Unloader bracing in osteoarthritis of the knee - Is there a direct effect on the damaged cartilage?

BACKGROUND: Unloading knee braces represent a conservative treatment option for non-pharmalogical management of unicompartmental osteoarthritis of the knee. Though there is consensus on the clinical effectiveness of unloading, the effect mechanism of bracing remains part of a debate. Our study was designed to assess the effect of unloader bracing on damaged cartilage via MRI cartilage mappings. METHODS: Fourteen patients (7 female, 7 male, mean age 43.1 ± 9.4 years) with unicompartmental cartilage wear in knees with varus or valgus malalignment were enrolled. Clinical scores, radiographs and MR-graphic properties (T2/T2* mapping, T1 Delayed Gadolinium Enhanced MRI of the cartilage (dGEMRIC) mapping, high-resolution PDw sequences) of knee cartilage were recorded before and three months after brace use. RESULTS: Bracing the knees for a mean of 14.4 ± 2.0 weeks (range 11 to 18 weeks) resulted in significant pain reduction (VAS changed from 5.9 ± 2.0 to 2.0 ± 1.3, p < 0.001) and improvement in knee function (KOOS increased from 42.1 ± 22.7 to 64.8 ± 18.7, p < 0.001). In the affected cartilage regions T2 relaxation times significantly decreased from 56.1 ± 11.4 ms to 46.5 ± 11.2 ms (p < 0.05). No changes in T1-dGEMRIC and T2* relaxation times, thickness or the extent of the damaged cartilage area could be detected. CONCLUSIONS: Our results suggest, that unloader bracing improves the biochemical properties of the damaged cartilage by increasing collagen and proteoglycan concentration as well as decreasing the cartilage edema.

Magnetic Direct-Write Skyrmion Nanolithography.

Magnetic skyrmions are stable spin textures with quasi-particle behavior and attract significant interest in fundamental and applied physics. The metastability of magnetic skyrmions at zero magnetic field is particularly important to enable, for instance, a skyrmion racetrack memory. Here, the results of the nucleation of stable skyrmions and formation of ordered skyrmion lattices by magnetic force microscopy in (Pt/CoFeSiB/W)n multilayers, exploiting the additive effect of the interfacial Dzyaloshinskii-Moriya interaction, are presented. The appropriate conditions under which skyrmion lattices are confined with a dense two-dimensional liquid phase are identified. A crucial parameter to control the skyrmion lattice characteristics and the number of scans resulting in the complete formation of a skyrmion lattice is the distance between two adjacent scanning lines of a magnetic force microscopy probe. The creation of skyrmion patterns with complex geometry is demonstrated, and the physical mechanism of direct magnetic writing of skyrmions is comprehended by micromagnetic simulations. This study shows a potential of a direct-write (maskless) skyrmion (topological) nanolithography with sub-100 nm resolution, where each skyrmion acts as a pixel in the final topological image.

[Apps in clinical use in orthopedics and trauma surgery : The status quo in Germany]. / Klinischer Einsatz mobiler Applikationen in der Orthopädie und Unfallchirurgie in Deutschland : Eine Bestandsaufnahme.

In the course of digitalization the smartphone is penetrating more and more areas of life giving the user mobile and almost ubiquitous access to the internet and other web applications. The advantages of mHealth are an integral part in some areas of patient care but in contrast to other disciplines, routine integration of mobile devices into orthopedics and trauma surgery is still in its infancy. A survey among German orthopedists and trauma surgeons revealed which kind of apps have become established in everyday clinical practice to date. Apps published by representative institutions such as the AO Foundation demonstrated the highest usage rates. In summary, the number of regularly used apps is low; however, the causes of this lack of acceptance have not yet been conclusively clarified. The authors of this study proclaim a significant increase in the use of mHealth and mobile devices in daily clinical practice in the future.

[Digitalization and artificial intelligence in orthopedics and traumatology]. / Digitalisierung und künstliche Intelligenz in Orthopädie und Unfallchirurgie.

In the course of digitalization it is becoming increasingly rare for medical documents to be handwritten. As a result, digitalization has already become an integral part of routine patient care but in contrast to other specialist disciplines, such as radiology or laboratory medicine, orthopedics and trauma surgery are still at the beginning of new technologies. Artificial intelligence is not only used in the form of surgical robots in joint surgery or in the design of individualized implants but also provides valuable decision-making aids through appropriate algorithms for diagnosis and treatment. It can be assumed that these technologies will be further developed and used increasingly more in the coming years. Typical examples are intuitively operable and autonomously working programs and systems that support the networking and work of medical personnel and make processes inside and outside inpatient care more precise and less vulnerable to disturbances.

[Is the discharge letter still relevant? : Chances and risks of "Medical apps" in orthopedics and traumatology]. / Ist der Entlassungsbrief noch zeitgemäß? : Chancen und Risiken von "Medical Apps" in Orthopädie und Unfallchirurgie.

CURRENT SITUATION: The discharge letter currently represents the gold standard of the information and transfer document in the field of inpatient orthopedic and trauma patient care. In the age of digitization, the smartphone is penetrating more and more areas of life as an omnipresent internet access medium and is thus fundamentally influencing the awareness of our society. Whereas the use of applications on smartphones is already well established today, the range of medical apps is rudimentary. The potential of apps on smartphones as an innovative digital communication medium is undeniable, but the currently available medical apps in orthopedics and trauma surgery are available to a small patient clientele only. FORECAST: Currently, the use of medical apps is not an adequate alternative to the discharge letter. However, it is only a matter of time before the innovative potential of applications is used as a communication tool in outpatient and inpatient care. It is, therefore, essential to start creating the legal, ethical and medical framework and to establish a relevant regulatory body.

Neurodevelopmental outcome and pulmonary morbidity two years after early versus late surfactant treatment: does it really differ?

AIM: To investigate whether neurodevelopmental outcome or pulmonary morbidity at age two years might be different after early versus late surfactant treatment in intubated preterm infants with severe respiratory distress syndrome (RDS). METHODS: In 185 ex-preterm infants of 27-32 completed weeks of gestation, who were enrolled in a controlled trial of early versus late surfactant treatment (31 +/- 19 min vs. 202 +/- 80 min, respectively), a standardized follow up of medical history, pulmonary morbidity and neurodevelopmental outcome using the Griffiths scales were carried out. RESULTS: Neurobehavioural and motor development was comparable in both groups, as was medical history and actual morbidity. However, in the early treatment group a delay in the subscale 'personal social' of the Griffiths test and in one 'milestone' of motor development (rolling over from supine to prone) was noticed, and the rate of increased muscular tone was significantly higher. CONCLUSION: In terms of long-term morbidity or neurological development there is no obvious advantage of an immediate surfactant administration after intubation in preterm infants with RDS. This is in line with our results published earlier on morbidity at discharge, so improvement of gas exchange after intubation can first be awaited before surfactant is indicated.

Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.

Polyunsaturated fatty acids (PUFAs) are essential membrane components in higher eukaryotes and are the precursors of many lipid-derived signaling molecules. Here, pathways for PUFA synthesis are described that do not require desaturation and elongation of saturated fatty acids. These pathways are catalyzed by polyketide synthases (PKSs) that are distinct from previously recognized PKSs in both structure and mechanism. Generation of cis double bonds probably involves position-specific isomerases; such enzymes might be useful in the production of new families of antibiotics. It is likely that PUFA synthesis in cold marine ecosystems is accomplished in part by these PKS enzymes.

Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch.

The expression of brain-derived neurotrophic factor (BDNF) mRNA is increased significantly within the high vocal center (HVc) of male but not female zebra finches from posthatching day 30-35 on. The population of HVc cells expressing BDNF mRNA included 35% of the neurons projecting to the nucleus robustus of the archistriatum (RA). In the RA and in RA-projecting neurons of the lateral portion of the magnocellular nucleus of the anterior neostriatum, BDNF mRNA was expressed at very low levels in both sexes. The BDNF-receptor trkB mRNA was expressed in the RA, in RA-projecting neurons of lateral portion of the magnocellular nucleus of the anterior neostriatum, and in the HVc, except in most of its RA-projecting neurons. Premature stimulation and an inhibitory effect on the normal increase of the BDNF mRNA expression in juvenile males occurred after treatments with 17beta-estradiol and the aromatase inhibitor fadrozole, respectively. The up-regulation of the BDNF expression in the HVc could be a mechanism by which estrogen triggers the differentiation of cells within and connected to the HVc of male zebra finches.

Fatty acid elongation in yeast--biochemical characteristics of the enzyme system and isolation of elongation-defective mutants.

Elongation of long-chain fatty acids was investigated in yeast mutants lacking endogenous de novo fatty acid synthesis. In this background, in vitro fatty acid elongation was dependent strictly on the substrates malonyl-CoA, NADPH and a medium-chain or long-chain acyl-CoA primer of 10 or more carbon atoms. Maximal activity was observed with primers containing 12-14 carbon atoms, while shorter-chain-length acyl-CoA were almost (octanoyl-CoA) or completely (hexanoyl-CoA, acetyl-CoA) inactive. In particular, acetyl-CoA was inactive as a primer and as extender unit. The Michaelis constants for octanoyl-CoA (0.33 mM), decanoyl-CoA (0.83 mM) lauroyl-CoA (0.05 mM), myristoyl-CoA (0.4 mM) and palmitoyl-CoA (0.13 mM) were determined and were comparable for fatty acid synthesis and elongation. In contrast, the affinity of malonyl-CoA was 17-fold lower for elongation (Km = 0.13 mM) than for the fatty acid synthase (FAS) system. With increasing chain length of the primer (> or = 12:0), fatty acid elongation becomes increasingly sensitive to substrate inhibition. Due to the activation of endogenous fatty acids, ATP exhibits a stimulatory effect at suboptimal but not at saturating substrate concentrations. In the yeast cell homogenate, the specific activity of fatty acid elongation is about 10-20-fold lower than that of de novo fatty acid synthesis. The same elongation activity is observed in respiratory competent and in mitochondrially defective cells. The products of in vitro fatty acid elongation are fatty acids of 15-17 or 22-26 carbon atoms, depending on whether tridecanoyl-CoA or stearoyl-CoA is used as a primer. In vitro, the elongation products are converted in part, by alpha-oxidation, to their odd-chain-length lower homologues or are hydrolyzed to fatty acids. In contrast, no odd-chain-length elongation products or very-long-chain fatty acids (VLCFA) shorter than 26:0 are observed in vivo. Hence, VLCFA synthesis exhibits a higher processivity in vivo than in the cell homogenate. In addition, the in vivo process appears to be protected against side reactions such as hydrolysis or alpha-oxidation. Yeast mutants defective in 12:0 or 13:0 elongation were derived from fas-mutant strains according to their failure to grow on 13:0-supplemented media. In vivo, 12:0 elongation was reduced to 0-10% of the normal level, while 16:0 elongation and VLCFA synthesis were unimpaired. It is concluded that yeast contains either two different elongation systems, or that the respective mutation interferes differentially with medium-chain and long-chain fatty acid elongation. The yeast gene affected in the elongation-defective mutants was isolated and, upon sequencing, identified as the known ELO1 sequence. It encodes a putative membrane protein of 32-kDa molecular mass with no obvious similarity to any of the known FAS component enzymes.

"Cut and combine": an easy membrane-supported combinatorial synthesis technique.

A combinatorial synthesis process involving sequential cycles of cutting a membrane support into pieces and combining these into groups and subjecting the groups to simultaneous solid-phase chemical reactions is demonstrated by the rapid assembly of four hundred N-terminally biotinylated, soluble, octameric peptide pools. Index patterns printed onto the synthesis membrane allowed a direct identification of the compounds. These were used to study protein kinase substrate selection in a parallel microplate adapted 32P-phosphorylation assay with subsequent spotting on a biotin-capture membrane.

Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons.

Brain-derived neurotrophic factor (BDNF) is a potential drug for treatment of amyotrophic lateral sclerosis. Previous studies have demonstrated little or no penetration of the blood-brain barrier by BDNF, hence systemic application does not result in significant penetration into the spinal cord to produce direct action on motoneurons. Intrathecal (i.th) application of BDNF to sheep was investigated as a mean of topical administration. After continuous infusion a caudalcranial gradient of BDNF concentration in cerebrospinal fluid (CSF) and at the meninges was observed. BDNF did not penetrate spinal parenchyma but accumulated in spinal motoneurons probably due to axonal uptake in ventral roots and subsequent retrograde transport. Spinal motoneurons showed reduced levels of tropomyosin receptor kinase (trk) B and increased levels of c-fos at high BDNF doses in comparison to treatment with saline, even after treatment periods of several months. After bolus injection and cessation of continuous delivery multiphasic reduction of the BDNF concentration in CSF was detected. Our study demonstrates that i.th. application of BDNF is feasible, setting the stage for future clinical trials.

Actions of CNTF and neurotrophins on degenerating motoneurons: preclinical studies and clinical implications.

Spinal motoneurons innervating skeletal muscle were amongst the first neurons shown to require the presence of their target cells to develop appropriately. Isolated embryonic chick and rat motoneurons have been used to identify neurotrophic factors and cytokines capable of supporting the survival of developing motoneurons. Such factors include ciliary neurotrophic factor (CNTF), which is present physiologically in high amounts in myelinating Schwann cells of peripheral nerves, and brain-derived neurotrophic factor (BDNF) which is synthesized in skeletal muscle and, after peripheral nerve lesion, in Schwann cells. These factors have been further analyzed for their physiological significance in maintaining motoneuron function in vivo, and for their potential therapeutic usefulness in degenerative motoneuron disease. Both CNTF and BDNF are capable of rescuing injured facial motoneurons in newborn rats. Furthermore, CNTF prolongs survival and improves motor function of pmn mice, an animal model for degenerative motoneuron disease, by preventing degeneration of motoneuron axons and somata. Thus treatment of human motoneuron disease with neurotrophic factors should be possible, provided that rational means for application of these factors can be established considering also the appearance of potential side effects.

Identification of the mouse helper T lymphocyte differentiation antigen 3G11 as the ganglioside IV3(NeuAc)2-GgOse4Cer.

The 3G11 antigen, originally defined by the monoclonal antibody SM3G11, is expressed to different extents by distinct murine CD4+ T helper cell subsets. This antigen was isolated from a 3G11+ murine thymoma by lipid extraction. Upon further purification 3G11 antigen was enriched in the disialoganglioside fraction and was finally purified by HPLC. Compositional and methylation analysis, liquid secondary ion mass spectroscopy (LSI-MS) and comparison with an authentic sample resulted in identification of the 3G11 antigen as the disialoganglioside IV3(NeuAc)2-GgOse4Cer.

Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat.

Ciliary neurotrophic factor (CNTF) supports the survival of motoneurons in vitro and in vivo. Recombinant CNTF is an investigational drug for the treatment of amyotrophic lateral sclerosis. We determined the pharmacokinetics of radioiodinated CNTF after intravenous injection into rats. CNTF shows a biphasic clearance with an initial plasma half-life of 2.9 minutes and is removed from the circulation by the liver. No accumulation of radioactivity was detectable in nerve tissue or skeletal muscle after intravenous injection of 0.1 microgram and 0.5 microgram of CNTF. Radioactive degradation products accumulate in the skin. Liver cells express specific binding proteins for CNTF, and the incorporation and degradation of intravenously injected CNTF by the liver may occur after association of CNTF with the soluble CNTF receptor alpha in the circulation. Probably as a consequence of its binding to hepatocytes, CNTF induces acute-phase responses in liver. The short half-life and the inflammatory side effect may limit the clinical usefulness of systematically administered CNTF in the treatment of human motoneuron disorders.

Characterisation of high-affinity and low-affinity receptors for ciliary neurotrophic factor.

Ciliary neurotrophic factor (CNTF) supports the survival of a wide variety of neuronal cells in culture. To characterise the receptor(s) mediating the biological responses of CNTF we measured the binding of radiolabelled CNTF to chick sympathetic neurons and human neuroblastoma cells. Two distinct CNTF-binding sites with high and low affinity for the ligand were identified by steady-state binding experiments. Furthermore, two low-affinity binding sites could be discriminated on the basis of the dissociation rates. Cross-linking experiments showed that CNTF interacts with two proteins, one of 80 kDa and one of 140 kDa. The identity of the 80-kDa protein was determined by transient transfection experiments with the rat CNTF-binding protein CNTFR alpha while the properties of the 140-kDa protein correspond to those of gp130. Antisense experiments confirmed that CNTFR alpha is necessary for high affinity binding of 125I-CNTF and therefore a necessary subunit of the high-affinity receptor.

[Effect of phototoxic substances on simple biological systems. I. Standardizing the method with furocoumarins]. / Untersuchungen über die Wirkung phototoxischer Substanzen auf einfache biologische Systeme I. Standardisierung der Methode mit Furocumarinen.

As a basis for the investigation of new substances in respect of their photosensitization effects, we established and standardized 3 microbiological test systems, which enabled us to do without animal experiments. Using several furocumarines and various sources of light, we performed a comparative study on the eukaryotes, Chlamydomonas reinhardii (CR) and Candida albicans, and the prokaryote, Bacillus subtilis. We found that, if different light qualities were employed, our test systems also allowed a comparison of different substances by means of half-quantitative evaluation of the inhibiting areolas, which appear after exposure. With regard to the furocumarines, 8- and 5-methoxypsoralene (MOP) had the strongest photosensitizing effect under all test conditions. The remaining furocumarines showed decreasing effectiveness from psoralene to trimethylpsoralene (TMP) and imperatorine; psoralene, however, was slightly more effective in CR than 5-MOP. With the exception of CR, TMP had a stronger effect on the micro-organisms than imperatorine.

[The effect of mucous excipient concentration on bioadhesion ex vivo]. / Einfluss der Schleimstoffkonzentration auf die Bioadhäsion ex vivo.

The bioadhesion of aqueous solutions of polyacrylics (1-3), hydroxyethylcellulose (4), sodium carboxymethylamylopectin (5), polyvinylalcohol (6) and tragant (7) was investigated using a tensiometer and fresh intestine of pigs. It was dependent on the concentration of the excipient as described by a quadratic equation and found in the maximum from 244 Pa (7) to 554 Pa (4). The maximum of bioadhesion corresponds to the concentration of the excipient from 0.15% (2) to 23.7% (4) and to the viscosity of the solutions from 0.11 Pa.s (3) to 3.6.10(6) Pa.s (4). There was not a correlation between the viscosity and the bioadhesion.