Inclusion body myositis and associated diseases: an argument for shared immune pathologies

Inclusion body myositis (IBM) is the most prevalent idiopathic inflammatory myopathy (IIM) affecting older adults. The pathogenic hallmark of IBM is chronic inflammation of skeletal muscle. At present, we do not classify IBM into different sub-entities, with the exception perhaps being the presence or absence of the anti-cN-1A-antibody. In contrast to other IIM, IBM is characterized by a chronic and progressive disease course. Here, we discuss the pathophysiological framework of IBM and highlight the seemingly prototypical situations where IBM occurs in the context of other diseases. In this context, understanding common immune pathways might provide insight into the pathogenesis of IBM. Indeed, IBM is associated with a distinct set of conditions, such as human immunodeficiency virus (HIV) or hepatitis C-two conditions associated with premature immune cell exhaustion. Further, the pathomorphology of IBM is reminiscent of other muscle diseases, notably HIV-associated myositis or granulomatous myositis. Distinct immune pathways are likely to drive these commonalities and senescence of the CD8(+) T cell compartment is discussed as a possible mechanism of pathogenesis. Future effort directed at understanding the co-occurrence of IBM and associated diseases could prove valuable to better understand the enigmatic IBM pathophysiology

Successful plasmapheresis and immunoglobulin treatment for severe lipid storage myopathy: Doing the right thing for the wrong reason

Three consecutive skeletal muscle biopsies during a several months time-frame, showing different degrees of neutral lipid storage. This is highlighted by Oil-red-O stains (D, E, F) and electron microscopy (G, H, I). Note the impact on mitochondrial morphology with so called 'parking lots (K, L). Zooming 'in and out' into the ultrastructure, using the nanotomy platform provides interesting detailled information (http://nanotomy.org). ​

Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology

Systemic sclerosis represents a chronic connective tissue disease featuring fibrosis, vasculopathy and autoimmunity, affecting skin, multiple internal organs, and skeletal muscles. The vasculopathy is considered obliterative, but its pathogenesis is still poorly understood. This may partially be due to limitations of conventional transmission electron microscopy previously being conducted only in single patients. The aim of our study was therefore to precisely characterize immune inflammatory features and capillary morphology of systemic sclerosis patients suffering from muscle weakness. In this study, we identified 18 individuals who underwent muscle biopsy because of muscle weakness and myalgia in a cohort of 367 systemic sclerosis patients. We performed detailed conventional and immunohistochemical analysis and large-scale electron microscopy by digitizing entire sections for in-depth ultrastructural analysis. Muscle biopsies of 12 of these 18 patients (67%) presented minimal features of myositis but clear capillary alteration, which we termed minimal myositis with capillary pathology (MMCP). Our study provides novel findings in systemic sclerosis-associated myositis. First, we identified a characteristic and specific morphological pattern termed MMCP in 67% of the cases, while the other 33% feature alterations characteristic of other overlap syndromes. This is also reflected by a relatively homogeneous clinical picture among MMCP patients. They have milder disease with little muscle weakness and a low prevalence of interstitial lung disease (20%) and diffuse skin involvement (10%) and no cases of either pulmonary arterial hypertension or renal crisis. Second, large-scale electron microscopy, introducing a new level of precision in ultrastructural analysis, revealed a characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation and pericyte proliferation. We provide open-access pan-and-zoom analysis to our datasets, enabling critical discussion and data mining. We clearly highlight characteristic capillary pathology in skeletal muscles of systemic sclerosis patients

Close-to-threshold Meson Production in Hadronic Interactions

Studies of meson production at threshold in the hadron--hadron interaction began in the fifties when sufficient energies of accelerated protons were available. A strong interdependence between developments in accelerator physics, detector performance and theoretical understanding led to a unique vivid field of physics. Early experiments performed with bubble chambers revealed already typical ingredients of threshold studies, which were superseded by more complete meson production investigations at the nucleon beam facilities TRIUMF, LAMPF, PSI, LEAR and SATURNE. Currently, with the advent of the new cooler rings as IUCF, CELSIUS and COSY the field is entering a new domain of precision and the next step of further progress. The analysis of this new data in the short range limit permits a more fundamental consideration and a quantitative comparison of the production processes for different mesons in the few--body final states. The interpretation of the data take advantage of the fact that production reactions close-to-threshold are characterized by only a few degrees of freedom between a well defined combination of initial and exit channels. Deviations from predictions of phase-space controlled one-meson-exchange models are indications of new and exciting physics. Precision data on differential cross sections, isospin and spin observables -- partly but by no means adequately available -- are presently turning up on the horizon. There is work for the next years and excitement of the physics expected. Here we try to give a brief and at the same time comprehensive overview of this field of hadronic threshold production studies.Comment: 100 pages, Review article to be published in Prog. Part. Nucl. Phys. Vol. 49, issue 1 (2002

Effect of Interferon-free HCV-eradication on cognitive function in HCV-monoinfected and HCV/HIV-coinfected patients

Die Zulassung neuer, gezielt wirkender antiviraler Medikamente (direct acting antivirals, DAA) hat die Therapieoptionen bei der chronischen Hepatitis C Infektion deutlich verbessert. Patienten können nun Interferon-frei und damit deutlich nebenwirkungsärmer behandelt werden. Es ist nun auch erstmals möglich, den Effekt der Infektion auf neurologische Symptome wie kognitive Defizite ohne Konfundierung durch die Nebenwirkungen des Interferons zu untersuchen. Hepatitis C-assoziierte kognitive Defizite betreffen auch Patienten, die nicht an einer fortgeschrittenen Lebererkrankung oder einer hepatischen Enzephalopathie leiden. Eine besondere Risikopopulation stellen mit dem Humanen Immundefizienzvirus (HIV) koinfizierte Patienten dar. Von diesen Patienten sind bis zu 60% von HIV-assoziierten kognitiven Defiziten (HAND) betroffen. Auch der Schweregrad der bestehenden Defizite ist bei diesen Patienten höher als bei Patienten mit einer HIV-Monoinfektion. Die Gruppe der HCV-/HIV-koinfizierten Patienten könnte somit besonders von einer HCV-Eradikation profitieren. Durch die Einführung der DAAs ist es erstmals möglich, den Effekt einer HCV-Eradikation auf die kognitive Leistung ohne Beeinflussung durch mögliche Nebenwirkungen der Interferontherapie zu untersuchen. Insgesamt 22 Patienten (8 HCV+, 14 HCV+/HIV+) konnten in diese Pilotstudie eingeschlossen werden. Die Kohorte bestand aus ausgewählten Patienten ohne weitere Komorbiditäten wie Leberfibrose/-zirrhose, Substanzabhängigkeit und zerebrale Vorerkrankungen und ohne Substanzabusus, die in infektiologischen Schwerpunktpraxen rekrutiert wurden. Wir führten eine longitudinale Analyse der Leistung in einer standardisierten neuropsychologischen Testung durch, an der alle Patienten vor Beginn einer Interferon-freien HCV-Therapie und 12 Wochen nach Therapieende teilnahmen. Als sekundäre Endpunkte wurden Ausprägung der Fatigue-Symptomatik, Lebensqualität und Depressivität erfasst. Für die Baseline-Testung standen die Daten einer Kontrollgruppe von 30 HIV-/HCV-negativen Probanden zur Verfügung. Für die Auswahl der neuropsychologischen Testverfahren maßgeblich war die Abbildung der kognitiven Domänen, die gemäß den Frascati-Kriterien bei HIV-Patienten untersucht werden müssen, um die Diagnose HAND stellen zu können ([visuelles] Gedächtnis/Lernen, Aufmerksamkeit, Sprache, Informationsverarbeitung, Feinmotorik, Exekutivfunktionen). Depressivität, Lebensqualität und Fatigue-Symptomatik wurden mittels Fragebögen erfasst. Die kognitive Leistung in der Gruppe der HCV-infizierten Patienten war vor Therapiebeginn signifikant schlechter als die Leistung in der HCV-negativen Kontrollgruppe. Vor Therapiebeginn war bei 54.5% der HCV-positiven Patienten ein kognitives Defizit nachzuweisen. Die Follow-up Analyse zeigte signifikante Verbesserungen in den Domänen visuelles Gedächtnis/Lernen, Exekutivfunktionen, semantische Wortflüssigkeit, Verarbeitungsgeschwindigkeit und Feinmotorik. In den Domänen verbales Lernen, phonematische Wortflüssigkeit und Aufmerksamkeit/Arbeitsgedächtnis zeigten sich keine Veränderungen. Die Fatigue-Symptomatik und Lebensqualität verbesserten sich signifikant. Die Studienergebnisse stützen die Hypothese, dass eine HCV-Eradikation durch Interferon-freie Therapien zu einer Verbesserung bestehender kognitiver Defizite führt. Folgestudien müssen zeigen, ob kognitive Defizite bei HCV-infizierten Patienten möglicherweise eine neue Therapieindikation darstellen.Approval of direct-acting antivirals (DAA) against the hepatitis C virus (HCV) has dramatically changed the management of HCV infection due to high cure rates and a favorable safety profile. Their influence on neurologic aspects is notably relevant, as studies demonstrated active HCV replication within the CNS and alterations in cerebral metabolism consistent with neuroinflammatory conditions. These findings may be causative for cognitive deficits in HCV-infected patients. Similar impairment has been demonstrated in patients coinfected with HIV, with a prevalence as high as 60%. Therefore, these patients may particularly benefit from HCV eradication. To date, studies addressing the issue of reversibility of cognitive deficits after HCV therapy are based on Interferon treatment, which itself can cause persisting cognitive impairment. With the approval of DAAs, an Interferon-free HCV therapy has become available. Whether HCV-associated cognitive deficits are indeed reversible after HCV eradication remains unsolved to date. To tackle this issue for the first time, we conducted a pilot study to perform a longitudinal analysis of cognitive performance of 22 patients (8 HCV+, 14 HCV+/HIV+) who completed neuropsychological testing before starting and at week 12 after an Interferon-free therapy for chronic HCV infection. Test selection was based on international recommendations for the evaluation of cognitive deficits in patients with HIV-associated neurocognitive disorder (HAND). Tests covered the domains verbal learning, visual learning/memory, attention/working memory, executive function, processing speed and motor function. Depression, fatigue and mental health were assessed as patient reported outcomes. At baseline, 54.5% of the patients met the criteria for cognitive impairment. Follow-up analysis revealed significant improvements in the domains visual memory/learning, executive functions, semantic verbal fluency, processing speed and motor skills but not in verbal learning, phonemic verbal fluency and attention/working memory. Fatigue and mental health significantly improved at follow-up. These findings indicate that successful DAA treatment leads to cognitive improvements in several domains measured by standard neuropsychological testing. In summary, DAA treatment seems to have a positive effect on some cognitive domains and leads to mental health and fatigue improvement in HCV-infected patients. Further studies are needed to clarify whether cognitive impairment may represent a new treatment indication for HCV therapy

Neurologische Komplikationen der Hepatitis-C-Infektion

Chronic hepatitis C virus (HCV) infection is a highly prevalent systemic disease, which can cause a variety of neurological complications. The HCV-associated symptoms can be differentiated into central and peripheral nervous systems as well as the musculature. Important pathomechanisms are HCV-associated autoimmunity (e.g. mixed cryoglobulinemia with polyneuropathy) and direct neurotoxic effects of the virus (e.g. HCV-associated cognitive deficits). Distal symmetric polyneuropathies, small fiber neuropathies and cognitive deficits are the most prevalent neurological manifestations. Furthermore, HCV infection is a risk factor for ischemic and hemorrhagic stroke as well as Parkinson's disease. As HCV infection has become a permanently curable disease in >90% of patients, early identification and antiviral treatment of HCV positive patients is of utmost importance

Beyond vacuolar pathology: Multiomic profiling of Danon disease reveals dysfunctional mitochondrial homeostasis.

Funder: Ministerium für Kultur und Wissenschaft des Landes Nordrhein‐Westfalen; doi: http://dx.doi.org/10.13039/501100014690Funder: Regierenden Bürgermeister von Berlin ‐ Senatskanzlei Wissenschaft und ForschungFunder: European Regional Development Fund; doi: http://dx.doi.org/10.13039/50110000853

Neurological complications of hepatitis C infections

Chronic hepatitis C virus (HCV) infection is a highly prevalent systemic disease, which can cause a variety of neurological complications. The HCV-associated symptoms can be differentiated into central and peripheral nervous systems as well as the musculature. Important pathomechanisms are HCV-associated autoimmunity (e.g. mixed cryoglobulinemia with polyneuropathy) and direct neurotoxic effects of the virus (e.g. HCV-associated cognitive deficits). Distal symmetric polyneuropathies, small fiber neuropathies and cognitive deficits are the most prevalent neurological manifestations. Furthermore, HCV infection is a risk factor for ischemic and hemorrhagic stroke as well as Parkinson's disease. As HCV infection has become a permanently curable disease in >90% of patients, early identification and antiviral treatment of HCV positive patients is of utmost importance.Die chronische Hepatitis-C-Virus(HCV)-Infektion ist eine hochprävalente Systemerkrankung, die verschiedene neurologische Komplikationen verursachen kann. Es lassen sich HCV-assoziierte Symptome im zentralen und peripheren Nervensystem sowie der Muskulatur unterscheiden. Wichtige Pathomechanismen sind die HCV-assoziierte Autoimmunität (z. B. gemischte Kryoglobulinämie mit Polyneuropathie) und direkte Neurotoxizität (z. B. bei HCV-assoziierten kognitiven Defiziten). Die häufigsten neurologischen Komplikationen sind distal-symmetrische Polyneuropathien, Small-fiber-Neuropathien und kognitive Defizite. Die HCV-Infektion stellt außerdem einen Risikofaktor für ischämische und hämorrhagische Schlaganfälle sowie den Morbus Parkinson dar. Die frühe Identifikation und antivirale Behandlung HCV-positiver Patienten steht im Zentrum der Behandlung. Durch neue antivirale Therapien können >90 % der Patienten dauerhaft von der HCV-Infektion geheilt werden

Systemic sclerosis-associated myositis features minimal inflammation and characteristic capillary pathology

Systemic sclerosis represents a chronic connective tissue disease featuring fibrosis, vasculopathy and autoimmunity, affecting skin, multiple internal organs, and skeletal muscles. The vasculopathy is considered obliterative, but its pathogenesis is still poorly understood. This may partially be due to limitations of conventional transmission electron microscopy previously being conducted only in single patients. The aim of our study was therefore to precisely characterize immune inflammatory features and capillary morphology of systemic sclerosis patients suffering from muscle weakness. In this study, we identified 18 individuals who underwent muscle biopsy because of muscle weakness and myalgia in a cohort of 367 systemic sclerosis patients. We performed detailed conventional and immunohistochemical analysis and large-scale electron microscopy by digitizing entire sections for in-depth ultrastructural analysis. Muscle biopsies of 12 of these 18 patients (67%) presented minimal features of myositis but clear capillary alteration, which we termed minimal myositis with capillary pathology (MMCP). Our study provides novel findings in systemic sclerosis-associated myositis. First, we identified a characteristic and specific morphological pattern termed MMCP in 67% of the cases, while the other 33% feature alterations characteristic of other overlap syndromes. This is also reflected by a relatively homogeneous clinical picture among MMCP patients. They have milder disease with little muscle weakness and a low prevalence of interstitial lung disease (20%) and diffuse skin involvement (10%) and no cases of either pulmonary arterial hypertension or renal crisis. Second, large-scale electron microscopy, introducing a new level of precision in ultrastructural analysis, revealed a characteristic capillary morphology with basement membrane thickening and reduplications, endothelial activation and pericyte proliferation. We provide open-access pan-and-zoom analysis to our datasets, enabling critical discussion and data mining. We clearly highlight characteristic capillary pathology in skeletal muscles of systemic sclerosis patients