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1.
Cell Mol Life Sci ; 81(1): 224, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38769196

RESUMEN

Synaptic loss is an early event in the penumbra area after an ischemic stroke. Promoting synaptic preservation in this area would likely improve functional neurological recovery. We aimed to detect proteins involved in endogenous protection mechanisms of synapses in the penumbra after stroke and to analyse potential beneficial effects of these candidates for a prospective stroke treatment. For this, we performed Liquid Chromatography coupled to Mass Spectrometry (LC-MS)-based proteomics of synaptosomes isolated from the ipsilateral hemispheres of mice subjected to experimental stroke at different time points (24 h, 4 and 7 days) and compared them to sham-operated mice. Proteomic analyses indicated that, among the differentially expressed proteins between the two groups, cystatin C (CysC) was significantly increased at 24 h and 4 days following stroke, before returning to steady-state levels at 7 days, thus indicating a potential transient and intrinsic rescue mechanism attempt of neurons. When CysC was applied to primary neuronal cultures subjected to an in vitro model of ischemic damage, this treatment significantly improved the preservation of synaptic structures. Notably, similar effects were observed when CysC was loaded into brain-derived extracellular vesicles (BDEVs). Finally, when CysC contained in BDEVs was administered intracerebroventricularly to stroked mice, it significantly increased the expression of synaptic markers such as SNAP25, Homer-1, and NCAM in the penumbra area compared to the group supplied with empty BDEVs. Thus, we show that CysC-loaded BDEVs promote synaptic protection after ischemic damage in vitro and in vivo, opening the possibility of a therapeutic use in stroke patients.


Asunto(s)
Isquemia Encefálica , Encéfalo , Cistatina C , Vesículas Extracelulares , Ratones Endogámicos C57BL , Sinapsis , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Cistatina C/metabolismo , Sinapsis/metabolismo , Ratones , Masculino , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Encéfalo/metabolismo , Encéfalo/patología , Proteómica/métodos , Sinaptosomas/metabolismo , Neuronas/metabolismo , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/terapia , Células Cultivadas , Modelos Animales de Enfermedad
2.
Acta Neuropathol ; 148(1): 2, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38980441

RESUMEN

Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.


Asunto(s)
Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide , Enfermedades Neurodegenerativas , Humanos , Proteína ADAM10/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Proteínas Priónicas/metabolismo , Proteínas de la Membrana/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Anticuerpos
3.
Arch Toxicol ; 97(6): 1577-1598, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37022444

RESUMEN

Uranium and thorium are heavy metals, and all of their isotopes are radioactive, so it is impossible to study chemical effects entirely independent of the radiation effects. In the present study, we tried to compare the chemo- and radiotoxicity of both metals, taking into account deterministic radiation damages reflected by acute radiation sickness and stochastic radiation damages leading to long-term health impairments (e.g., tumor induction). We made at first a literature search on acute median lethal doses that may be expected to be caused by chemical effects, as even acute radiation sickness as a manifestation of acute radiotoxicity occurs with latency. By simulations based on the biokinetic models of the International Commission on Radiological Protection and using the Integrated Modules for Bioassay Analysis software, we determined the amounts of uranium at different enrichment grades and thorium-232 leading to a short-term red bone marrow equivalent dose of 3.5 Sv considered to cause 50% lethality in humans. Different intake pathways for incorporation were considered, and values were compared to the mean lethal doses by chemotoxicity. To assess stochastic radiotoxicity, we calculated the uranium and thorium amounts leading to a committed effective dose of 200 mSv that is often considered critical. Mean lethal values for uranium and thorium are in the same order of magnitude so that the data do not give evidence for substantial differences in acute chemical toxicity. When comparing radiotoxicity, the reference units (activity in Bq or weight in g) must always be taken into account. The mean lethal equivalent dose to the red bone marrow of 3.5 Sv is reached by lower activities of thorium compared to uranium in soluble compounds. However, for uranium as well as thorium-232, acute radiation sickness is expected only after incorporation of amounts exceeding the mean lethal doses by chemotoxicity. Thus, acute radiation sickness is not a relevant clinical issue for either metal. Concerning stochastic radiation damages, thorium-232 is more radiotoxic than uranium if incorporating the same activities. Using weight units for comparison show that for soluble compounds, thorium-232 is more radiotoxic than low-enriched uranium in the case of ingestion but even more toxic than high-enriched uranium after inhalation or intravenous administration. For insoluble compounds, the situation differs as the stochastic radiotoxicity of thorium-232 ranges between depleted and natural uranium. For acute effects, the chemotoxicity of uranium, even at high enrichment grades, as well as thorium-232 exceeds deterministic radiotoxicity. Simulations show that thorium-232 is more radiotoxic than uranium expressed in activity units. If the comparison is based on weight units, the rankings depend on the uranium enrichment grades and the route of intake.


Asunto(s)
Traumatismos por Radiación , Uranio , Humanos , Torio/toxicidad , Torio/análisis , Uranio/toxicidad , Uranio/análisis , Relación Dosis-Respuesta en la Radiación
4.
Arch Toxicol ; 96(11): 2947-2965, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35922584

RESUMEN

In the case of nuclear incidents, radioiodine may be released. After incorporation, it accumulates in the thyroid and enhances the risk of thyroidal dysfunctions and cancer occurrence by internal irradiation. Pregnant women and children are particularly vulnerable. Therefore, thyroidal protection by administering a large dose of stable (non-radioactive) iodine, blocking radioiodide uptake into the gland, is essential in these subpopulations. However, a quantitative estimation of the protection conferred to the maternal and fetal thyroids in the different stages of pregnancy is difficult. We departed from an established biokinetic model for radioiodine in pregnancy using first-order kinetics. As the uptake of iodide into the thyroid and several other tissues is mediated by a saturable active transport, we integrated an uptake mechanism described by a Michaelis-Menten kinetic. This permits simulating the competition between stable and radioactive iodide at the membrane carrier site, one of the protective mechanisms. The Wollf-Chaikoff effect, as the other protective mechanism, was simulated by adding a total net uptake block for iodide into the thyroid, becoming active when the gland is saturated with iodine. The model's validity was confirmed by comparing predicted values with results from other models and sparse empirical data. According to our model, in the case of radioiodine exposure without thyroid blocking, the thyroid equivalent dose in the maternal gland increases about 45% within the first weeks of pregnancy to remain in the same range until term. Beginning in the 12th pregnancy week, the equivalent dose in the fetal thyroid disproportionately increases over time and amounts to three times the dose of the maternal gland at term. The maternal and fetal glands' protection increases concomitantly with the amount of stable iodine administered to the mother simultaneously with acute radioiodine exposure. The dose-effect curves reflecting the combined thyroidal protection by the competition at the membrane carrier site and the Wolff-Chaikoff effect in the mother are characterized by a mean effective dose (ED50) of roughly 1.5 mg all over pregnancy. In the case of the fetal thyroid, the mean effective doses for thyroid blocking, taking into account only the competition at the carrier site are numerically lower than in the mother. Taking into account additionally the Wolff-Chaikoff effect, the dose-effect curves for thyroidal protection in the fetus show a shift to the left over time, with a mean effective dose of 12.9 mg in the 12th week of pregnancy decreasing to 0.5 mg at term. In any case, according to our model, the usually recommended dose of 100 mg stable iodine given at the time of acute radioiodine exposure confers a very high level of thyroidal protection to the maternal and fetal glands over pregnancy. For ethical reasons, the possibilities of experimental studies on thyroid blocking in pregnant women are extremely limited. Furthermore, results from animal studies are associated with the uncertainties related to the translation of the data to humans. Thus model-based simulations may be a valuable tool for better insight into the efficacy of thyroidal protection and improve preparedness planning for uncommon nuclear or radiological emergencies.


Asunto(s)
Yodo , Glándula Tiroides , Animales , Niño , Femenino , Feto , Humanos , Yoduros/metabolismo , Yodo/farmacología , Radioisótopos de Yodo , Madres , Embarazo , Glándula Tiroides/metabolismo
5.
PLoS Pathog ; 15(1): e1007520, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30608982

RESUMEN

The cellular prion protein (PrPC) is a cell surface glycoprotein attached to the membrane by a glycosylphosphatidylinositol (GPI)-anchor and plays a critical role in transmissible, neurodegenerative and fatal prion diseases. Alterations in membrane attachment influence PrPC-associated signaling, and the development of prion disease, yet our knowledge of the role of the GPI-anchor in localization, processing, and function of PrPC in vivo is limited We exchanged the PrPC GPI-anchor signal sequence of for that of Thy-1 (PrPCGPIThy-1) in cells and mice. We show that this modifies the GPI-anchor composition, which then lacks sialic acid, and that PrPCGPIThy-1 is preferentially localized in axons and is less prone to proteolytic shedding when compared to PrPC. Interestingly, after prion infection, mice expressing PrPCGPIThy-1 show a significant delay to terminal disease, a decrease of microglia/astrocyte activation, and altered MAPK signaling when compared to wild-type mice. Our results are the first to demonstrate in vivo, that the GPI-anchor signal sequence plays a fundamental role in the GPI-anchor composition, dictating the subcellular localization of a given protein and, in the case of PrPC, influencing the development of prion disease.


Asunto(s)
Glicosilfosfatidilinositoles/metabolismo , Proteínas PrPC/metabolismo , Enfermedades por Prión/metabolismo , Animales , Modelos Animales de Enfermedad , Glicosilfosfatidilinositoles/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ácido N-Acetilneuramínico/metabolismo , Proteínas PrPC/fisiología , Enfermedades por Prión/genética , Proteínas Priónicas/metabolismo , Priones/genética , Priones/metabolismo , Señales de Clasificación de Proteína/fisiología , Transporte de Proteínas/fisiología , Proteolisis , Transducción de Señal
6.
Arch Toxicol ; 95(7): 2335-2350, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34003340

RESUMEN

Radioactive iodine released in nuclear accidents may accumulate in the thyroid and by irradiation enhances the risk of cancer. Radioiodine uptake into the gland can be inhibited by large doses of stable iodine or perchlorate. Nutritional iodine daily intake may impact thyroid physiology, so that radiological doses absorbed by the thyroid as well as thyroid blocking efficacy may differ in Japanese with a very rich iodine diet compared to Caucasians. Based on established biokinetic-dosimetric models for the thyroid, we derived the parameters for Caucasians and Japanese to quantitatively compare the effects of radioiodine exposure and the protective efficacy of thyroid blocking by stable iodine at the officially recommended dosages (100 mg in Germany, 76 mg in Japan) or perchlorate. The maximum transport capacity for iodine uptake into the thyroid is lower in Japanese compared to Caucasians. For the same radioiodine exposure pattern, the radiological equivalent thyroid dose is substantially lower in Japanese in the absence of thyroid blocking treatments. In the case of acute radioiodine exposure, stable iodine is less potent in Japanese (ED50 = 41.6 mg) than in Caucasians (ED50 = 2.7 mg) and confers less thyroid protection at the recommended dosages because of a delayed responsiveness to iodine saturation of the gland (Wolff-Chaikoff effect). Perchlorate (ED50 = 10 mg in Caucasians) at a dose of 1000 mg has roughly the same thyroid blocking effect as 100 mg iodine in Caucasians, whereas it confers a much better protection than 76 mg iodine in Japanese. For prolonged exposures, a single dose of iodine offer substantially lower protection than after acute radioiodine exposure in both groups. Repetitive daily iodine administrations improve efficacy without reaching levels after acute radioiodine exposure and achieve only slightly better protection in Japanese than in Caucasians. However, in the case of continuous radioiodine exposure, daily doses of 1000 mg perchlorate achieve a high protective efficacy in Caucasians as well as Japanese (> 0.98). In Caucasians, iodine (100 mg) and perchlorate (1000 mg) at the recommended dosages seem alternatives in case of acute radioiodine exposure, whereas perchlorate has a higher protective efficacy in the case of longer lasting radioiodine exposures. In Japanese, considering protective efficacy, preference should be given to perchlorate in acute as well as prolonged radioiodine exposure scenarios.


Asunto(s)
Yodo , Neoplasias de la Tiroides , Humanos , Radioisótopos de Yodo/efectos adversos , Japón , Percloratos/toxicidad , Neoplasias de la Tiroides/prevención & control
7.
Acta Neuropathol ; 139(3): 527-546, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31673874

RESUMEN

Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/-) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.


Asunto(s)
Proteína ADAM10/metabolismo , Heparitina Sulfato/metabolismo , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Priones/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Ratones
8.
Z Rheumatol ; 79(2): 200-202, 2020 Mar.
Artículo en Alemán | MEDLINE | ID: mdl-32040754

RESUMEN

An interdisciplinary collaboration is required in the medical care of chronically ill patients with complex illnesses. Especially in the field of internistic rheumatology, interdisciplinary work is essential to consider the complex somatic and psychosocial aspects of a chronic illness. Nevertheless, the aspects of interprofessional work in the study of medicine and psychology are insufficiently addressed. For this reason, a model project for interdisciplinary university teaching was conceived, which combines both subjects. The course was held for the first time in semester 2019/2020 and was rated excellent by the participants. The main goal of the course is the implementation of interprofessional work in the training of medical personnel. In addition, the discipline of internistic rheumatology could be brought closer to the students.


Asunto(s)
Curriculum , Relaciones Interprofesionales , Grupo de Atención al Paciente/organización & administración , Psicología , Reumatología , Enfermedad Crónica , Humanos , Estudiantes de Medicina/psicología , Universidades
9.
Circulation ; 137(21): e661-e689, 2018 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-29674324

RESUMEN

Intracranial endovascular interventions provide effective and minimally invasive treatment of a broad spectrum of diseases. This area of expertise has continued to gain both wider application and greater depth as new and better techniques are developed and as landmark clinical studies are performed to guide their use. Some of the greatest advances since the last American Heart Association scientific statement on this topic have been made in the treatment of ischemic stroke from large intracranial vessel occlusion, with more effective devices and large randomized clinical trials showing striking therapeutic benefit. The treatment of cerebral aneurysms has also seen substantial evolution, increasing the number of aneurysms that can be treated successfully with minimally invasive therapy. Endovascular therapies for such other diseases as arteriovenous malformations, dural arteriovenous fistulas, idiopathic intracranial hypertension, venous thrombosis, and neoplasms continue to improve. The purpose of the present document is to review current information on the efficacy and safety of procedures used for intracranial endovascular interventional treatment of cerebrovascular diseases and to summarize key aspects of best practice.


Asunto(s)
Trastornos Cerebrovasculares/terapia , Procedimientos Endovasculares , Malformaciones Vasculares del Sistema Nervioso Central/cirugía , Malformaciones Vasculares del Sistema Nervioso Central/terapia , Trastornos Cerebrovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/cirugía , Embolización Terapéutica , Fibrinolíticos/uso terapéutico , Humanos , Aneurisma Intracraneal/terapia , Trombosis Intracraneal/cirugía , Trombosis Intracraneal/terapia , Radiocirugia , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/terapia
10.
Biochim Biophys Acta Mol Cell Res ; 1864(11 Pt B): 2128-2137, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28693923

RESUMEN

Proteolytic processing of the cellular and disease-associated form of the prion protein leads to generation of bioactive soluble prion protein fragments and modifies the structure and function of its cell-bound form. The nature of proteases responsible for shedding, α-, ß-, and γ-cleavage of the prion protein are only partially identified and their regulation is largely unknown. Here, we provide an overview of the increasingly multifaceted picture of prion protein proteolysis and shed light on physiological and pathological roles associated with these cleavages. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.


Asunto(s)
Enfermedades por Prión/genética , Proteínas Priónicas/genética , Proteolisis , Animales , Humanos , Enfermedades por Prión/patología , Proteínas Priónicas/metabolismo , Agregación Patológica de Proteínas/genética
11.
Z Rheumatol ; 77(2): 113-126, 2018 Mar.
Artículo en Alemán | MEDLINE | ID: mdl-28929232

RESUMEN

BACKGROUND: Rheumatoid arthritis (RA) has an increased number of comorbidities compared with the general population. OBJECTIVE: Study aim was to collect epidemiological data on prevalence, incidence and comorbidities of RA as well as utilization of outpatient and inpatient care services. MATERIAL AND METHODS: In an age and gender-adjusted case control study, a total of 3.4 million patients insured by the AOK Baden-Württemberg were analysed with respect to visits to physicians, prevalence, incidence and comorbidities of RA. The study was based on out- and inpatient diagnoses from 2013. RESULTS: The RA prevalence was 0.64% (n = 26,919), the incidence was 0.04%. Patients with RA have significant more comorbidities in almost all diagnosis groups, especially in musculoskeletal and cardiovascular diseases, compared to a control group (n = 181,209). 22.8% of RA patients had not contacted an internist rheumatologist, orthopedist or orthopedic surgeon. Biological disease-modifying anti-rheumatic drugs (DMARDs) were almost exclusively prescribed by internist rheumatologists, while conventional DMARDs were equally prescribed by general practitioners and rheumatologists. Of the RA patients 32.6% were hospitalized at least once a year and were nearly twice as frequently inpatient as the control group. CONCLUSION: RA patients need more in- and outpatient healthcare services and suffer significantly more often from comorbidities. The general practitioner is the most frequently visited physician. Other consulted physicians are rheumatologists, ophthalmologists, orthopedists/orthopedic surgeons and internists not specialized in rheumatology. The study highlights the need to create consensus treatment algorithms and maintain a close interdisciplinary and intersectoral cooperation and communication.


Asunto(s)
Artritis Reumatoide , Pacientes Ambulatorios , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/epidemiología , Estudios de Casos y Controles , Comorbilidad , Alemania/epidemiología , Humanos , Pacientes Internos , Prevalencia
12.
Klin Monbl Augenheilkd ; 234(7): 924-929, 2017 Jul.
Artículo en Alemán | MEDLINE | ID: mdl-27508886

RESUMEN

Background: Optic nerve disease can occur from a variety of different causes, with vascular, inflammatory or toxic pathologies. In such cases, it is hardly possible to clarify the aetiology. These diseases of the optic nerve are usually accompanied by progressive loss of visual field and visual impairment. Patient: We report a case of a 74-year-old woman complaining of loss of visual acuity, visual and blurred vision in the left eye in 2010. We made the diagnosis of non-arteritic ischemic optic neuropathy (NAION). With steroid therapy, there was an improvement in both visual acuity and visual field defects. But if an attempt was made to reduce steroids, her condition progressed. Except for a very small optic disk and arterial hypotension, there were no typical risk factors for NAION. We started treatment with methotrexate (MTX), with a starting dose of 10 mg per week, and observed the patient over two years. Results: Using MTX therapy, the swelling of the optic nerve head and visual field loss were reversible, so we increased the dose of MTX up to 15 mg/week. Steroid therapy could be stopped and the patient's visual acuity and visual field have now been stable for two years. There was no visible pallor in the optic nerve head, as normally occurs after AION, so we considered different underlying pathologies, including autoimmune disease. There were no adverse events with MTX therapy. Conclusion: If the course of the disease is atypical, the pathology may include an autoimmune component. Immunosuppressive MTX therapy may be started in order to avoid long-term steroid use. It may then be possible to maintain a stable visual field and prevent remitting episodes.


Asunto(s)
Metotrexato/uso terapéutico , Neuropatía Óptica Isquémica/tratamiento farmacológico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Neuropatía Óptica Isquémica/diagnóstico , Agudeza Visual/efectos de los fármacos , Campos Visuales/efectos de los fármacos
13.
Orthopade ; 45(12): 1015-1026, 2016 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-27518117

RESUMEN

BACKGROUND: Musculoskeletal illnesses and injuries are among the most common ailments in the Federal Republic of Germany. In 2008 they generated costs of nearly 29 billion euros. Figures about their incidence and prevalence are necessary for a demand-oriented planning of future patient-centred care. METHOD: Pseudonymised data of 3.8 million people insured by AOK Baden-Württemberg between 2008 and 2013 were evaluated. The diagnoses were assigned to nine injury groups. For outpatient care confirmed diagnoses were considered, and for inpatient care both primary and secondary diagnoses were considered. For all patients with structural knee injuries, it was evaluated whether they made use of one of five eligible treatment paradigms either in the quarter in which they were injured or in the following quarter. RESULTS: 418,257 patients were treated in 2013 for at least one new-onset injury (10.9 % of all insurees); 86,783 insurees (2.3 % of all insurees) had a newly occurring knee injury. The vast majority of the patients were treated by specialist doctors. While magnetic resonance imaging clearly increased during the observation period, the incidence of surgical therapy did not change. Striking are the different age distributions regarding the types of injuries, with a high injury incidence amongst young men and a significant increase in injuries between 2008 and 2013, especially amongst women. CONCLUSION: For the first time, the data quantify the knee injury incidences of a large cohort in Germany. They show which inpatient and outpatient health care services have been claimed and that an age- and gender-adapted prevention and an increased awareness are needed.


Asunto(s)
Atención Ambulatoria/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Pacientes Internos/estadística & datos numéricos , Reembolso de Seguro de Salud/estadística & datos numéricos , Traumatismos de la Rodilla/epidemiología , Traumatismos de la Rodilla/terapia , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Alemania/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Traumatismos de la Rodilla/diagnóstico , Masculino , Persona de Mediana Edad , Factores de Riesgo , Distribución por Sexo , Adulto Joven
14.
Tissue Antigens ; 85(3): 155-66, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25720504

RESUMEN

In order to provide specificity for T cell responses against pathogens and tumours, major histocompatibility complex (MHC) class I molecules present high-affinity peptides at the cell surface to T cells. A key player for peptide loading is the MHC class I-dedicated chaperone tapasin. Recently we discovered a second MHC class I-dedicated chaperone, the tapasin-related protein TAPBPR. Here, we review the major steps in the MHC class I pathway and the TAPBPR data. We discuss the potential function of TAPBPR in the MHC class I pathway and the involvement of this previously uncharacterised protein in human health and disease.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunoglobulinas/inmunología , Proteínas de la Membrana/inmunología , Proteínas de Transporte de Membrana/inmunología , Secuencia de Aminoácidos , Presentación de Antígeno , Células Presentadoras de Antígenos/citología , Membrana Celular/química , Membrana Celular/inmunología , Retículo Endoplásmico/inmunología , Retículo Endoplásmico/metabolismo , Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Inmunoglobulinas/genética , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana/genética , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/química , Péptidos/genética , Péptidos/inmunología , Transporte de Proteínas , Transducción de Señal
15.
Schmerz ; 29(5): 516-21, 2015 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-26289393

RESUMEN

AIM: Chronic and debilitating pediatric pain has a prevalence of 5% and as such constitutes a considerable health problem. The aim of this article is to provide an overview of current research activities on pediatric pain, available health care for children with chronic pain and education and training programs for health professionals. METHOD: This overview is based on the authors' personal experience, information available from medical, research and professional associations, as well as a PubMed literature search for the time period 2012-2015 using "children";"pain" and "Germany" as search terms. RESULTS: There are numerous research activities in Germany focusing on the epidemiology, the underlying psychobiological mechanisms and on the multimodal treatment of chronic pediatric pain. This research is internationally widely acknowledged and makes a significant contribution to current developments in pediatric pain research. By contrast, health services and basic science research is clearly lacking in Germany. Moreover, specialized health care for youth with chronic pain is far less institutionalized when compared to adults suffering from chronic pain. Indeed, primary and secondary care services have rarely been studied or even evaluated. CONCLUSION: Similar to international trends, research on chronic pediatric pain has also grown and advanced in Germany. Indeed, not only the amount of research has increased but also its scope. Nonetheless, there is clearly a need for more research efforts with regard to the understanding of (pediatric) pain mechanisms, clinical studies and, especially, investigations on health care services. It is particularly important to focus on the implementation, improvement and systematic evaluation of specialized health care services which would be available and accessible for children and adolescents with chronic pain and not be restricted to tertiary care.


Asunto(s)
Dolor Crónico/epidemiología , Dolor Crónico/etiología , Adolescente , Investigación Biomédica/tendencias , Niño , Estudios Transversales , Predicción , Alemania , Accesibilidad a los Servicios de Salud/tendencias , Necesidades y Demandas de Servicios de Salud/tendencias , Humanos
16.
Nat Commun ; 15(1): 7754, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-39237588

RESUMEN

Cytomegalovirus (CMV) infection poses risks to newborns, necessitating effective therapies. Given that the damage includes both viral infection of brain cells and immune system-related damage, here we investigate the involvement of cellular prion protein (PrP), which plays vital roles in neuroprotection and immune regulation. Using a murine model, we show the role of PrP in tempering neonatal T cell immunity during CMV infection. PrP-null mice exhibit enhanced viral control through elevated virus-specific CD8 T cell responses, leading to reduced viral titers and pathology. We further unravel the molecular mechanisms by showing CMV-induced upregulation followed by release of PrP via the metalloproteinase ADAM10, impairing CD8 T cell response specifically in neonates. Additionally, we confirm PrP downregulation in human CMV (HCMV)-infected fibroblasts, underscoring the broader relevance of our observations beyond the murine model. Furthermore, our study highlights how PrP, under the stress of viral pathogenesis, reveals its impact on neonatal immune modulation.


Asunto(s)
Animales Recién Nacidos , Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Citomegalovirus , Ratones Noqueados , Animales , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Femenino , Fibroblastos/metabolismo , Fibroblastos/virología , Proteínas Priónicas/metabolismo , Proteínas Priónicas/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Proteína ADAM10/metabolismo , Proteína ADAM10/genética
17.
Transl Neurodegener ; 12(1): 12, 2023 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-36915212

RESUMEN

α-Synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfolded α-synuclein (αSyn), referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions (Papp-Lantos bodies). Even though the specific cellular distribution of aggregated αSyn differs in PD and DLB patients, both groups show a significant pathological overlap, raising the discussion of whether PD and DLB are the same or different diseases. Besides clinical investigation, we will focus in addition on methodologies, such as protein seeding assays (real-time quaking-induced conversion), to discriminate between different types of α-synucleinopathies. This approach relies on the seeding conversion properties of misfolded αSyn, supporting the hypothesis that different conformers of misfolded αSyn may occur in different types of α-synucleinopathies. Understanding the pathological processes influencing the disease progression and phenotype, provoked by different αSyn conformers, will be important for a personalized medical treatment in future.


Asunto(s)
Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Sinucleinopatías , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Sinucleinopatías/diagnóstico , Sinucleinopatías/genética , Sinucleinopatías/metabolismo , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Cuerpos de Lewy/patología , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología
18.
Neural Regen Res ; 18(9): 1869-1875, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36926701

RESUMEN

In the last decades, the role of the prion protein (PrP) in neurodegenerative diseases has been intensively investigated, initially in prion diseases of humans (e.g., Creutzfeldt-Jakob disease) and animals (e.g., scrapie in sheep, chronic wasting disease in deer and elk, or "mad cow disease" in cattle). Templated misfolding of physiological cellular prion protein (PrPC) into an aggregation-prone isoform (termed PrP "Scrapie" (PrPSc)), self-replication and spreading of the latter inside the brain and to peripheral tissues, and the associated formation of infectious proteopathic seeds (termed "prions") are among the essential pathogenic mechanisms underlying this group of fatal and transmissible spongiform encephalopathies. Later, key roles of the correctly folded PrPC were identified in more common human brain diseases (such as Alzheimer's disease or Parkinson's disease) associated with the misfolding and/or accumulation of other proteins (such as amyloid-ß, tau or α-synuclein, respectively). PrPC has also been linked with neuroprotective and regenerative functions, for instance in hypoxic/ischemic conditions such as stroke. However, despite a mixed "bouquet" of suggested functions, our understanding of pathological and, especially, physiological roles played by PrPC in the brain and beyond is certainly incomplete. Interactions with various other proteins at the cell surface or within intracellular compartments may account for the functional diversity linked with PrPC. Moreover, conserved endogenous proteolytic processing of PrPC generates several defined PrPC fragments, possibly holding intrinsic functions in physiological and pathological conditions, thus making the "true and complete biology" of this protein more complicated to be elucidated. Here, we focus on one of those released PrPC fragments, namely shed PrP (sPrP), generated by a membrane-proximate ADAM10-mediated cleavage event at the cell surface. Similar to other soluble PrPC fragments (such as the N1 fragment representing PrP's released N-terminal tail upon the major α-cleavage event) or experimentally employed recombinant PrP, sPrP is being suggested to act neuroprotective in Alzheimer's disease and other protein misfolding diseases. Several lines of evidence on extracellular PrPC (fragments) suggest that induction of PrPC release could be a future therapeutic option in various brain disorders. Our recent identification of a substrate-specific approach to stimulate the shedding by ADAM10, based on ligands binding to cell surface PrPC, may further set the stage for research into this direction.

19.
Arch Toxicol ; 86(9): 1369-78, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22532026

RESUMEN

Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups.


Asunto(s)
Carcinógenos Ambientales/toxicidad , Cromosomas Humanos Par 2/genética , Sitios Genéticos , Glucuronosiltransferasa/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/genética , Animales , Carcinógenos Ambientales/administración & dosificación , Carcinógenos Ambientales/farmacocinética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glucuronosiltransferasa/metabolismo , Humanos , Inactivación Metabólica , Intrones , Isoenzimas/genética , Isoenzimas/metabolismo , Familia de Multigenes , Exposición Profesional , Riesgo , Fumar/efectos adversos , Toxicogenética/métodos , Neoplasias de la Vejiga Urinaria/metabolismo
20.
Arch Toxicol ; 86(2): 195-203, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21892705

RESUMEN

Currently, twelve validated genetic variants have been identified that are associated with urinary bladder cancer (UBC) risk. However, those validated variants explain only 5-10% of the overall inherited risk. In addition, there are more than 100 published polymorphisms still awaiting validation or disproval. A particularly promising of the latter unconfirmed polymorphisms is rs2854744 that recently has been published to be associated with UBC risk. The [A] allele of rs2854744 has been reported to be associated with a higher promoter activity of the insulin-like growth factor-binding protein-3 (IGFBP3) gene, which may lead to increased IGFBP-3 plasma levels and cancer risk. Therefore, we investigated the association of rs2854744 with UBC in the IfADo case-control series consisting of 1,450 cases and 1,725 controls from Germany, Hungary, Venezuela and Pakistan. No significant association of rs2854744 with UBC risk was obtained (all study groups combined: unadjusted P = 0.4446; adjusted for age, gender and smoking habits P = 0.6510), besides a small effect of the [A] allele in the Pakistani study group opposed to the original findings (unadjusted P = 0.0508, odds ratio (OR) = 1.43 for the multiplicative model) that diminished after adjustment for age, gender and smoking habits (P = 0.7871; OR = 0.93). Associations of rs2854744 with occupational exposure to urinary bladder carcinogens and smoking habits were also not present. A meta-analysis of all available case-control series including the original discovery study resulted in an OR of 1.00 (P = 0.9562). In conclusion, we could not confirm the recently published hypothesis that rs2854744 in the IGFBP3 gene is associated with UBC risk.


Asunto(s)
Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/etnología , Alemania , Humanos , Hungría , Masculino , Persona de Mediana Edad , Pakistán , Polimorfismo de Nucleótido Simple , Neoplasias de la Vejiga Urinaria/etnología , Venezuela
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