pathology

Virtual Pathology Learning Resource: A Promising Strategy in Teaching Pathology to Allied Health Science Students

Aim/Purpose: The objective of this study was to concept test a new instructional aid called Virtual Pathology Learning Resource (VPLR), which was used as a vehicle to communicate information and enhance teaching and learning of basic sciences (Anatomy, Physiology, and Pathology) to allied health science students at a South Australian university. Background: Pathology was traditionally taught using potted specimens to review disease manifestations independently. However, this approach was found inadequate and ineffective. VPLR is a new teaching platform comprising of digitised human normal and human pathology specimens (histology, histopathology), patient case studies, short answer and critical thinking questions, and self-assessment quizzes. Using authentic learning theory as an educational pedagogy, this learning resource was developed to enhance the teaching and learning of Pathology. Methodology: Cross-sectional study design was used. A survey, given at the end of the course, gathered qualitative and quantitative data concerning the perceptions and experiences of the students about VPLR and its components. The online tool SurveyMonkey was utilised so that students could respond anonymously to a web link that displayed the questionnaire. The perceived impact on students was assessed using an 18-item questionnaire seeking agreement or disagreement with statements about VPLR, multiple choice and open-ended questions querying the best things about VPLR, benefits to be derived, and areas for improvement. Descriptive and frequency analyses were performed. Contribution: The VPLR approach involved rich learning situations, contextualised content, and facilitated greater understanding of disease concepts and problems. Findings: In a sample of 103 Medical Radiation students, 42% of students (N=43) responded to the post-intervention survey. The majority of students reported highly positive effects for each component of the VPLR. The overall results indicated that this tool was a promising strategy in teaching Pathology as it assisted students’ gaining knowledge of the science, facilitated connections between sciences, and allowed students to make better links with professional practice and skills. Recommendations for Practitioners: As students found VPLR to be beneficial, it is recommended that the same approach is applied for the teaching of Pathology to other health science students, such as Nursing. Other universities might consider adopting the innovation for their courses. Recommendation for Researchers: Applying VPLR to teaching other allied health science students will be undertaken next. The innovation will be appropriate for other health science students with particular emphasis on case-based or problem-based learning and combined with clinical experiences. Impact on Society: In reshaping the way of teaching a science course, students are benefited with greater depth of understanding of content and increase motivation to study. These are important to keep students engaged and ready for practice. VPLR may impact on education and technology trends so that exploration and possibilities of initiatives are ongoing to help students become successful learners. Other impacts are the new forms of learning discovered, the renewed focus on group work and collaboration, and maximising the use of technology in innovation. Future Research: Future directions of this research would be to conduct a follow-up of this cohort of students to determine whether the impacts of the innovation were durable, meaning the change in perceptions and behaviour is sustained over time.




pathology

Distance Learning: Effectiveness of an Interdisciplinary Course in Speech Pathology and Dentistry

Objective: Evaluate the effectiveness of distance learning courses for the purpose of interdisciplinary continuing education in Speech Pathology and Dentistry. Methods: The online course was made available on the Moodle platform. A total of 30 undergraduates participated in the study (15 from the Dentistry course and 15 from the Speech Pathology course). Their knowledge was evaluated before and after the course, in addition to the user satisfaction by means of specific questionnaires. The course was evaluated by 6 specialists on the following aspects: presentation and quality of the content, audio-visual quality, adequacy to the target public, and information made available. To compare the obtained results in the pre- and post-course questionnaires, the test Wilcoxon was carried out, with a 5% significance level. Results: the teaching/learning process, including the theoretical/practical application for the interdisciplinary training, proved to be effective as there was a statistically significant difference between the pre- and post- course evaluations (p<0.001), the users’ satisfaction degree was favorable and the specialists evaluated the material as adequate regarding the target public, the audio-visual information quality and the strategies of content availability. Conclusion: The suggested distance-learning course proved to be effective for the purpose of Speech Pathology and Dentistry interdisciplinary education.




pathology

Peripersonal Space Plasticity in Relation to Psychopathology and Anomalous Subjective Experiences in Individuals With Early‐Onset and Adult‐Onset Schizophrenia

ABSTRACT Introduction Individuals with schizophrenia present anomalies in the extension and plasticity of the peripersonal space (PPS), the section of space surrounding the body, shaped through motor experiences. A weak multisensory integration in PPS would contribute to an impairment of self-embodiment processing, a core feature of the disorder linked to specific subjective experiences. In this […]

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  • Journal Article Abstracts

pathology

William M. Witt, DVM, PhD, Celebrated for Dedication to the Field of Research Pathology

Dr. Witt lends years of varied experience to his work with Toxicologic Pathology Associates, Inc.




pathology

Researchers Unlock the Key and Identify Serious Pathology in Low Back Pain

Chiropractic researchers had investigated behind increasing cases of serious pathology such as cancer. Investigators from the CDAHK, had resolve the puzzle and estimate the prevalence and types of serious pathology among adults with low back pain.




pathology

Saroja Bharati, MD, Celebrated for Excellence in the Field of Cardiac Pathology

An accomplished physician, scholar and educator, Saroja Bharati has secured a distinguished reputation in the healthcare industry




pathology

Marquis Who's Who Honors John T. Fallon, MD, PhD, for Success in Pathology and Higher Education

Dr. Fallon is noted for his success as a pathologist and professor of pathology.





pathology

Sphingolipids as Critical Players in Retinal Physiology and Pathology [Thematic Reviews]

Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.




pathology

Predicting Pathologic Complete Response in Locally Advanced Rectal Cancer with [68Ga]Ga-FAPI-04 PET, [18F]FDG PET, and Contrast-Enhanced MRI: Lesion-to-Lesion Comparison with Pathology

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. 68Ga-labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) PET/MRI, [18F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [68Ga]Ga-FAPI-04 PET/MRI and [18F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [68Ga]Ga-FAPI-04 change in SULpeak percentage, where SULpeak is SUVpeak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [68Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SULpeak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.




pathology

The Pathology of False Disciples, Part 2




pathology

The Pathology of False Disciples, Part 1




pathology

The Pathology of False Disciples, Part 3




pathology

Pathology: Cornerstone of Modern Medicine

Highlights: Pathologists play an important role in diagnosing and understanding diseases International Pathologi




pathology

Progress and pathology : Medicine and culture in the nineteenth century [Electronic book] / ed. by Sally Shuttleworth, Melissa Dickson, Emilie Taylor-Brown.

Manchester : Manchester University Press, [2020]




pathology

Phrenitis and the Pathology of the Mind in Western Medical Thought : (Fifth Century BCE to Twentieth Century CE) [Electronic book] / Chiara Thumiger.

Cambridge : Cambridge University Press, 2023.




pathology

OECD Guidance on the GLP Requirements for Peer Review of Histopathology

This advisory document provides guidance on how pathology peer reviews should be planned, conducted and reported within the context of OECD Good Laboratory Practice.




pathology

Western Hemisphere: ICITAP Webinar Supports Pathology and Crime Scene Investigation During COVID-19 Pandemic

On April 27, ICITAP’s Central America mission conducted a webinar titled “Pathology and Crime Scene Investigation (CSI) During the COVID-19 Pandemic” for hundreds of subject matter experts from throughout the Western Hemisphere. Chaired by ICITAP-Central America’s Attaché, the 80-minute webinar began with a pre-recorded media interview from the Dominican Republic, which highlighted the critical work currently carried out by the Office of the Chief Medical Examiner (OCME) in Washington, DC.




pathology

Multi-task pre-training of deep neural networks for digital pathology. (arXiv:2005.02561v2 [eess.IV] UPDATED)

In this work, we investigate multi-task learning as a way of pre-training models for classification tasks in digital pathology. It is motivated by the fact that many small and medium-size datasets have been released by the community over the years whereas there is no large scale dataset similar to ImageNet in the domain. We first assemble and transform many digital pathology datasets into a pool of 22 classification tasks and almost 900k images. Then, we propose a simple architecture and training scheme for creating a transferable model and a robust evaluation and selection protocol in order to evaluate our method. Depending on the target task, we show that our models used as feature extractors either improve significantly over ImageNet pre-trained models or provide comparable performance. Fine-tuning improves performance over feature extraction and is able to recover the lack of specificity of ImageNet features, as both pre-training sources yield comparable performance.




pathology

Generative Adversarial Networks in Digital Pathology: A Survey on Trends and Future Potential. (arXiv:2004.14936v2 [eess.IV] UPDATED)

Image analysis in the field of digital pathology has recently gained increased popularity. The use of high-quality whole slide scanners enables the fast acquisition of large amounts of image data, showing extensive context and microscopic detail at the same time. Simultaneously, novel machine learning algorithms have boosted the performance of image analysis approaches. In this paper, we focus on a particularly powerful class of architectures, called Generative Adversarial Networks (GANs), applied to histological image data. Besides improving performance, GANs also enable application scenarios in this field, which were previously intractable. However, GANs could exhibit a potential for introducing bias. Hereby, we summarize the recent state-of-the-art developments in a generalizing notation, present the main applications of GANs and give an outlook of some chosen promising approaches and their possible future applications. In addition, we identify currently unavailable methods with potential for future applications.




pathology

CTE pathology in a neurodegenerative disorders brain bank




pathology

Heterocyclic compounds as imaging probes of tau pathology

Heterocyclic compounds of formula (I) useful as imaging probes of Tau pathology in Alzheimer's disease are described. Compositions and methods of making such compounds are also described.




pathology

Digital pathology system

The present invention may include an illumination source; a TDI sensor having a plurality of rows of TDI pixels, wherein each of the TDI pixels have a 1:1 aspect ratio; a multicolor filter contacted to the surface of the TDI sensor, wherein the multicolor filter has alternating sections of a first color filter, a second color filter, and at least a third color, wherein adjacent rows of TDI pixels are grouped in order to form a plurality of rows of integrated multicolor pixels; an objective having a first end positioned proximate to the specimen; a second lens configured to focus light from the image path onto the TDI sensor; and an anamorphic optics element configured to magnify an image of the one or more specimens such that the image is magnified by a factor of three along a direction orthogonal to an integrating direction of the TDI sensor.




pathology

Inhibition of the renin-angiotensin system for the treatment of renal, vascular and cartilage pathology

A method of treating a disease or condition in which up-regulating GAGs is therapeutically beneficial is disclosed, in particular osteoarthritis and skin diseases. The method comprises locally administering to a subject a therapeutically effective amount of an agent capable of down-regulating activity or expression of a component of the renin-angiotensin system.




pathology

Tasmanian parents struggling to access speech pathology treatment for their children

Parents in Tasmania are struggling to access speech pathology treatment for their children because NDIS funding has caused an explosion in demand for services.




pathology

Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes

Anne Jörns
Apr 1, 2020; 69:624-633
Islet Studies




pathology

Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.




pathology

Head-to-Head Comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and Immunohistochemical Analysis as a Reference Standard

18F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)–based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of 18F-PSMA-1007 with 68Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate- or high-risk PCa. Methods: Sixteen patients with intermediate- or high-risk PCa underwent 18F-PSMA-1007 and 68Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen -coefficient was used to assess the concordance between 18F-PSMA-1007 and 68Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUVmax was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers ( ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with 18F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both 18F-PSMA-1007 and 68Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediate- or high-risk PCa at staging. 18F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.




pathology

Gujarat university, second MBBS examination, pathology question papers, January 2015

Gujarat university, second MBBS examination, pathology question papers, January 2015




pathology

Diarrhoea and dysentery : modern views of their pathology and treatment / by Alonzo B. Palmer.

Detroit, Mich. : G.S. Davis, 1887.




pathology

A dictionary of medicine : including general pathology, general therapeutics, hygiene, and the diseases of women and children / by various writers ; edited by Richard Quain ; assisted by Frederick Thomas Roberts and J. Mitchell Bruce.

London : Longmans, Green, 1894.




pathology

Discussion on the pathology of phthisis pulmonalis.

Glasgow : Alex MacDougall, 1881.




pathology

Diseases of the nervous system : their prevalence and pathology / by Julius Althaus.

London : Smith, Elder, 1877.




pathology

Diseases of the skin : their description, pathology, diagnosis, and treatment / by H. Radcliffe Crocker.

London : H.K. Lewis, 1903.




pathology

Diseases of women, including their pathology, causation, symptoms, diagnosis and treatment : a manual for students and practitioners / by Arthur W. Edis.

London : Smith, Elder, 1881.




pathology

The Edinburgh medical and physical dictionary : containing an explanation of the terms of art in anatomy, physiology, pathology ... as employed in the present improved state of medical science ... : to which is added, a copious glossary of obsolete terms

Edinburgh : Bell & Bradfute, 1807.




pathology

Elements of general pathology / by John Fletcher ; edited by John J. Drysdale and John R. Russell.

Edinburgh : MacLachlan, Stewart, 1842.




pathology

Elements of pathology and therapeutics being the outlines of a work, intended to ascertain the nature, causes, and most efficacious modes of prevention and cure, of the greater number of the diseases incidental to the human frame : illustrated by numerous

Bath : And sold by Underwood, London, 1825.




pathology

Elements of surgical pathology / by Augustus J. Pepper.

London : Cassell, 1894.




pathology

Enteric fever : its prevalence and modifications, aetiology, pathology and treatment as illustrated by Army data at home and abroad / by Francis H. Welch.

London : H.K. Lewis, 1883.




pathology

Epilepsy : its pathology and treatment : being an essay to which was awarded a prize of four thousand francs by the Academie Royale de Médécine de Belgique, December 31, 1889 / by Hobart Amory Hare.

London : Philadelphia, 1890.




pathology

The Erasmus Wilson lectures on the pathology and diseases of the thyroid gland / by Walter Edmunds.

Edinburgh : Young J. Pentland, 1901.




pathology

Surgical pathology of the liver

Torbenson, Michael S., author.
9781496365798




pathology

Atlas of mohs and frozen section cutaneous pathology

9783319748474 978-3-319-74847-4




pathology

A Bayesian mark interaction model for analysis of tumor pathology images

Qiwei Li, Xinlei Wang, Faming Liang, Guanghua Xiao.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1708--1732.

Abstract:
With the advance of imaging technology, digital pathology imaging of tumor tissue slides is becoming a routine clinical procedure for cancer diagnosis. This process produces massive imaging data that capture histological details in high resolution. Recent developments in deep-learning methods have enabled us to identify and classify individual cells from digital pathology images at large scale. Reliable statistical approaches to model the spatial pattern of cells can provide new insight into tumor progression and shed light on the biological mechanisms of cancer. We consider the problem of modeling spatial correlations among three commonly seen cells observed in tumor pathology images. A novel geostatistical marking model with interpretable underlying parameters is proposed in a Bayesian framework. We use auxiliary variable MCMC algorithms to sample from the posterior distribution with an intractable normalizing constant. We demonstrate how this model-based analysis can lead to sharper inferences than ordinary exploratory analyses, by means of application to three benchmark datasets and a case study on the pathology images of $188$ lung cancer patients. The case study shows that the spatial correlation between tumor and stromal cells predicts patient prognosis. This statistical methodology not only presents a new model for characterizing spatial correlations in a multitype spatial point pattern conditioning on the locations of the points, but also provides a new perspective for understanding the role of cell–cell interactions in cancer progression.




pathology

Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39. However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.

SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.




pathology

Treatment with Mesenchymal-Derived Extracellular Vesicles Reduces Injury-Related Pathology in Pyramidal Neurons of Monkey Perilesional Ventral Premotor Cortex

Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.

SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.




pathology

Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology [RESEARCH]

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.




pathology

[Molecular Pathology] The Formation of Coronary Vessels in Cardiac Development and Disease

Understanding how coronary blood vessels form and regenerate during development and progression of cardiac diseases will shed light on the development of new treatment options targeting coronary artery diseases. Recent studies with the state-of-the-art technologies have identified novel origins of, as well as new, cellular and molecular mechanisms underlying the formation of coronary vessels in the postnatal heart, including collateral artery formation, endocardial-to-endothelial differentiation and mesenchymal-to-endothelial transition. These new mechanisms of coronary vessel formation and regeneration open up new possibilities targeting neovascularization for promoting cardiac repair and regeneration. Here, we highlight some recent studies on cellular mechanisms of coronary vessel formation, and discuss the potential impact and significance of the findings on basic research and clinical application for treating ischemic heart disease.




pathology

[Molecular Pathology] Toward Combined Cell and Gene Therapy for Genodermatoses

To date, more than 200 monogenic, often devastating, skin diseases have been described. Because of unmet medical needs, development of long-lasting and curative therapies has been consistently attempted, with the aim of correcting the underlying molecular defect. In this review, we will specifically address the few combined cell and gene therapy strategies that made it to the clinics. Based on these studies, what can be envisioned for the future is a patient-oriented strategy, built on the specific features of the individual in need. Most likely, a combination of different strategies, approaches, and advanced therapies will be required to reach the finish line at the end of the long and winding road hampering the achievement of definitive treatments for genodermatoses.