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Introduction: The newest intravenous (IV) iron products show an improved safety profile over predecessors, allowing for the rapid administration of relatively high doses. Ferric derisomaltose (FDI; also known as iron isomaltoside), ferric carboxymaltose (FCM), and ferumoxytol (FER), are successful treatments for iron deficiency (Europe; FDI and FCM) and iron deficiency anemia (US; FDI, FCM, and FER). Areas covered: This review focusses on the chemistry and structure of FDI, FCM, and FER, and on three key aspects of IV iron safety: (1) hypersensitivity; (2) hypophosphatemia and sequelae; (3) cardiovascular safety. Expert opinion: Although the safety of modern IV iron has improved, immediate infusion reactions and the development of hypophosphatemia must be appreciated and recognized by those who prescribe and administer IV iron. Immediate infusion reactions can occur with any IV iron and are usually mild; severe reactions – particularly anaphylaxis – are extremely rare. The recognition and appropriate management of infusion reactions is an important consideration to the successful administration of IV iron. Severe, persistent, hypophosphatemia is a specific side effect of FCM. No cardiovascular safety signal has been identified for IV iron. Ongoing trials in heart failure will provide additional long-term efficacy and safety data.
New reactive coenzyme analogues for affinity labeling of NAD+ and NADP+ dependent dehydrogenases
(1995)
Reactive coenzyme analogues ω-(3-diazoniumpyridinium)alkyl adenosine diphosphate were prepared by reaction of ω-(3-aminopyridinium)alkyl adenosine diphosphate with nitrous acid. In these compounds the nicotinamide ribose is substituted by hydrocarbon chains of varied lengths (n-ethyl to n-pentyl). The diazonium compounds are very unstable and decompose rapidly at room temperature. They show a better stability at 0 °C. L actate and alcohol dehydrogenase do not react with any of the analogues. Glyceraldehyde-3-phosphate dehydrogenase reacts rapidly with the diazonium pentyl compound. Decreasing the length of the alkyl chain significantly decreases the inactivation velocity. 3α,20β-Hydroxysteroid dehydrogenase reacts at 0 °C with the ethyl homologue and slowly with the propyl compound. The butyl-and pentyl analogues do not inactivate at 0 °C. Tests with 14C -labeled 2-(3-diazoniumpyridinium)ethyl adenosine diphosphate show that complete loss of enzyme activity results after incorporation of 2 moles of inactivator into 1 mole of tetrameric enzyme. 4-(3-Acetylpyridinium)butyl 2 ′-phospho-adenosine diphosphate, a structural analogue of NADP +, was prepared by condensation of adenosine-2,3-cyclophospho-5′-phosphomorpholidate with (3-acetylpyridinium)butyl phosphate, followed by hydrolysis of the cyclic phosphoric acid ester with 2 ′:3′-cyclonucleotide-3′-phosphodiesterase. Because of the redox potential (-315 mV) and the distance between the pyridinium and phosphate groups, this analogue is a hydrogen acceptor and its reduced form a hydrogen donor in tests with alcohol dehyd rogenase from Thermoanaerobium brockii. The reduced form of the coenzyme analogue also is a hydrogen donor with glutathione reductase. With other NADP +-dependent dehydrogenases the com pound has been show n to be a competitive inhibitor against the natural coenzyme. The acetyl group reacts with bromine to form the bromoacetyl group. This reactive bromoacetyl analogue is a specific active-site directed irreversible inhibitor of isocitrate dehydrogenase.
Background: The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown. Objective: To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits. Methods: Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1β, IL10, TGFβ, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice. Results: First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1β+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1β in cMC from Chrna7-KO and in IL1β-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1β in cMC when HIF1α was blocked. Conclusions: These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1β expression if SLURP-1 is involved.
Atrial fibrillation (AF) continues to be a leading cause of cerebrovascular morbidity and mortality resulting from cardioembolic stroke. Oral anticoagulation therapy has been shown to decrease the incidence of cardioembolic stroke in patients with AF by more than 50%. Appropriate use of anticoagulation with vitamin K antagonists requires precise adherence and monitoring. A number of factors that potentially induce patients' dissatisfaction reduce quality of patient life. New direct oral anticoagulants, such as the direct factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and the thrombin inhibitor dabigatran, were developed to overcome the limitations of the conventional anticoagulant drugs. However, models to optimize the benefit of therapy and to ensure that therapy can be safely continued are missing for the new oral anticoagulants. This review will briefly describe the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban with focus on their use for prevention of embolic events in AF. Moreover, it will discuss the safety, efficacy, cost data, and benefit for patients' quality of life and adherence.
Angiogenesis is essential for tumor growth and progression. It has been demonstrated that tumor growth beyond a size 1 to 2 mm3 requires the induction of new vessels. Angiogenesis is regulated by several endogenous stimulators and inhibitors of endothelial cell migration, proliferation and tube formation. Under physiological conditions these mediators of endothelial cell growth are in balance and vessel growth is limited. In fact, within the angiogenic balance endothelial cell turnover is sufficient to maintain a functional vascular wall but does not allow vessel growth. Tumor growth an progression has successfully been correlated to the serum concentration of angiogenic mediators. Furthermore, the vascular density of tumor tissues could be correlated to the clinical course of the disease in several tumor entities. Within the last years several new mediators of endothelial cell growth have been isolated e.g. angiopoietin 1, angiopoietin 2, midkine, pleiotropin, leptin and maspin. In this review we discuss the mechanisms leading to tumor angiogenesis and describe some of the newer mediators of endothelial cell stimulation and inhibition.
Objectives: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease.
Methods: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation.
Results: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy.
Conclusions: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
Clinical trial registration number: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).
Lyme disease (LD), which is caused by genospecies of the Borrelia burgdorferi sensu lato complex, is the most common vector-borne disease in the Northern hemisphere. Spirochetes are transmitted by Ixodes ticks and maintained in diverse vertebrate animal hosts. Following tick bite, spirochetes initially establish a localized infection in the skin. However, they may also disseminate hematogenously to several distal sites, including heart, joints, or the CNS. Because they need to survive in diverse microenvironments, from tick vector to mammalian hosts, spirochetes have developed multiple strategies to combat the numerous host defense mechanisms. One of these strategies includes the production of a number of complement-regulator acquiring surface proteins (CRASPs) which encompass CspA, CspZ, and OspE paralogs to blunt the complement pathway. These proteins are capable of preventing complement activation on the spirochete surface by binding to complement regulator Factor H. The genes encoding these CRASPs differ in their expression patterns during the tick-to-host infection cycle, implying that these proteins may exhibit different functions during infection. This review summarizes the recent published reports which investigated the roles that each of these molecules plays in conferring tick-borne transmission and dissemination in vertebrate hosts. These findings offer novel mechanistic insights into LD pathobiology and may facilitate the identification of new targets for preventive strategies against Lyme borreliosis.
New histone deacetylase inhibitors as potential therapeutic tools for advanced prostate carcinoma
(2008)
The anti-epileptic drug valproic acid is also under trial as an anti-cancer agent due to its histone deacetylase (HDAC) inhibitory properties. However, the effects of valproic acid (VPA) are limited and concentrations required for exerting anti-neoplastic effects in vitro may not be reached in tumour patients. In this study, we tested in vitro and in vivo effects of two VPA-derivatives (ACS2, ACS33) on pre-clinical prostate cancer models. PC3 and DU-145 prostate tumour cell lines were treated with various concentrations of ACS2 or ACS33 to perform in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and to evaluate tumour cell adhesion to endothelial cell monolayers. Analysis of acetylated histones H3 and H4 protein expression was performed by western blotting. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. Tumour sections were assessed by immunohistochemistry for histone H3 acetylation and proliferation. ACS2 and ACS33 significantly up-regulated histone H3 and H4 acetylation in prostate cancer cell lines. In micromolar concentrations both compounds exerted growth arrest in PC3 and DU-145 cells and prevented tumour cell attachment to endothelium. In vivo, ACS33 inhibited the growth of PC3 in subcutaneous xenografts. Immunohistochemistry and western blotting confirmed increased histone H3 acetylation and reduced proliferation. ACS2 and ACS33 represent novel VPA derivatives with superior anti-tumoural activities, compared to the mother compound. This investigation lends support to the clinical testing of ACS2 or ACS33 for the treatment of prostate cancer.
In this manuscript a comprehensive coverage of recent developments in the drug therapy of vasospasm while providing the background information that neuroscientists need to understand its rationale. The range of new agents available for treatment of cerebral vasospasm is expanding rapidly along with rapid advances in pharmacology and physiology that are uncovering the mechanisms of this disease. Although there are many publications for treatment of cerebral vasospasm, most are focusing on different aspects of vasospasm treatment and many have limited value due to insufficient quality. Moreover, the complexity of this, in many cases deleterious condition, is enormous and the information needed to understand drug effects is accordingly often not readily available in a single source. A number of pharmacological and medical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Current research efforts promise the eventual production of new medical therapies. At last, recommendations for the use of different treatment stages based on currently available clinical data are provided.
In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.
Background: Supracondylar fractures of the humerus are a common injury in pediatric traumatology. The most common operative therapy is closed reduction and percutaneous pinning using K-wires. Common complications associated with this entity are neurovascular lesions, especially of the brachial artery and the median nerve.
Methods: We report two cases of patients treated in our trauma-center with supracondylar fracture of the humerus (AO IV°) and neurovascular complications.
Results: Both patients underwent open revision and recovered completely in their further course.
Conclusion: We recommend detailed neurovascular examination initially and after reposition of the fracture. The threshold for open reduction in cases of irreducible fractures should be low. In the presence of neurovascular impairment an open revision is mandatory, even months after the initial Trauma.
Cancer therapies have experienced significant advances in recent years. While conventional cytotoxic chemotherapy has long been the cornerstone for the treatment of many tumor entities, uprising immunotherapies have revolutionized the therapeutic landscape. Among them, immune checkpoint inhibitors (ICIs) with their demonstrated increased overall survival rates and response rates in cancer patients are now FDA-approved for metastatic melanoma and multiple other malignancies. Despite their clinical benefit in cancer therapies, ICIs can induce unique autoimmune-like toxicities known as immune-related adverse events (irAEs), which can involve any organ system including the nervous system. Although neurotoxicities are rare complications of ICI therapy they are often severe and can lead to long-term disability or even death if left untreated.
Neurological irAEs exhibit a broad spectrum of clinical presentations affecting the entire nervous system. Diagnosing neurological irAEs is often challenging as symptoms and laboratory findings can be uncharacteristic for common neurological disorders and clinical experience with ICI-mediated toxicities is still limited. In light of expanding clinical indications for ICIs, physicians will encounter ICI-mediated neurotoxicities more frequently. Thus, thorough characterizations of the diverse set of neurological irAEs are essential for optimal patient care, the prevention of severe ICI-mediated complications, and the development of diagnostic and therapeutic algorithms. This work portrays the clinical presentation, management and outcome of neurological irAEs following ICI therapies.
Patients with neurotoxicities related to ICIs who presented at the Yale New Haven Hospital between January 2014 and June 2018 were retrospectively identified from the quality control database. A comprehensive chart review was performed and data regarding patient demographics, medical history, ICI regimen and neurotoxicity were recorded. In total, 18 patients with neurological irAEs following ICI therapy for melanoma, small cell lung cancer, non-small cell lung cancer, and Merkel-cell carcinoma were identified. Neurotoxicities included central nervous system disorders comprising central demyelinating disorder,autoimmune encephalitis predominantly affecting the grey matter, and aseptic meningitis. Peripheral nervous system toxicities included sensorimotor polyneuropathy and myasthenia gravis. Cases of hypophysitis were also recorded. Time to onset of neurological irAEs ranged from 1 to72 weeks with a median of five weeks. In all patients ICIs were held and steroids initiated. Additional immunomodulatory therapies were required in nine patients. Sixteen of 18 patients showed neurological improvement. Fourteen patients had highgrade neurotoxicity (grade 3-4), six of whom deceased due to cancer progression, while none of the low-grade neurotoxicity patients (grade 1-2) died. High-grade neurotoxicity was identified as a negative prognostic marker for overall survival (p = 0.046).
This work shows that neurotoxicities present early-onset, rapidly progressive complications of ICIs with a broad spectrum of clinical phenotypes affecting the central nervous system, peripheral nervous system, and neuroendocrine system. A high index of caution for neurological irAEs is warranted throughout ICI therapy as timely diagnosis and management can reduce morbidity and mortality. Randomized clinical trials are needed to develop standardized diagnostic and therapeutic algorithms of ICI-induced neurotoxicities.
Given the ongoing global SARS-CoV-2-vaccination efforts, clinical awareness needs to be raised regarding the possibility of an increased incidence of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia in patients with intracerebral hemorrhage (ICH) secondary to cerebral sinus and vein thrombosis (CVT) requiring (emergency) neurosurgical treatment in the context of vaccine-induced immune thrombotic thrombocytopenia (VITT). Only recently, an association of vaccinations and cerebral sinus and vein thrombosis has been described. In a number of cases, neurosurgical treatment is warranted for these patients and special considerations are warranted when addressing the perioperative coagulation. We, herein, describe the past management of patients with VITT and established a literature-guided algorithm for the treatment of patients when addressing the impaired coagulation in these patients. Increasing insights addressing the pathophysiology of SARS-CoV-2-vaccine-related immune-mediated thrombocytopenia guide physicians in developing an interdisciplinary algorithm taking into account the special considerations of this disease.
Mycophenolat-Mofetil (MMF) hemmt die Aktivität von Mikrogliazellen und verringert den exzitotoxischen neuronalen Schaden in organotypischen hippocampalen Schnittkulturen (OHSC). Der Tractus perforans ist die wichtigste neuronale afferente Verbindung zwischen entorhinalem Kortex (EC) und Gyrus dentatus (GD) im Hippocampus. Er besteht aus Axonen, deren Ursprungsneurone im EC liegen und die im GD terminieren. Ziel dieser Arbeit war es, die Wirkung von MMF auf den Erhalt dieser Projektion zu untersuchen. Methodisch wurde zu diesem Zweck die Fluoreszenzmarkierung des Tractus perforans in der organotypischen hippokampalen Schnittkultur (OHSC) etabliert. Die von uns angestrebte retrograde Färbemethode sollte entorhinale Neurone unter der Voraussetzung markieren, dass deren Axone (Tractus perforans) intakt waren. Ein guter neuronaler Erhalt sollte sich in einem entsprechend erhaltenen Tractus perforans und retrograd markierten entorhinalen Neuronen wiederspiegeln. OHSC aus 8 Tage alten Wistar Ratten wurden für 9 div (days in vitro) mit oder ohne MMF (100 mikro g/ml) kultiviert. Zunächst wurde methodisch die retrograde Markierung des Tractus perforans mit dem lipophilen Farbstoff DiI (1,1’-Dioctadecyl-3,3,3’,3’-tetramethylindo-carbocyaninperchlorat) in der OHSC etabliert und mit dem hydrophilen Dextranamin Mini Ruby versucht. Die retrograde Markierung entorhinaler Neurone und die durchgängige Darstellung des Tractus perforans in der OHSC mit Mini Ruby gelang in unseren Versuchen nicht, während die Markierung mit DiI erfolgreich war. Nach der Fixierung wurde die retrograde Markierung des Tractus perforans durch das Platzieren eines DiI-Kristalles im GD eingeleitet. Die auf diese Weise mit DiI markierten entorhinalen Neurone wurden mit neuronenspezifischen Antikörpern gegen NeuN gegengefärbt und somit zweifelsfrei als Neurone identifiziert. An diesem Modell wurde der Einfluß von MMF auf die Zahl DiI/NeuN doppelmarkierter entorhinaler Neurone quantitativ ausgewertet. Die quantitative Analyse erfolgte an Bildern, die mit einem konfokalen Laser Scanning Mikroskop gewonnen wurden. Die quantitative Auswertung retrograd mit DiI markierter OHSC zeigte, dass die Anzahl der DiI-NeuN doppelmarkierten entorhinalen Neurone in den MMF behandelten OHSC 19fach höher war als in den unbehandelten OHSC (p<0,05). Unsere Ergebnisse zeigen, dass MMF den Erhalt ganzer neuronaler Fasertrakte und Projektionen in der OHSC verbessert. Vor dem Hintergrund vorhandener Arbeiten, die auf neuroprotektive Effekte der MMF deuten, scheint MMF ein aussichtsreicher Kandidat für die Reduzierung des Sekundärschadens im Rahmen von Verletzungen des zentralen Nervensystems zu sein.
Einleitung In ihrer klinischen Symptomatik lassen sich der ischämische Schlaganfall (IS) und die intrazerebrale Blutung (ICH) nicht sicher unterscheiden. Hinsichtlich der Akuttherapie, die eine möglichst schnelle Wiederherstellung der zerebralen Sauerstoffversorgung („time is brain“) zum Ziel hat, ist diese Differenzierung jedoch essentiell. Das Ziel der vorliegenden Arbeit ist der Nachweis serologischer Biomarker in der Frühphase des Schlaganfalls zur Differenzierung zwischen IS und ICH. Hypothesen-gestützt wurden aufgrund pathophysiologischer Überlegungen hierfür die ZNS-spezifischen Proteine GFAP, UCH-L1, pNf-H, MBP und Tau untersucht. In einem hypothesenfreien Ansatz wurden Serumproben von Schlaganfallpatienten massenspektrometrisch analysiert.
Material und Methoden Die Patientenrekrutierung für die vorliegende Arbeit erfolgte im Rahmen der prospektiven, multizentrischen BE FAST II-Studie zur Evaluation von GFAP als Biomarker der akuten ICH. Von Mai 2012 bis April 2014 wurden Serumproben von Patienten mit akuter Schlaganfallsymptomatik in der Klinik für Neurologie der Goethe-Universität Frankfurt am Main gesammelt. Mittels kommerziell verfügbaren ELISA-Kits wurden die Serumkonzentrationen der Proteine UCH-L1, pNf-H, MBP und Tau bestimmt. Die Analyse der GFAP-Serumkonzentration erfolgte durch Roche Diagnostics mit Hilfe des Elecsys®-Systems, einem Elektrochemiluminiszenz-Immunoassay. Für die Massenspektrometrie wurden Serumproben aus der BE FAST-I-Studie, die von Ende des Jahres 2010 bis Anfang des Jahres 2011 asserviert wurden, eingesetzt. Die massenspektrometrischen Untersuchungen wurden in der Abteilung „Funktionelle Proteomics“ im Fachbereich Medizin der Goethe-Universität Frankfurt am Main durchgeführt.
Ergebnisse Tau und MBP ließen sich in den meisten Serumproben nicht nachweisen. In der pNf-H-Messung lag die Konzentration bei 27 von 35 Patienten oberhalb der Nachweisgrenze, wobei sich kein signifikanter Unterschied zwischen IS und ICH ergab (p = 0,69). UCH-L1 ließ sich bei 28 von 29 Patienten nachweisen. In der IS-Gruppe war eine signifikant (p = 0,005) höhere UCH-L1-Konzentration nachweisbar (Median 5,71 ng/ml) als in der ICH-Gruppe (Median 2,37 ng/ml). GFAP war bei allen 45 Patienten nachweisbar mit signifikant (p < 0,00005) höherer Konzentration in der ICH-Gruppe (Median 2,87 ng/ml) verglichen mit der IS-Gruppe (Median 0,01 ng/ml). Zudem fand sich eine positive Korrelation der UCH-L1-Werte in der IS-Gruppe mit dem Patientenalter (r = 0,62, p = 0,01), sowie eine positive Korrelation der GFAP-Werte in der ICH-Gruppe mit dem Patientenalter (r = 0,54, p = 0,03), dem NIHSS-Wert (r = 0,69, p = 0,04) und mit dem ICB-Volumen (r = 0,60, p = 0,01). In der massenspektrometrischen Analyse ließ sich eine Top Liste aus 22 Proteinen erstellen, die jeweils signifikante Unterschiede zwischen IS und ICH aufweisen.
Diskussion Die Rolle des Ubiquitin-Proteasom-System (UPS) und insbesondere von UCH-L1 beim IS ist bislang noch nicht abschließend geklärt. Nach einer zerebralen Ischämie ist jedoch eine Upregulation von UCH-L1 beschrieben, u.a. durch eine verstärkte UPS-Aktivität durch Aggregate fehlgefalteter Proteine. Daneben reagieren Neurone sensibler auf eine Hypoxie als Gliazellen mit einer dominierenden Freisetzung neuronaler Proteine wie UCH-L1. Bei ICH kommt es dagegen eher zu einer unspezifischen Destruktion des Hirngewebes mit vorwiegender glialer Schädigung und rascher Freisetzung glialer Proteine wie GFAP. Mit UCH-L1 und GFAP konnten zwei Proteine als erfolgsversprechende Kandidaten zur Differenzierung zwischen IS und ICH in der Frühphase identifiziert werden. Zur weiteren Validierung sind Untersuchungen an einer großen Population notwendig, die auch kleinere Infarkte und Hirnblutungen einschließt. Auch der Einfluss epidemiologischer und klinischer Faktoren wie z.B. dem Patientenalter muss weiter evaluiert werden.
Die mittels Massenspektrometrie erstellte Top Liste aus 22 Proteinen enthält vielversprechende Biomarker-Kandidaten, die signifikante Unterschiede zwischen IS und ICH aufweisen und ebenso an einem großen Patientenkollektiv weiter untersucht werden müssen.
Die Objekterkennung spielt für die menschliche Wahrnehmung eine zentrale Rolle. Hierzu nutzen wir das visuelle System in ähnlichem Maße wie den Tastsinn zur Exploration unserer Umwelt. In Kombination beider Sinne gelingt es uns unser Umfeld adäquat wahrzunehmen. Um postulierte Interaktionen zwischen visuellem und haptischem System aufzudecken und näher zu untersuchen, bedienten wir uns der Methode der funktionellen Magnetresonanztomographie.
Vorangehende funktionell bildgebende Studien über visuo-haptische zerebrale Informationsverarbeitung beschrieben den lateralen okzipi-talen taktil-visuellen Kortex (LOtv) und den intraparietalen Sulcus (IPS) als Hauptkandidaten für visuo-haptische Integration (Amedi et al., 2005; Sathian, 2005). Die meisten Studien betrachteten jedoch alleinig Schnittmengen aus Ergebnissen nach unimodaler Aktivierung. Um nun strengere statistische Kriterien für das Auffinden visuo-haptischer Integrationsareale zu testen (Beauchamp, 2005; Laurienti et al., 2005), suchten wir nach Regionen, welche durch direkte bimodale Stimulation stärker aktiviert werden, als nach Darbietung unimodaler Reize. Ziel dieser Arbeit war es, in Anlehnung an vorbestehende Literatur unter Zuhilfenahme strengerer statistischer Kriterien und mittels abstrakten Stimulations-Materials nach Integrationseffekten infolge simultaner visuo-haptischer Stimulation im menschlichen Gehirn zu suchen. Neurophysiologische Grundlage dieses Vorhabens ist dabei die Annahme, dass neuronale Gruppen spezifische Funktionen erfüllen und deren Aktivität über das sogenannte „Blood Oxygen Level Dependend-Signal“ (BOLD-Signal) mittels fMRT sichtbar gemacht werden kann.
Sechzehn gesunde Probanden partizipierten an der vorliegenden Studie. Während des Experiments kamen Schwarz-weiß-Fotografien und haptisch zu explorierende Figuren wahlweise von Tieren oder abstrakten Objekten zum Einsatz. Diese wurden dem jeweiligen Probanden teils als Einzelreiz (rein visuell/rein haptisch), teils simultan als visuo-haptische Reize während des fMRT-Messvorgangs dargeboten. Diese visuo-haptische Objektdarbietung führte zu einer signifikanten Aktivierung verschiedener kortikaler Gehirnregionen. Im Rahmen unseres Experiments konnten hauptsächlich drei bilaterale Regionen identifiziert werden, welche einen visuo-haptischen Integrationseffekt für das verwendete Stimulusmaterial zeigten: LOtv, IPS und das anteriore Cerebellum. Interessanterweise zeigte das rechtslaterale Cerebellum den robustesten visuo-haptischen Effekt, der weder vom Stimulusmaterial (Tiere/Fribbles), noch von der Kongruenz der dargebotenen Reize abzuhängen schien.
Aufgrund der Beobachtung, dass selbst isolierte motorische Beanspruchung Aktivationssignale im Gehirn auslösen kann, wurde ein zweites Studienprotokoll zum Ausschluss motorischer Aktivität als alleinige Komponente der Signalantwort entwickelt und eine zusätzliche rein motorische Kontrollbedingung eingeführt. Im Folgenden ließen sich die im Hauptexperiment identifizierten Regionen auch unter dieser zusätzlichen Bedingung abbilden. Mit unserem Studiendesign gelang es, die in der Literatur als multisensorisch vorbeschriebenen Regionen erneut nachzuweisen. Zusätzlich deuten unsere Ergebnisse darauf hin, dass es cerebelläre bimodal integrierende Areale gibt, welche auch in Abwesenheit zusätzlicher Aufgabenstellungen eine wichtige Rolle in visuo-haptischen Verarbeitungsprozessen spielen. Es bleibt jedoch abzuwarten, ob diese Regionen zukünftig endgültig als multisensorisch einzustufen sind.