesis stimulated by VEGFC but not VEGFD. Together, these studies reveal that lymphangiogenesis is regulated by two distinct proteolytic mechanisms of ligand activation: one in which VEGFC activation by ADAMTS3 and CCBE1 spatially and temporally patterns developing lymphatics, and one in which VEGFD activation by a distinct proteolytic mechanism may be stimulated during inflammatory lymphatic growth.
Sporadic Creutzfeldt–Jakob disease (sCJD) is a transmissible brain proteinopathy. Five main clinicopathological subtypes (sCJD-MM(V)1, -MM(V)2C, -MV2K, -VV1, and -VV2) are currently distinguished. ...Histopathological evidence suggests that the localisation of prion aggregates and spongiform lesions varies among subtypes. Establishing whether there is an initial site with detectable imaging abnormalities (epicentre) and an order of lesion propagation would be informative for disease early diagnosis, patient staging, management and recruitment in clinical trials. Diffusion magnetic resonance imaging (MRI) is the most-used and most-sensitive test to detect spongiform degeneration. This study was designed to identify, in vivo and for the first time, subtype-dependent epicentre and lesion propagation in the brain using diffusion-weighted images (DWI), in the largest known cross-sectional dataset of autopsy-proven subjects with sCJD. We estimate lesion propagation by cross-sectional DWI using event-based modelling, a well-established data-driven technique. DWI abnormalities of 594 autopsy-diagnosed subjects (448 patients with sCJD) were scored in 12 brain regions by 1 neuroradiologist blind to the diagnosis. We used the event-based model to reconstruct sequential orderings of lesion propagation in each of five pure subtypes. Follow-up data from 151 patients validated the estimated sequences. Results showed that epicentre and ordering of lesion propagation are subtype specific. The two most common subtypes (-MM1 and -VV2) showed opposite ordering of DWI abnormality appearance: from the neocortex to subcortical regions, and vice versa, respectively. The precuneus was the most likely epicentre also in -MM2 and -VV1 although at variance with -MM1, abnormal signal was also detected early in cingulate and insular cortices. The caudal-rostral sequence of lesion propagation that characterises -VV2 was replicated in -MV2K. Combined, these data-driven models provide unprecedented dynamic insights into subtype-specific epicentre at onset and propagation of the pathologic process, which may also enhance early diagnosis and enable disease staging in sCJD.
Objective
The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance ...centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center.
Methods
Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy.
Results
Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort.
Discussion
Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.
The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The ...mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission, and a summary of the CDC and WHO guidelines for prevention of prion disease transmission and decontamination of prion-contaminated neurosurgical instruments.
IMPORTANCE: Opioid addiction affects approximately 2.4 million Americans. Nearly 1 million individuals, including a growing subset of 21 000 minors, abuse heroin. Its annual cost within the United ...States amounts to $51 billion. Inhaled heroin use represents a global phenomenon and is approaching epidemic levels east of the Mississippi River as well as among urban youth. Chasing the dragon (CTD) by heating heroin and inhaling its fumes is particularly concerning, because this method of heroin usage has greater availability, greater ease of administration, and impressive intensity of subjective experience (high) compared with sniffing or snorting, although it also has a safer infectious profile compared with heroin injection. This is relevant owing to peculiar and often catastrophic brain complications. Following the American Medical Association Opioid Task Force mandate, we contribute a description of the pharmacology, pathophysiology, clinical spectrum, neuroimaging, and neuropathology of CTD leukoencephalopathy, as distinct from other heroin abuse modalities. OBSERVATIONS: The unique spectrum of CTD-associated health outcomes includes an aggressive toxic leukoencephalopathy with pathognomonic neuropathologic features, along with sporadic instances of movement disorders and hydrocephalus. Clinical CTD severity is predominantly moderate at admission, frequently unmodified at discharge, and largely improved in the long term. Mild cases survive with minor sequelae, while moderate to severe presentations might deteriorate and progress to death. Other methods of heroin use may complicate with stroke, seizure, obstructive hydrocephalus, and (uncharacteristically) leukoencephalopathy. CONCLUSIONS AND RELEVANCE: The distinct pharmacology of CTD correlates with its specific clinical and radiological features and prompts grave concern for potential morbidity and long-term disability costs. Proposed diagnostic criteria and standardized reporting would ameliorate the limitations of CTD literature and facilitate patient selection for a coenzyme Q10 therapeutic trial.
The emergence of American Cutaneous Leishmaniasis (ACL) has been associated with changes in the relationship between people and forests, leading to the view that forest ecosystems increase infection ...risk and subsequent proposal that deforestation could reduce re-emergence of this disease.
We analyzed county-level incidence rates of ACL in Costa Rica (1996-2000) as a function of social and environmental variables relevant to transmission ecology with statistical models that incorporate breakpoints. Once social marginality was taken into account, the effect of living close to a forest on infection risk was small, and diminished exponentially above a breakpoint. Forest cover was associated with the modulation of temporal effects of El Niño Southern Oscillation (ENSO) at small spatial scales, revealing an additional complex interplay of environmental forces and disease patterns.
Social factors, which previously have not been evaluated rigorously together with environmental and climatic factors, appear to play a critical role that may ultimately determine disease risk.
Iron-sulfur (Fe-S) proteins are key players in vital processes involving energy homeostasis and metabolism from the simplest to most complex organisms. We report a 1.5 Å x-ray crystal structure of ...the first identified outer mitochondrial membrane Fe-S protein, mitoNEET. Two protomers intertwine to form a unique dimeric structure that constitutes a new fold to not only the almost equal to650 reported Fe-S protein structures but also to all known proteins. We name this motif the NEET fold. The protomers form a two-domain structure: a β-cap domain and a cluster-binding domain that coordinates two acid-labile 2Fe-2S clusters. Binding of pioglitazone, an insulin-sensitizing thiazolidinedione used in the treatment of type 2 diabetes, stabilizes the protein against 2Fe-2S cluster release. The biophysical properties of mitoNEET suggest that it may participate in a redox-sensitive signaling and/or in Fe-S cluster transfer.
It is increasingly evident that the association of glycans with the prion protein (PrP), a major post-translational modification, significantly impacts the pathogenesis of prion diseases. A recent ...bioassay study has provided evidence that the presence of PrP glycans decreases spongiform degeneration and disease-related PrP (PrPD) deposition in a murine model. We challenged (PRNPN181Q/197Q) transgenic (Tg) mice expressing glycan-free human PrP (TgGlyc-), with isolates from sporadic Creutzfeldt-Jakob disease subtype MM2 (sCJDMM2), sporadic fatal insomnia and familial fatal insomnia, three human prion diseases that are distinct but share histotypic and PrPD features. TgGlyc- mice accurately replicated the basic histotypic features associated with the three diseases but the transmission was characterized by high attack rates, shortened incubation periods and a greatly increased severity of the histopathology, including the presence of up to 40 times higher quantities of PrPD that formed prominent deposits. Although the engineered protease-resistant PrPD shared at least some features of the secondary structure and the presence of the anchorless PrPD variant with the wild-type PrPD, it exhibited different density gradient profiles of the PrPD aggregates and a higher stability index. The severity of the histopathological features including PrP deposition appeared to be related to the incubation period duration. These findings are clearly consistent with the protective role of the PrP glycans but also emphasize the complexity of the conformational changes that impact PrPD following glycan knockout. Future studies will determine whether these features apply broadly to other human prion diseases or are PrPD-type dependent.
Abstract
Infiltrating gliomas comprise the most common group of primary intraparenchymal brain tumors and present a level of complexity which requires careful integration of histopathology and ...molecular diagnostics for optimal therapy. To this end, the fourth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) has been followed by a series of publications by cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) incorporating molecular signatures to propose updated diagnostic categories in anticipation of the upcoming fifth edition of CNS tumor classification. Integration of histopathology, immunophenotyping, and molecular findings is profoundly changing the practice of diagnostic surgical neuropathology and enabling a more personalized approach to treating patients with gliomas.
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