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Circulating P2X7 receptor signaling components as diagnostic biomarkers for temporal lobe epilepsy
(2021)
Circulating molecules have potential as biomarkers to support the diagnosis of epilepsy and to assist with differential diagnosis, for example, in conditions resembling epilepsy, such as in psychogenic non-epileptic seizures (PNES). The P2X7 receptor (P2X7R) is an important regulator of inflammation and mounting evidence supports its activation in the brain during epilepsy. Whether the P2X7R or P2X7R-dependent signaling molecules can be used as biomarkers of epilepsy has not been reported. P2X7R levels were analyzed by quantitative ELISA using plasma samples from controls and patients with temporal lobe epilepsy (TLE) or PNES. Moreover, blood cell P2X7R expression and P2X7R-dependent cytokine signature was measured following status epilepticus in P2X7R-EGFP reporter, wildtype, and P2X7R-knockout mice. P2X7R plasma levels were higher in TLE patients when compared with controls and patients with PNES. Plasma levels of the broad inflammatory marker protein C-Reactive protein (CRP) were similar between the three groups. Using P2X7R-EGFP reporter mice, we identified monocytes as the main blood cell type expressing P2X7R after experimentally evoked seizures. Finally, cytokine array analysis in P2X7R-deficient mice identified KC/GRO as a potential P2X7R-dependent plasma biomarker following status epilepticus and during epilepsy. Our data suggest that P2X7R signaling components may be a promising subclass of circulating biomarkers to support the diagnosis of epilepsy.
Objective: The NADPH oxidase Nox4 is an important source of H2O2. Nox4-derived H2O2 limits vascular inflammation and promotes smooth muscle differentiation. On this basis, the role of Nox4 for restenosis development was determined in the mouse carotid artery injury model. Methods and results: Genetic deletion of Nox4 by a tamoxifen-activated Cre-Lox-system did not impact on neointima formation in the carotid artery wire injury model. To understand this unexpected finding, time-resolved single-cell RNA-sequencing (scRNAseq) from injured carotid arteries of control mice and massive-analysis-of-cDNA-ends (MACE)-RNAseq from the neointima harvested by laser capture microdissection of control and Nox4 knockout mice was performed. This revealed that resting smooth muscle cells (SMCs) and fibroblasts exhibit high Nox4 expression, but that the proliferating de-differentiated SMCs, which give rise to the neointima, have low Nox4 expression. In line with this, the first weeks after injury, gene expression was unchanged between the carotid artery neointimas of control and Nox4 knockout mice. Conclusion: Upon vascular injury, Nox4 expression is transiently lost in the cells which comprise the neointima. NADPH oxidase 4 therefore does not interfere with restenosis development after wire-induced vascular injury.
Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both p < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p < 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
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.
Introduction: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. Methods: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. Results: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups). By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14–6.33, p ≤ 0.01)). Conclusion: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.
Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.
Background: The aim of this study was to evaluate the longer-term results of bicuspid aortic valve (BAV) repair with or without aortic root replacement. Methods: From 1999 to 2017, 142 patients with or without aortic root dilatation who underwent repair of a regurgitant BAV were included in the study. Ninety-four patients underwent isolated BAV repair (Group 1; median age 43 years) and 48 patients underwent valve-sparing aortic root replacement plus BAV repair (aortic valve reimplantation—Group 2; median age 48 years). Median clinical follow-up time was 5.9 years (range 0.5–15) in Group 1 and 3 years (range 0.5–16) in Group 2, respectively. Results: In-hospital mortality was 1% in Group 1, and 2% in Group 2 (p = .6). The 5- and 10-year survival was 93 ± 2.9% and 81 ± 5.8% in Group 1 and 96 ± 3.1% and 96 ± 3.1% in Group 2, respectively (p = .31). Eleven patients of Group 1 (1.7%/patient-year) and five patients of Group 2 (2.2%/patient-year) underwent reoperation of the aortic valve (p = .5). The 5- and 10-year freedom from reoperation were 93.0 ± 2.1% and 77.1 ± 7.1% in Group 1 and 93.0 ± 5.0% and 76.7 ± 9.6% in Group 2 (p = .83), respectively. At the latest follow-up, only two patients of Group 1 and 1 patient of Group 2 had AV regurgitation = 2° (p = .7). The cumulative linearized incidence of all valve-related complications (bleeding, stroke, endocarditis, and reoperation) was 2.9%/patient-year in Group 1% and 4%/patient-year in Group 2, respectively (p = .6). Conclusions: Isolated BAV repair and combined aortic valve reimplantation plus BAV repair provide good clinical longer-term outcomes with relatively low reoperation rate and durable valve function.
Objective: Evaluation of survival of teeth with class III furcation involvement (FI) ≥5 years after active periodontal treatment (APT) and identification of prognostic factors. Methods: All charts of patients who completed APT at the Department of Periodontology of Goethe-University Frankfurt, Germany, beginning October 2004 were screened for teeth with class III FI. APT had to be accomplished for ≥5 years. Charts were analysed for data of class III FI teeth at baseline (T0), at accomplishment of APT (T1), and at the last supportive periodontal care (T2). Baseline radiographic bone loss (RBL) and treatment were assessed. Results: One-hundred and sixty patients (age: 54.4 ± 9.8 years; 82 females; 39 active smokers; 9 diabetics, 85 stage III, 75 stage IV, 59 grade B, 101 grade C) presented 265 teeth with class III FI. Ninety-eight teeth (37%) were lost during 110, 78/137 (median, lower/upper quartile) months. Logistic mixed-model regression and mixed Cox proportional hazard model associated adjunctive systemic antibiotics with fewer tooth loss (26% vs. 42%; p = .019/.004) and RBL (p = .014/.024) and mean probing pocket depth (PPD) at T1 (p < .001) with more tooth loss. Conclusions: Subgingival instrumentation with adjunctive systemic antibiotics favours retention of class III furcation-involved teeth. Baseline RBL and PPD at T1 deteriorate long-term prognosis.
Objective: This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. Methods: A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. Results: Long-term data for 262 patients (mean age = 40 years, range = 5–81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25–400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. Significance: BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes. Key Points Long-term postmarketing data for brivaracetam in 262 patients showed an overall retention rate of 50.8%; At 12 months, the 50% responder rate for brivaracetam was 33.1%, with 10.9% reporting seizure freedom; Previous treatment with levetiracetam (90%) did not impact brivaracetam retention or efficacy; Levetiracetam treatment failure should not preclude brivaracetam introduction; No long-term efficacy predictors could be identified.
Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness–resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.
Purpose: Amblyopia with eccentric fixation, especially when not diagnosed early, is a therapeutic challenge, as visual outcome is known to be poorer than in amblyopia with central fixation. Consequently, treatment after late diagnosis is often denied. Electronic monitoring of occlusion provides us the chance to gain first focussed insight into age-dependent dose response and treatment efficiency, as well as the shift of fixation in this rare group of paediatric patients. Methods: In our prospective pilot study, we examined amblyopes with eccentric fixation during 12 months of occlusion treatment. We evaluated their visual acuity, recorded patching duration using a TheraMon®-microsensor, and determined their fixation with a direct ophthalmoscope. Dose-response relationship and treatment efficiency were calculated. Results: The study included 12 participants with strabismic and combined amblyopia aged 2.9–12.4 years (mean 6.5). Median prescription of occlusion was 7.7 h/day (range 6.6–9.9) and median daily received occlusion was 5.2 h/day (range 0.7–9.7). At study end, median acuity gain was 0.6 log units (range 0–1.6) and residual interocular visual acuity difference (IOVAD) 0.3 log units (range 0–1.8). There was neither significant acuity gain nor reduction in IOVAD after the 6th month of treatment. Children younger than 4 years showed best response with lowest residual IOVAD at study end. Efficiency calculation showed an acuity gain of approximately one line from 100 h of patching in the first 2 months and half a line after 6 months. There was a significant decline of treatment efficiency with age (p = 0.01). Foveolar fixation was achieved after median 3 months (range 1–6). Three patients (> 6 years) did not gain central fixation. Conclusion: Eccentric fixation is a challenge to therapy success. Based on electronic monitoring, our study quantified for the first time the reduction of treatment efficiency with increasing age in amblyopes with eccentric fixation. Despite some improvement in patients up to 8 years, older patients showed significantly lower treatment efficiency. In younger patients with good adherence, despite poor initial acuity, central fixation and low residual IOVAD could be attained after median 3 months. Hence, the necessity of early diagnosis and intensive occlusion should be emphasized.
Musculoskeletal disorders of the trunk and neck are common among cleaners. Vacuum cleaning is a demanding activity. The aim of this study was to present the movement profile of the trunk and neck during habitual vacuuming. The data were collected from 31 subjects (21f./10 m) using a 3D motion analysis system (Xsens). 10 cycles were analysed in vacuuming PVC and carpet floors with 8 vacuum cleaners. The joint angles and velocities were represented statistically descriptive. When vacuuming, the trunk is held in a forwardly inclined position by a flexion in the hip and rotated from this position. In the joint angles and velocities of the spine, the rotation proved to be dominant. A relatively large amount of movement took place in the cervical spine and also in the lumbar spine. The shown movement profile is rather a comfort area of vacuuming which may serve as a reference for ergonomics in vacuuming.
Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
Körpergrößenschätzung und Geschlechtsdiskrimination anhand von metrischen Schädeldachparametern
(2021)
1. Körpergrößenschätzung und Geschlechtsdiskrimination; Messung des maximalen Längs- und Querdurchmessers des Schädels
Knöcherne Schädel sind häufig die einzigen Skelettüberreste, die für forensisch-osteologische Untersuchungen zur Verfügung stehen. Am Schädel lassen sich gute Hinweise für Geschlechtsdiskriminierung, Lebensalter und Herkunft erlangen. Es sollte überprüft werden, ob mithilfe der an der frischen Sägefläche des Hirnschädels gemessenen maximalen Schädellänge und -breite eine Schätzung der Körpergröße oder eine Geschlechtsdiskrimination möglich ist.
In die Untersuchung gingen die Autopsieberichte von 959 Verstorbenen ein, die das 21. Lebensjahr vollendet hatten und in den Jahren 2004 bis 2008 am Institut für Rechtsmedizin der Universität Gießen obduziert worden waren. Um den Einfluss der Herkunft der Individuen auf die untersuchten Maße abzuschätzen, wurde eine getrennte Betrachtung der in Deutschland (n=760) und außerhalb von Deutschland geborenen Individuen (n=199) durchgeführt. Trotz signifikanter Korrelationen der maximalen Schädellänge mit der Körpergröße konnte aufgrund der hohen Standardfehler keine sinnvolle einsetzbare Regressionsformel berechnet werden. Die maximale Schädelbreite zeigte keine nennenswerte Korrelation zur Körperlänge. Bezüglich der Geschlechtsdiskrimination konnte für kaukasoide Individuen folgende Aussage getroffen werden: Schädellängen kleiner 15,5 cm sprechen für weibliche und größer 19 cm für männliche Individuen. Bei der Schädelbreite weisen Werte kleiner 12,5 cm auf eine Frau und größer 15,5 cm auf einen Mann hin.
2. Über die Korrelation von Schädelnahtlängen und Körperhöhe bei Mitteleuropäern
An den Stellen des Schädeldachs, an denen 2 benachbarte Knochenanlagen aneinanderstoßen, bildet das Bindegewebe Knochennähte, Suturae (Sutura sagitalis, Sutura coronalis, Sutura lambdoidea) aus (Schiebler et al. 2002).
Ein vielversprechender Ansatz hinsichtlich der Verwendung der Schädelnähte zur Körperhöhenschätzung wurde von Rao et al. (2009) publiziert. Sie konnten in ihrer Studie an 87 Schädeln südindischer männlicher Individuen eine Korrelation sowohl zwischen Sagittal- als auch Coronarnaht und Körperhöhe nachweisen und für deren Berechnung eine Regressionsformel ableiten. In der vorliegenden prospektiven Studie sollte überprüft werden, ob sich die Ergebnisse von Rao et al. auf eine mitteleuropäische Population übertragen lassen, und ob sich anhand von Sektionsfällen eine Korrelation zwischen Schädelnahtlängen (Sagittal- und Coronarnaht) einerseits und Körperlänge andererseits nachweisen lässt.
Am Gießener Institut für Rechtsmedizin wurden in den Jahren 2009 und 2010 bei 117 Verstorbenen prospektiv die Längen der Sagittal- und Coronarnaht sowie die Körperhöhen gemessenen. Das Alter der Verstorbenen lag zwischen 15 und 96 Jahren (Mittelwert 52,8 Jahre, Median 51 Jahre); 82 Personen waren männlich und 35 weiblich. Die Länge der Sagittalnaht in Bezug auf die Körperhöhe ergab in der Regressionsanalyse einen Korrelationskoeffizienten von lediglich r = 0,045 (p = 0,617). Ähnliche Ergebnisse wurden für die Coronarnaht ermittelt; hierbei betrug der Korrelationskoeffizient r = 0,015. Bei Annahme einer maximal zulässigen Fehlerwahrscheinlichkeit von α = 0,05 erwies sich keine der durchgeführten Regressionsanalysen als statistisch signifikant. Nach den erhobenen Befunden ist weder die Länge der Sagittal- noch die Länge der Coronarnaht geeignet, bei Mitteleuropäern die Körperhöhe zu schätzen.
Die Therapie des critical size defects stellt eine große Herausforderung der Medizin dar. Die Knochendefekte können beispielsweise in Folge von Tumorresektionen, Knochenheilungsstörungen oder nach Frakturen entstehen. Den aktuellen Goldstandard in der Therapie großer Knochendefekte stellt die Transplantation von autologem Knochenmaterial dar. Die Entnahme des Materials aus dem Beckenkamm ist allerdings mit Nachteilen wie der Entnahmemorbididät verbunden. Alternativ können Tissue-Engineering Techniken eingesetzt werden, bei denen Zellen mit regenerativem Potential mit Knochenersatzmaterialien und Wachstumsfaktoren kombiniert werden, um eine Defektheilung zu erzielen. Der Einsatz von bone marrow mononuclear cells (BMC) mit einem osteokonduktiven Gerüst wie b-TCP hat sich als geeignetes Therapiekonzept bewiesen. Einen weiteren Ansatz stellt die Verwendung von autologen Blutkonzentraten wie beispielsweise des platelet rich fibrin (PRF) dar. Das PRF kann innerhalb weniger Minuten aus patienteneigenem Blut mittels Zentrifugation hergestellt und direkt angewandt werden. Durch seine charakteristische dreidimensionale Fibrinmatrix dient das PRF als Reservoir für Wachstums- und Regenerationsfaktoren.
Die Kombination von BMC mit PRF könnte also durch die gesteigerte Konzentration an Zytokinen und Wachstumsfaktoren wie VEGF und TGF-b zu einer Unterstützung der regenerativen Wirkung der BMC führen. Ziel dieser Arbeit war es daher, den Effekt von PRF auf BMC in vitro zu analysieren.
In Anlehnung an das low speed centrifugation concept wurden zwei verschiedene PRF-Matrices hergestellt. Diese wurden entweder mit mittlerer relativer Zentrifugalbeschleunigung (RCF) (208g) oder mit geringer RCF (60g) zentrifugiert. Um eine geeignete Konzentration des PRF zur Kombination mit den BMC zu finden, wurde im Vorfeld eine Dosisfindungskurve erstellt. Zu diesem Zweck wurde der Einfluss ansteigender PRF-Konzentrationen auf die metabolische Aktivität der BMC nach 7 Tagen Inkubation analysiert. Wir konnten einen Trend zu erhöhten Werten bei einer Konzentration von 10% des PRF beobachten. Die metabolische Aktivität der BMC wurde durch höhere PRF-Konzentrationen nicht weiter gesteigert.
Aufgrund dieser Ergebnisse wurde für die nachfolgenden Experimente eine Konzentration von 10% der PRF-Aufbereitungen und der Serum-Kontrolle eingesetzt.
Zur Charakterisierung der beiden PRF-Aufbereitungen wurde der Gehalt an Wachstumsfaktoren im Vergleich zu humanem Serum untersucht. Es zeigten sich signifikant gesteigerte Konzentrationen von Insulin-like Growth Factor-1 (IGF-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1) und Transforming Growth Factor-b (TGF-b) in dem PRF. Bezüglich des Vascular Endothelial Growth Factor (VEGF)-Gehaltes ließ sich allerdings kein Unterschied zwischen humanem Serum und den PRF-Matrices darstellen.
Der Effekt des PRF low-RCF und PRF medium-RCF auf die Viabilität der BMC wurde anhand der metabolischen Aktivität nach 2, 7 und 14 Tagen Inkubation untersucht. Als Kontrollgruppe diente hierbei der Zusatz von humanem Serum. Die metabolische Aktivität der BMC zeigte sich an Tag 14 in allen Gruppen signifikant gesteigert.
Außerdem konnten wir zeigen, dass der Zusatz von PRF zu BMC zu einer statistisch signifikant erhöhten Genexpression der Matrix-Metalloproteasen (MMP) -2, -7 und - 9 im Vergleich zur Serum-Kontrollgruppe führt.
In unseren Versuchen konnte nachgewiesen werden, dass die apoptotische Aktivität der BMC durch Kombination mit PRF nicht negativ beeinflusst wird. Zusammenfassend lässt sich sagen, dass sich PRF-Matrices als geeignete allogene oder autologe Quelle von Wachstums- und Regenerationsfaktoren nutzen lassen. Sie besitzen damit die Kapazität, Zellen wie die BMC zu stimulieren und zu aktivieren. Unsere Studie zeigt, dass der Zusatz von PRF für BMC-gestützte Therapien förderlich sein könnte. Dies muss jedoch in geeigneten Tiermodellen überprüft werden.
Doping ist ein Thema, das den modernen Leistungssport – und nicht nur diesen – seit jeher begleitet. Immer wieder werden Sportler – oft noch nach Jahren – überführt, illegale Substanzen zur Leistungssteigerung eingenommen zu haben. Der Landessportbund Hessen e. V. hat im Sommer 2013 Professor Dr. Dr. Gerd Geißlinger zum Anti-Doping-Beauftragten berufen. Für den UniReport hat Dr. Beate Meichsner mit dem Direktor des Instituts für Klinische Pharmakologie am Klinikum der Goethe-Universität über die damit verbundenen Aufgaben, Ziele und
Möglichkeiten gesprochen.