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Aims: Diagnosis of idiopathic inflammatory myopathies (IIM) is based on morphological characteristics and the evaluation of disease‐related proteins. However, although broadly applied, substantial bias is imposed by the respective methods, observers and individual staining approaches. We aimed to quantify the protein levels of major histocompatibility complex (MHC)‐1, (MHC)‐2 and intercellular adhesion molecule (ICAM)‐1 using an automated morphometric method to mitigate bias. Methods: Double immunofluorescence staining was performed on whole muscle sections to study differences in protein expression in myofibre and endomysial vessels. We analysed all IIM subtypes including dermatomyositis (DM), anti‐synthetase syndrome (ASyS), inclusion body myositis (IBM), immune‐mediated‐necrotising myopathy (IMNM), dysferlinopathy (DYSF), SARS‐CoV‐2 infection and vaccination‐associated myopathy. Biopsies with neurogenic atrophy (NA) and normal morphology served as controls. Bulk RNA‐Sequencing (RNA‐Seq) was performed on a subset of samples. Results: Our study highlights the significance of MHC‐1, MHC‐2 and ICAM‐1 in diagnosing IIM subtypes and reveals distinct immunological profiles. RNASeq confirmed the precision of our method and identified specific gene pathways in the disease subtypes. Notably, ASyS, DM and SARS‐CoV‐2‐associated myopathy showed increased ICAM‐1 expression in the endomysial capillaries, indicating ICAM‐1‐associated vascular activation in these conditions. In addition, ICAM‐1 showed high discrimination between different subgroups with high sensitivity and specificity. Conclusions: Automated morphometric analysis provides precise quantitative data on immune‐associated proteins that can be integrated into our pathophysiological understanding of IIM. Further, ICAM‐1 holds diagnostic value for the detection of IIM pathology. [ABSTRACT FROM AUTHOR]

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease‐associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype‐specific morphological features. Here, we aimed at enhancing the understanding of these subtype‐specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot–Marie‐Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non‐myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle. [ABSTRACT FROM AUTHOR]

We report the first case of primary non-Hodgkin lymphoma of the central nervous system in a 69-year-old patient with chronic inflammatory demyelinating polyneuropathy (CIDP) on long-termimmunosuppression. CIDPwas diagnosed 4 years earlier and treated with plasma exchange, corticosteroids, azathioprine andmycophenolate mofetil. The patient developed an organic brain syndrome and cerebralMRIrevealed multiple enhancingT1 lesions in the periventricular parenchyma. A stereotactic biopsy was not diagnostic, but Epstein-Barr virus (EBV) was detected in the cerebrospinal fluid. After a fulminant course of an illness resembling an encephalitis the patient died. Postmortem analysis confirmed the diagnosis of EBVassociated diffuse large B cell lymphoma. This case illustrates the risks of life-threatening infections associated with continuous immunosuppression, and emphasizes the need for an extensive diagnostic work-up in patients who present with signs and symptoms of an unexpected encephalopathy. [ABSTRACT FROM AUTHOR]

Glutamate-mediated neurodysfunction in human immunodeficiency virus (HIV) infection has been primarily suggested by in vitro studies. The regulation of glutamatergic neurotransmission in inflammation is a complex interaction between activation of immune mediators and adaptive changes in the functional elements of the glutamatergic synapse. We have used simian immunodeficiency virus (SIV)-infected macaques to answer the questions (i) whether perturbation of glutamate neurotransmission is evident during progression of immunodeficiency disease and (ii) what are the mechanisms underlying this impairment. Disease progression in SIV-infected macaques both in the periphery and in the brain was documented by clinical and general pathological examination, plasma and brain viral RNA load, T-cell analysis and brain histopathology. We report for the first time, disruption of excitatory amino acid transporters (EAATs), the cardinal glutamate clearing system, during SIV infection and a dramatic loss of EAATs associated with development of rapid acquired immunodeficiency syndrome (AIDS). EAATs impairment was correlated with activation status of microglia. Our data support the glutamate hypothesis for the development of HIV dementia and suggest that the pathogenetic mechanism for the neurodysfunction is the impairment of glutamate clearing which occurs in the stage of AIDS and which is associated with activated microglia. [ABSTRACT FROM AUTHOR]

The article discusses a study on the frequency of structural changes in the vastus medialis muscle in patients with osteoarthritis (OA) of the knee. The research also assessed morphological changes in relation to clinical features that might have contributed to muscle injury. Atrophy of type 1 fibers was noted in 32 percent of patients included in the study. It cites the cofactors in the development of OA, such as neurogenic muscular atrophy and muscle fiber degeneration.

Movement disorders are a common neurological complication of immunodeficiency virus infection and are thought to result from dopaminergic dysfunction in the basal ganglia. We measured levels of dopamine, and its metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid, in the putamen of healthy and simian immunodeficiency virus (SIV)-infected rhesus monkeys from infection until the development of AIDS. Changes in expression levels of cAMP response element binding protein (CREB), a transcription factor involved in the signalling pathway of dopamine, were also examined. Furthermore, we isolated microglia from the same animals and investigated their activation status in order to explore whether neurochemical findings are associated with immune activation. Plasma and CSF viral RNA load, T-cell analysis and basal ganglia histopathology provided information about disease progression in the animals. Putamen dopamine content was significantly reduced within 3 months of SIV infection, due to decreased dopamine synthesis initially, followed by loss of tyrosine hydroxylase-positive cells in substantia nigra, and accompanied by a decrease in total CREB expression. Pharmacological manipulation of dopaminergic tone with l-DOPA and selegiline showed that the reduction in CREB expression was due to reduced levels of dopamine. These neurochemical changes were significantly correlated with microglia activation in the absence of gross histopathological lesions. Our data demonstrate that putamen dopaminergic function is impaired during SIV infection and indicate that microglia may trigger endogenous mechanisms involved in the dysfunction of dopaminergic systems. [ABSTRACT FROM AUTHOR]