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Objectives Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease. Methods Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data. Results Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients. Conclusions Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases.

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry. All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed. All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia. Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Microvascular Changes in the Brain in Covid-19 High-resolution MRI and histopathological study of the brains of patients who had died from Covid-19 showed punctate hyperintensities and punctate or ...

Polymerization of deoxygenated sickle hemoglobin (HbS) leads to erythrocyte sickling. Enhancing activity of the erythrocyte glycolytic pathway has anti-sickling potential as this reduces 2,3-diphosphoglycerate (2,3-DPG) and increases ATP, factors that decrease HbS polymerization and improve erythrocyte membrane integrity. These factors can be modulated by mitapivat, which activates erythrocyte pyruvate kinase (PKR) and improves sickling kinetics in SCD patients. We investigated mechanisms by which mitapivat may impact SCD by examining its effects in the Townes SCD mouse model. Control (HbAA) and sickle (HbSS) mice were treated with mitapivat or vehicle. Surprisingly, HbSS had higher PKR protein, higher ATP, and lower 2,3-DPG levels, compared to HbAA mice, in contrast with humans with SCD, in whom 2,3-DPG is elevated compared to healthy subjects. Despite our inability to investigate 2,3-DPG-mediated sickling and hemoglobin effects, mitapivat yielded potential benefits in HbSS mice. Mitapivat further increased ATP without significantly changing 2,3-DPG or hemoglobin levels, and decreased levels of leukocytosis, erythrocyte oxidative stress, and the percentage of erythrocytes that retained mitochondria in HbSS mice. These data suggest that, even though Townes HbSS mice have increased PKR activity, further activation of PKR with mitapivat yields potentially beneficial effects that are independent of changes in sickling or hemoglobin levels.

The current project is to explore feasibility of direct intra-renal injection of human bone marrow derived mesenchymal stem cells (hMSC) for treatment of lupus nephritis in mice. The treatment protocol involved aged male BXSB (20 weeks) injected with 1 × 106 hMSC unilaterally under the renal capsule. Mice were harvested after 10 weeks follow-up for postmortem exam. Controls included untreated age matched male BXSB and healthy C57Bl/6. At the end of follow-up period, the survival of treated BXSB was 10 folds higher at 62.5% compared to survival of untreated control at 6.3%. The survival of C57Bl/6 remained at 100% with or without similar treatment. The renal pathology review was most significant for decreased tissue inflammation in treated BXSB compared to untreated controls. Renal tissue expression of IL-1b, IL17 were decreased and CTLA-4 was increased by RT PCR among treated compared to untreated BXSB. Thus, direct delivery of hMSC by intrarenal injection is a promising route for treatment of lupus nephritis as shown in this xenogeneic model. Further studies -using expanded numbers of mice to include other lupus strains- are warranted to investigate the mechanisms involved and to optimize treatment protocol for safety and efficacy.

Background: Pleomorphic xanthoastrocytomas (PXAs) are uncommon intradural and typically intramedullary astrocytic central nervous system tumors. Although they commonly occur supratentorially, they are rarely seen in the spine. Case Description: A 43-year-old male presented with cervical neck pain and right-sided radicular symptoms. He was found to have an intradural extramedullary mass at the C5–C6 level. The lesion was fully excised and proved to be a PXA. Of interest, the lesion did not recur on postoperative MR imaging studies obtained 7 months later. Conclusion: While rare, primary intradural extramedullary spinal PXA has been reported. Here, we review such a lesion occurring in a 43-year-old male who did well following gross total excision of the tumor.

Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases. We present clinical and genetic study results from seven adult male subjects with recurrent exertional rhabdomyolysis. In all subject, whole exome sequencing identified multiple heterozygous variants in genes associated with monogenic metabolic and/or mitochondrial disorders. These variants consisted of known pathogenic and/or new likely pathogenic variants in combination with other rare deleterious alleles. The presence of heterozygous pathogenic and rare deleterious variants in multiple genes suggests an oligogenic inheritance for exertional rhabdomyolysis etiology. Our data imply that exertional rhabdomyolysis can reflect cumulative effects or synergistic interactions of deleterious variants in multiple genes that are likely to compromise muscle metabolism under the stress of exercise. Keywords: Exertional rhabdomyolysis, Metabolic disorders, Mitochondrial diseases, Multiple genetic variants, Synergistic heterozygosity, Oligogenic inheritance

Objective Autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult myositis patients. The aim of this study was to characterize the features of juvenile anti-HMGCR-positive myositis patients. Methods The sera of 440 juvenile myositis patients were screened for anti-HMGCR autoantibodies. Demographic and clinical features, responses to therapy, and HLA alleles were assessed. The features of anti-HMGCR-positive patients were compared to those of previously described adult patients with this autoantibody and to children with other myositis-specific autoantibodies (MSAs). Results Five of 440 patients (1.1%) were anti-HMGCR-positive; none had taken statin medications. Three patients had rashes characteristic of juvenile dermatomyositis and 2 patients had immune-mediated necrotizing myopathies. The median highest creatine kinase (CK) level of anti-HMGCR-positive subjects was 17,000 IU/liter. All patients had severe proximal muscle weakness, distal weakness, muscle atrophy, joint contractures, and arthralgias, which were all more prevalent in HMGCR-positive subjects compared to MSA-negative patients or those with other MSAs. Anti-HMGCR-positive patients had only partial responses to multiple immunosuppressive medications, and their disease often took a chronic course. The DRB1*07:01 allele was present in all 5 patients, compared to 26.25% of healthy controls (corrected P = 0.01); none of the 5 juvenile patients had DRB1*11:01. Conclusion Compared to children with other MSAs, muscle disease appears to be more severe in those with anti-HMGCR autoantibodies. Like adults, children with anti-HMGCR autoantibodies have severe weakness and high CK levels. In contrast to adults, in anti-HMGCR-positive children, there is a strong association with HLA–DRB1*07:01.

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

White matter diseases include a wide spectrum of disorders that have in common impairment of normal myelination, either by secondary destruction of previously myelinated structures (demyelinating processes) or by primary abnormalities of myelin formation (dysmyelinating processes). The pathogenesis of many white matter diseases remains poorly understood. Demyelinating disorders are the object of this review and will be further divided into autoimmune, infectious, vascular, and toxic-metabolic processes. Autoimmune processes include multiple sclerosis and related diseases: tumefactive demyelinating lesions, Balo concentric sclerosis, Marburg and Schilder variants, neuromyelitis optica (Devic disease), acute disseminated encephalomyelitis, and acute hemorrhagic leukoencephalopathy (Hurst disease). Infectious processes include Lyme disease (neuroborreliosis), progressive multifocal leukoencephalopathy, and human immunodeficiency virus (HIV) encephalopathy. Vascular processes include different types of small-vessel disease: arteriolosclerosis, cerebral amyloid angiopathy, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), primary angiitis of the central nervous system, Susac syndrome, and neurolupus. Toxic-metabolic processes include osmotic myelinolysis, methotrexate leukoencephalopathy, and posterior reversible encephalopathy syndrome. The imaging spectrum can vary widely from small multifocal white matter lesions to confluent or extensive white matter involvement. Understanding the pathologic substrate is fundamental for understanding the radiologic manifestations, and a systematic approach to the radiologic findings, in correlation with clinical and laboratory data, is crucial for narrowing the differential diagnosis. (©)RSNA, 2016.

Summary Background No evidence-based guidelines are available for the definitive diagnosis or directed treatment of most blast-associated traumatic brain injuries, partly because the underlying pathology is unknown. Moreover, few neuropathological studies have addressed whether blast exposure produces unique lesions in the human brain, and if those lesions are comparable with impact-induced traumatic brain injury. We aimed to test the hypothesis that blast exposure produces unique patterns of damage, differing from that associated with impact-induced, non-blast traumatic brain injuries. Methods In this post-mortem case series, we investigated several features of traumatic brain injuries, using clinical histopathology techniques and markers, in brain specimens from male military service members with chronic blast exposures and from those who had died shortly after severe blast exposures. We then compared these results with those from brain specimens from male civilian (ie, non-military) cases with no history of blast exposure, including cases with and without chronic impact traumatic brain injuries and cases with chronic exposure to opiates, and analysed the limited associated clinical histories of all cases. Brain specimens had been archived in tissue banks in the USA. Findings We analysed brain specimens from five cases with chronic blast exposure, three cases with acute blast exposure, five cases with chronic impact traumatic brain injury, five cases with exposure to opiates, and three control cases with no known neurological disorders. All five cases with chronic blast exposure showed prominent astroglial scarring that involved the subpial glial plate, penetrating cortical blood vessels, grey–white matter junctions, and structures lining the ventricles; all cases of acute blast exposure showed early astroglial scarring in the same brain regions. All cases of chronic blast exposure had an antemortem diagnosis of post traumatic stress disorder. The civilian cases, with or without history of impact traumatic brain injury or a history of opiate use, did not have any astroglial scarring in the brain regions analysed. Interpretation The blast exposure cases showed a distinct and previously undescribed pattern of interface astroglial scarring at boundaries between brain parenchyma and fluids, and at junctions between grey and white matter. This distinctive pattern of scarring may indicate specific areas of damage from blast exposure consistent with the general principles of blast biophysics, and further, could account for aspects of the neuropsychiatric clinical sequelae reported. The generalisability of these findings needs to be explored in future studies, as the number of cases, clinical data, and tissue availability were limited. Funding Defense Health Program of the United States Department of Defense.

Strokes are feared complications of sickle cell disease (SCD) and yield significant neurologic and neurocognitive deficits. However, even without detectable strokes, SCD patients have significant neurocognitive deficits in domains of learning and memory, processing speed and executive function. In these cases, mechanisms unrelated to major cerebrovascular abnormalities likely underlie these deficits. While oxidative stress and stress-related signaling pathways play a role in SCD pathophysiology, their role in cerebral injury remains unknown. We have shown that Townes and BERKs SCD mice, while not having strokes, recapitulate neurocognitive deficits reported in humans. We hypothesized that cognitive deficits in SCD mice are associated with cerebral oxidative stress. We showed that SCD mice have increased levels of reactive oxygen species, protein carbonylation, and lipid peroxidation in hippocampus and cortex, thus suggesting increased cerebral oxidative stress. Further, cerebral oxidative stress was associated with caspase-3 activity alterations and vascular endothelial abnormalities, white matter changes, and disruption of the blood brain barrier, similar to those reported after ischemic/oxidative injury. Additionally, after repeated hypoxia/reoxygenation exposure, homozygous Townes had enhanced microglia activation. Our findings indicate that oxidative stress and stress-induced tissue damage is increased in susceptible brain regions, which may, in turn, contribute to neurocognitive deficits in SCD mice.

Patients with sickle cell disease (SCD) can develop strokes and as a result, present neurologic and neurocognitive deficits. However, recent studies show that even without detectable cerebral parenchymal abnormalities on imaging studies, SCD patients can have significant cognitive and motor dysfunction, which can present as early as during infancy. As the cerebellum plays a pivotal role in motor and non-motor functions including sensorimotor processing and learning, we examined cerebellar behavior in humanized SCD mice using the Erasmus ladder. Homozygous (sickling) mice had significant locomotor malperformance characterized by miscoordination and impaired locomotor gait/stepping pattern adaptability. Conversely, Townes homozygous mice had no overall deficits in motor learning, as they were able to associate a conditioning stimulus (high-pitch warning tone) with the presentation of an obstacle and learned to decrease steptimes thereby increasing speed to avoid it. While these animals had no cerebellar strokes, these locomotor and adaptive gait/stepping patterns deficits were associated with oxidative stress, as well as cerebellar vascular endothelial and white matter abnormalities and blood brain barrier disruption, suggestive of ischemic injury. Taken together, these observations suggest that motor and adaptive locomotor deficits in SCD mice mirror some of those described in SCD patients and that ischemic changes in white matter and vascular endothelium and oxidative stress are biologic correlates of those deficits. These findings point to the cerebellum as an area of the central nervous system that is vulnerable to vascular and white matter injury and support the use of SCD mice for studies of the underlying mechanisms of cerebellar dysfunction in SCD.

BACKGROUND: Optimizing nerve regeneration and mitigating muscle atrophy are the keys to successful outcomes in peripheral nerve damage. We investigated whether mesenchymal stem cell (MSC) therapy can improve limb function recovery in peripheral nerve damage. MATERIALS AND METHODS: We used sciatic nerve transection/repair (SNR) and individual nerve transection/repair (INR; branches of sciatic nerve - tibial, peroneal, sural) models to study the effect of MSCs on proximal and distal peripheral nerve damages, respectively, in male Lewis rats. Syngeneic MSCs (5 × 10(6); passage≤6) or saline were administered locally and intravenously. Sensory/motor functions (SF/MF) of the limb were assessed. RESULTS: Rat MSCs (>90%) were CD29(+), CD90(+), CD34(−), CD31(−) and multipotent. Total SF at two weeks post-SNR & INR with or without MSC therapy was ∼1.2 on a 0–3 grading scale (0 = No function; 3 = Normal); by 12 weeks it was 2.6–2.8 in all groups (n ≥ 9/group). MSCs accelerated SF onset. At eight weeks post-INR, sciatic function index (SFI), a measure of MF (0 = Normal; −100 = Nonfunctional) was −34 and −77 in MSC and vehicle groups, respectively (n ≥ 9); post-SNR it was −72 and −92 in MSC and vehicle groups, respectively. Long-term MF (24 weeks) was apparent in MSC treated INR (SFI -63) but not in SNR (SFI -100). Gastrocnemius muscle atrophy was significantly reduced (P 0.05) in MSC treated INR compared to the naive contralateral nerve. CONCLUSION: MSC therapy in peripheral nerve damage appears to improve nerve regeneration, mitigate flexion-contractures, and promote limb functional recovery.

We report a case of a 15-year-old boy who presented with an intraventricular angiomatoid fibrous histiocytoma. The patient suffered a concussion during a wrestling match and underwent a head and spine CT, which prompted an MRI. MRI revealed an enhancing 2.3-cm mass in the posterior horn of the right lateral ventricle with no hydrocephalus. The patient subsequently admitted to having had headaches with associated appetite suppression but no visual problems or weakness. The tumor was resected. It was composed of sheets and cords of histiocytoid cells with focal pleomorphism. Interspersed throughout was a robust lymphoplasmacytic infiltration with Russell bodies and lymphoid follicles. The histiocytoid neoplastic cells were desmin, EMA, and sparsely S100 protein positive. They were negative for CD31, CD34, Cam 5.2, CD163, CD1a, HMB45, Melan-A, progesterone, and ERG. The abundant plasma cell population was confirmed by CD138 reactivity and was polyclonal by kappa and lambda immunohistochemistry. Fluorescence in situ hybridization revealed an EWSR gene rearrangement. The patient was radiographically free of disease 3 years after surgery with headaches as residual sequela. The differential diagnosis for this case included a lymphoplasmacyte-rich meningioma or a plasmacytoma. The EWSR rearrangement made both of these unlikely. The polyclonal nature of the plasma cell component and the age of the patient also argued against plasmacytoma. A literature search revealed one other ventricular-based angiomatoid fibrous histiocytoma in a pediatric patient.

Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by various other acquired and inherited factors. We report an SCT positive service member with an exertional rhabdomyolysis event, recurrent hematuria with transient proteinuria, and episodic burning pain in the lower extremities. Clinical and genetic studies revealed the multifactorial nature of his complex phenotype. The service member was taking prescription medications known to be associated with exertional rhabdomyolysis. He carried a pathogenic mutation,NPHS2p.V260E, reported in nephropathy and a new variant p.R838Q inSCN11A, a gene involved in familial episodic pain syndrome. Results suggest that drug-to-drug interactions coupled with the stress of exercise, coinheritance of HbAS andNPHS2p.V260E, and p. R838Q inSCN11Acontributed to exertional rhabdomyolysis, recurrent hematuria with proteinuria, and episodic pain, respectively. This case underscores the importance of comprehensive clinical and genetic evaluations to identify underlying causes of health complications reported in SCT individuals.

The potential relationship between chronic traumatic encephalopathy (CTE) and head injuries such as blast-related traumatic brain injury (TBI) is an important area of study, particularly for military and contact sports populations, yet little is known about this relationship. To address this topic, the Department of Defense (DoD) Blast Injury Research Program Coordinating Office organized the 2015 International State-of-The-Science Meeting, which brought together subject matter experts from the DoD, other federal agencies, academia, industry, foreign allies, and the sports community. Over the course of the meeting, this community of experts reached a consensus regarding the current body of knowledge and the future of the field. The overarching finding was that there is insufficient existing scientific evidence to link blast-related TBI with CTE. The meeting's Expert Panel also agreed on 13 additional findings describing research and knowledge gaps, clinical gaps, and research opportunities that, if addressed with focused effort, would further the understanding of the relationship between blast-related TBI and CTE. To this end, the Expert Panel also developed six recommendations for advancing research, each with short-and long-Term goals. Among the six recommendations, the Expert Panel identified the first four as highest priority for addressing pressing research needs. These four high-priority recommendations include, in order of priority: (1) more collection and study of clinical neuropathology samples, (2) standardization of clinical diagnostic criteria, (3) development of clinically appropriate and standardized animal models, and (4) development of noninvasive serial assessment strategies (i.e., imaging or biospecimen biomarkers). © Copyright 2017, Mary Ann Liebert, Inc. 2017.

Introduction Optimizing nerve regeneration and mitigating denervation atrophy of target muscles are the keys to achieving successful VCA such as limb and face transplants. Methods Lewis rat was anesthetized, sciatic or individual sciatic nerve branches (tibial, peroneal and sural) of the right hind-limb were transected and surgically repaired. MSC (5 million; passage ≤6) or vehicle were administered locally and intravenously. Results Rat MSCs expanded ex vivo were CD29+, CD90+, CD34−, CD31−, CD45low, MHC Class I+, Class II−, and were pluripotent. Total sensory function recovery at 2 weeks post sciatic or individual nerve repair (SNR or INR) with or without MSC was ~ 1.2 on a scale of Grade 0–3 (0=No function; 3=Normal); by 12 weeks it was 2.6–2.8 (n≥6/group). Peroneal sensory function recovery was as early as 1 week but not tibial or sural. MSC treatment accelerated sensory function onset. At 8 weeks post-INR, the sciatic nerve function index (SFI), a measure of motor function (0=Normal; −100=Nonfunctional) was −34 and −77 in MSC and vehicle groups, respectively (n≥9); with SNR it was −72 and −92 in MSC and vehicle groups, respectively. Long-term motor function (24 weeks) was apparent in MSC treated INR (SFI −63) but not in SNR (SFI −100) model. Gastrocnemius muscle atrophy was lower (P ≤0.05) in INR compared to SNR model. Significant reduction in axonal area (P ≤0.002), g ratio/axonal myelination (P ≤0.05), reduced nerve fiber density, and increased degenerating axons in the distal segment of the transected/repaired tibial nerve was observed compared to the contralateral naive tibial nerve. Histology and molecular studies are ongoing. Conclusion MSC therapy appears to promote peripheral nerve regeneration and functional recovery.