Die Spontanheilungsversuche des vorderen Kreuzbands : eine experimentelle Untersuchung

Fragestellung Spontanheilungen von Rupturen des vorderen Kreuzbandes (VKB) wurden wiederholt mittels MRT beschrieben. In grundlegenden tierexperimentellen Untersuchungen wird geschlussfolgert, dass es keine Regeneration gäbe. Die Morphologie der Spontanheilung des VKB wurde im Tiermodell des Kaninchens untersucht. Methoden 32 männliche Kaninchen wurden medial arthrotomiert und das VKB durchtrennt. Die Durchtrennung erfolgte unter Sicht mittels Nr. 15 Skalpell, zusätzlich wurde die vollständige Trennung der Stümpfe durch mehrfache Instrumentenpassage kontrolliert. Eine Resektion von Fasern erfolgte nicht. Je 8 Tiere wurden 2, 4, 8 und 12 Wochen nach dem Eingriff getötet. Die Morphologie der Heilungsverläufe wurde nach Lo et al. [1] klassifiziert, neue Typen der Klassifikation hinzugefügt. Typ B (intrasynoviale Ruptur) und Typ C (knöcherner Ausriss) waren studienbedingt nicht möglich. Die Studie war vom Regierungspräsidium genehmigt. Ergebnisse Die untersuchten Tiere hatten einen unauffälligen postoperativen Verlauf. Bei unterschiedlicher Ausprägung hatten alle Tiere makroskopisch eine Knorpelschädigung. Nach chirurgischer Durchtrennung waren die VKBenden durchschnitten (mop ended Typ A). Dieser Typ wurde bei der Dissektion nicht mehr vorgefunden. Die VKBstümpfe waren bei Dissektion: retrahiert (Typ D), mit dem hinteren Kreuzband verwachsen (E), resorbiert (F), miteinander verbunden = narbengeheilt (G), oder es lag eine Kombination (H) verschiedener Typen vor. Als neue Typen wurden Verwachsungen mit dem Meniskus (I) oder mit der Gelenkkapsel bzw. dem Fettkörper (K) beschrieben. Die VKBstümpfe waren gering (G 1 = 7), deutlich (G2 = 3 bzw. 4 insges. bei zusätzlicher Verwachsung mit dem Innenmeniskus) oder hypertroph (G 3 = 3) miteinander verwachsen. [Tab. 1] Schlussfolgerungen Der VKBriss führt häufig zur Kniegelenksinstabilität und Osteoarthrose. Nach Durchtrennung des VKB wird in Studien der Osteoarthroseforschung im Kaninchenmodell der Befund nie detailliert. In einem systematischen Vergleich der Regenerationsfähigkeit von partiell und komplett durchtrennten VKBs fanden Hefti et al. [2] weder bei skeletall unreifen noch bei jungen erwachsenen Kaninchen eine Regeneration nach kompletter Durchtrennung. Sie berichteten als Regelfall die Resorption nach 3 Monaten, in 2 Fällen Verwachsungen mit dem hinteren Kreuzband. Die hier berichteten Daten sind im Gegensatz zu Hefti's Untersuchungen. Sie stimmen aber gut mit humanen MRT-Untersuchungen und Arthroskopien nach Kreuzbandverletzungen überein. Das VKB versucht durch Verwachsung eine Heilung der VKBstümpfe zu erzielen oder Anschluss an andere Kniegelenksstrukturen zu gewinnen. Somit besteht auch im Tiermodell des Kaninchens eine gewisse Spontanheilungsaktivität des VKB, deren biomechanische Stabilität allerdings oft unzureichend erschien. Eine Kniegelenksarthrose entwickelte sich in den untersuchten Gelenken

Protection against Chlamydia Promoted by a Subunit Vaccine (CTH1) Compared with a Primary Intranasal Infection in a Mouse Genital Challenge Model

Background: The chlamydial proteins CT443 (OmcB) and CT521 (rl16) have previously been identified as human B and/or T cell targets during a chlamydial infection in humans. Here we compare the protective effector mechanism promoted by a fusion protein composed of CT521 and CT443 (CTH1) with a primary intranasal Chlamydia muridarum infection known to provide high levels of protection against a genital chlamydial challenge. Methodology/Principal Findings: The fusion protein CTH1, adjuvanted with a strong Th1 inducing cationic adjuvant (CAF01), significantly reduced the bacterial shedding compared to a control group in both a C. trachomatis Serovar D and C. muridarum challenge model. The CTH1/CAF01 vaccine was found to induce polyfunctional T cells consisting of TNFa/IL-2 and TNFa/IL-2/IFN-c positive cells and high titers of CTH1 specific IgG2a and IgG1. By depletion experiments the protection in the C. muridarum challenge model was demonstrated to be mediated solely by CD4 + T cells. In comparison, an intranasal infection with C. muridarum induced a T cell response that consisted predominantly of TNFa/IFN-c co-expressing effector CD4 + T cells and an antibody response consisting of C. muridarum specific IgG1, IgG2a but also IgA. This response was associated with a high level of protection against challenge—a protection that was only partially dependent on CD4 + T cells. Furthermore, whereas the antibody response induced by intranasal infection was strongly reactive against the native antigens displayed in the chlamydial elementary body, only low levels of antibodies against this preparation were foun

Influence of different alloying strategies on the mechanical behavior of tool steel produced by laser-powder bed fusion

Additive manufacturing is a high-potential technique that allows the production of components with almost no limitation in complexity. However, one of the main factors that still limits the laser-based additive manufacturing is a lack of processable alloys such as carbon martensitic hardenable tool steels, which are rarely investigated due to their susceptibility to cold cracking. Therefore, this study aimed to expand the variety of steels for laser powder bed fusion (L-PBF) by investigating an alternative alloying strategy for hot work tool steel powder. In this study, a comprehensive investigation was performed on the powder and L-PBF processed specimen properties and their correlation with the existing defects. Cubical specimens were created using the following two alloying strategies by means of L-PBF: conventional pre-alloyed gas-atomized powder and a mixture of gas-atomized powder with mechanically crushed pure elements and ferroalloys. The influence of the particle parameters such as morphology were correlated to the defect density and resulting quasi-static mechanical properties. Micromechanical behavior and damage evolution of the processed specimens were investigated using in situ computed tomography. It was shown that the properties of the L-PBF processed specimens obtained from the powder mixture performs equal or better compared to the specimens produced from conventional powder

Biochemisches Monitoring nach Meniskektomie

Fragestellung Die Schädigung des Kollagennetzwerks ist ein frühes Ereignis der Arthrose (OA). Wir untersuchten ein Kollagen Typ II -Neoepitop (CTX) in der Synovialflüssigkeit (SF) nach kompletter medialer Meniskektomie (ME). Methoden 32 NZW-Kaninchen hatten eine ME des rechten Kniegelenks. Kontrolle: 11 shamoperierte, 8 unoperierte Kaninchen. Die ME-Kaninchen wurden nach 2 (n = 8), 4 (n = 8) , 8 (n = 8) und 12 (n = 8) Wochen getötet, SF-lavagen beider Kniegelenke durchgeführt. Der ELISA misst ein Kollagen Typ II - Neoepitop, das nach Spaltung der C-telopeptide cross-linking Domaine entsteht. Makroskopisch: Grading beider Kniegelenke mit einem 9 Felder-Schema: Einzelflächen und Gesamtsummen von Tibia, Femur (jeweils medial und lateral) und Patella Histologisch: Grading mit H&E und Safranin O Schnitten (u.a. Proteoglykangehalt, Matrixstruktur, Zellularität, Tidemark und Osteophyten) Statistik: Wilcoxon - und Mann - Whitney U Test. Ergebnisse Makroskopisch: signifikante Veränderungen von medialer Tibia und Femur ab 2 Wochen nach ME, im Vergleich mit Gegenseite und mit nichtoperierten Kaninchen. Histologisch: beginnende OA zu allen Zeitpunkten. ME Knie: CTX Werte in der SF deutlich erhöht, zum kontralateralen Knie für 2, 4, 8 und 12 Wochen signifikant. Nichtoperierte Tiere: keine Unterschiede linkes vs. rechtes Knie, im Vergleich zur ME zu allen Zeitpunkten signifikant niedriger. Schlussfolgerungen Knorpelmarker sind Parameter der OA. Die Metalloproteinasen 1, 8 und 13 erzeugen ein Kollagen Typ II - Neoepitop, das zum Monitoring der arthrotischen Veränderungen geeignet erscheint

Free Breathing Real-Time Cardiac Cine Imaging With Improved Spatial Resolution at 3 T

Objectives: The aim of this study was to evaluate free-breathing single-shot real-time cine imaging for functional cardiac imaging at 3 +/- with increased spatial resolution. Special emphasis of this study was placed on the influence of parallel imaging techniques. Materials and Methods: Gradient echo phantom images were acquired with GRAPPA and modified SENSE reconstruction using both integrated and separate reference scans as well as TGRAPPA and TSENSE. In vivo measurements were performed for GRAPPA reconstruction with an integrated and a separate reference scan, as well as TGRAPPA using balanced steady-state free precession protocols. Three clinical protocols, rtLRInt (T-res = 51.3 milliseconds; voxel, 2.5 x 5.0 x 10 mm(3)), rtMRSep (T-res = 48.8 milliseconds; voxel, 1.9 x 3.1 x 10 mm(3)), and rtHRSep ((Tres) = 48.3 milliseconds; voxel, 1.6 x 2.6 x 10 mm(3)), were investigated on 20 volunteers using GRAPPA reconstruction with internal as well as separate reference scans. End-diastolic volume, end-systolic volume, ejection fraction, peak ejection rate, peak filling rate, and myocardial mass were evaluated for the left ventricle and compared with an electrocardiogram-triggered segmented readout cine protocol used as standard of reference. All studies were performed at 3 T. Results: Phantom and in vivo data demonstrate that the combination of GRAPPA reconstruction with a separate reference scan provides an optimal compromise of image quality as well as spatial and temporal resolution. Functional values (P values) for the standard of reference, rtLRInt, rtMRSep, and rtHRSep end-diastolic volume were 141 +/- 24 mL, 138 +/- 21 mL, 138 +/- 19 mL, and 128 +/- 33 mL, respectively (P = 0.7, 0.7, 0.4); end-systolic volume, 55 +/- 15 mL, 61 +/- 14 mL, 58 +/- 12 mL, and 55 +/- 20 mL, respectively (P = 0.23, 0.43, 0.62); ejection fraction, 61% +/- 5%, 57% +/- 5%, 58% +/- 4%, and 56% +/- 8%, respectively (P = 0.01, 0.11, 0.06); peak ejection rate, 481 +/- 73 mL/s, 425 +/- 62 mL/s, 434 +/- 67 mL/s, and 381 +/- 86 mL/s, respectively (P = 0.03, 0.04, 0.01); peak filling rate, 555 +/- 80 mL/s, 480 +/- 70 mL/s, 500 +/- 70 mL/s, and 438 +/- 108 mL/s, respectively (P = 0.007, 0.05, 0.004); and myocardial mass, 137 +/- 26 g, 141 T 25 g, 141 +/- 23 g, and 130 +/- 31 g, respectively (P = 0.62, 0.54, 0.99). Conclusions: Using a separate reference scan and high acceleration factors up to R = 6, single-shot real-time cardiac imaging offers adequate temporal and spatial resolution for accurate assessment of global left ventricular function in free breathing with short examination times

Free Breathing Real-Time Cardiac Cine Imaging With Improved Spatial Resolution at 3 T

Objectives: The aim of this study was to evaluate free-breathing single-shot real-time cine imaging for functional cardiac imaging at 3 +/- with increased spatial resolution. Special emphasis of this study was placed on the influence of parallel imaging techniques. Materials and Methods: Gradient echo phantom images were acquired with GRAPPA and modified SENSE reconstruction using both integrated and separate reference scans as well as TGRAPPA and TSENSE. In vivo measurements were performed for GRAPPA reconstruction with an integrated and a separate reference scan, as well as TGRAPPA using balanced steady-state free precession protocols. Three clinical protocols, rtLRInt (T-res = 51.3 milliseconds; voxel, 2.5 x 5.0 x 10 mm(3)), rtMRSep (T-res = 48.8 milliseconds; voxel, 1.9 x 3.1 x 10 mm(3)), and rtHRSep ((Tres) = 48.3 milliseconds; voxel, 1.6 x 2.6 x 10 mm(3)), were investigated on 20 volunteers using GRAPPA reconstruction with internal as well as separate reference scans. End-diastolic volume, end-systolic volume, ejection fraction, peak ejection rate, peak filling rate, and myocardial mass were evaluated for the left ventricle and compared with an electrocardiogram-triggered segmented readout cine protocol used as standard of reference. All studies were performed at 3 T. Results: Phantom and in vivo data demonstrate that the combination of GRAPPA reconstruction with a separate reference scan provides an optimal compromise of image quality as well as spatial and temporal resolution. Functional values (P values) for the standard of reference, rtLRInt, rtMRSep, and rtHRSep end-diastolic volume were 141 +/- 24 mL, 138 +/- 21 mL, 138 +/- 19 mL, and 128 +/- 33 mL, respectively (P = 0.7, 0.7, 0.4); end-systolic volume, 55 +/- 15 mL, 61 +/- 14 mL, 58 +/- 12 mL, and 55 +/- 20 mL, respectively (P = 0.23, 0.43, 0.62); ejection fraction, 61% +/- 5%, 57% +/- 5%, 58% +/- 4%, and 56% +/- 8%, respectively (P = 0.01, 0.11, 0.06); peak ejection rate, 481 +/- 73 mL/s, 425 +/- 62 mL/s, 434 +/- 67 mL/s, and 381 +/- 86 mL/s, respectively (P = 0.03, 0.04, 0.01); peak filling rate, 555 +/- 80 mL/s, 480 +/- 70 mL/s, 500 +/- 70 mL/s, and 438 +/- 108 mL/s, respectively (P = 0.007, 0.05, 0.004); and myocardial mass, 137 +/- 26 g, 141 T 25 g, 141 +/- 23 g, and 130 +/- 31 g, respectively (P = 0.62, 0.54, 0.99). Conclusions: Using a separate reference scan and high acceleration factors up to R = 6, single-shot real-time cardiac imaging offers adequate temporal and spatial resolution for accurate assessment of global left ventricular function in free breathing with short examination times

A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children.

BACKGROUND: GMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda. METHODS: Children 12-60months old were randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL. RESULTS: A cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). CONCLUSIONS: GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role

Micro-magnetic and microstructural characterization of wear progress on case-hardened 16MnCr5 gear wheels

The evaluation of wear progress of gear tooth flanks made of 16MnCr5 was performed using non-destructive micro-magnetic testing, specifically Barkhausen noise (BN) and incremental permeability (IP). Based on the physical interaction of the microstructure with the magnetic field, the micro-magnetic characterization allowed the analysis of changes of microstructure caused by wear, including phase transformation and development of residual stresses. Due to wide parameter variation and application of bandpass filter frequencies of micro-magnetic signals, it was possible to indicate and separate the main damage mechanisms considering the wear development. It could be shown that the maximum amplitude of BN correlates directly with the profile form deviation and increases with the progress of wear. Surface investigations via optical and scanning electron microscopy indicated strong surface fatigue wear with micro-pitting and micro-cracks, evident in cross-section after 3 × 105 cycles. The result of fatigue on the surface layer was the decrease of residual compression stresses, which was indicated by means of coercivity by BN-analysis. The different topographies of the surfaces, characterized via confocal white light microscopy, were also reflected in maximum BN-amplitude. Using complementary microscopic characterization in the cross-section, a strong correlation between micro-magnetic parameters and microstructure was confirmed and wear progress was characterized in dependence of depth under the wear surface. The phase transformation of retained austenite into martensite according to wear development, measured by means of X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) was also detected by micro-magnetic testing by IP-analysis

Antibody levels to multiple malaria vaccine candidate antigens in relation to clinical malaria episodes in children in the Kasena-Nankana district of Northern Ghana

BACKGROUND: Considering the natural history of malaria of continued susceptibility to infection and episodes of illness that decline in frequency and severity over time, studies which attempt to relate immune response to protection must be longitudinal and have clearly specified definitions of immune status. Putative vaccines are expected to protect against infection, mild or severe disease or reduce transmission, but so far it has not been easy to clearly establish what constitutes protective immunity or how this develops naturally, especially among the affected target groups. The present study was done in under six year old children to identify malaria antigens which induce antibodies that correlate with protection from Plasmodium falciparum malaria. METHODS: In this longitudinal study, the multiplex assay was used to measure IgG antibody levels to 10 malaria antigens (GLURP R0, GLURP R2, MSP3 FVO, AMA1 FVO, AMA1 LR32, AMA1 3D7, MSP1 3D7, MSP1 FVO, LSA-1and EBA175RII) in 325 children aged 1 to 6 years in the Kassena Nankana district of northern Ghana. The antigen specific antibody levels were then related to the risk of clinical malaria over the ensuing year using a negative binomial regression model. RESULTS: IgG levels generally increased with age. The risk of clinical malaria decreased with increasing antibody levels. Except for FMPOII-LSA, (p = 0.05), higher IgG levels were associated with reduced risk of clinical malaria (defined as axillary temperature ≥37.5°C and parasitaemia of ≥5000 parasites/ul blood) in a univariate analysis, upon correcting for the confounding effect of age. However, in a combined multiple regression analysis, only IgG levels to MSP1-3D7 (Incidence rate ratio = 0.84, [95% C.I.= 0.73, 0.97, P = 0.02]) and AMA1 3D7 (IRR = 0.84 [95% C.I.= 0.74, 0.96, P = 0.01]) were associated with a reduced risk of clinical malaria over one year of morbidity surveillance. CONCLUSION: The data from this study support the view that a multivalent vaccine involving different antigens is most likely to be more effective than a monovalent one. Functional assays, like the parasite growth inhibition assay will be necessary to confirm if these associations reflect functional roles of antibodies to MSP1-3D7 and AMA1-3D7 in this population

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice

Introduction: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. Methods: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. Results: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). Conclusion: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings