Proton and Heavy Atom Motions during the Stepwise Proton Tautomerism of Various Oxalamidines. A Semiempirical PM3-MNDO Study

The tautomerism of oxalamidine (OA) and the substituted analogs tetraphenyloxalamidine (TPOA), 2,2’-bis-(4,5-dihydro-1,3-diazole) (OA5), 2,2\u27-bis-(3)4,5,6-tetrahydro-l,3-diazixine) (OA6) and 2,2\u27-bis-(4,5,6,7-tetra- hydro-1,3-diazepine) (OA7) has been studied theoretically using the semiempirical PM3-MNDO method. According to a previous experimental study, this process consists of an intramolecular degenerate double proton transfer in weak intramolecular N-H- N hydrogen bonds, where the two protons are transferred stepwise involving a zwitterionic intermediate. In addition, evidence was obtained for a substantial heavy atom reorganisation which is strongly dependent on the chemical structure. In the present study, this interpretation is confirmed theoretically by calculation of the energies and geometries of the initial states, transition states and intermediate states of the tautomerism. For A06 and A07, sin- and anti-forms are obtained which differ in the confirmation of methylene bridges. The geometry of anti-OKI agrees remarkably well with the crystal geometry of OA7. Therefore, although the calculated barrier heights of the tautomerism highly exceed the experimental values, the calculated molecular geometries seem to be reliable. Especially interesting is the nature of reorganisation of the molecular skeleton during proton transfer in various oxalamidines. This reorganisation mainly involves a decrease of the nitrogen-nitrogen distances of the hydrogen bond in which the proton transfer takes place, thus lowering the barrier for the tautomerism. The reorganisation energy strongly depends on the chemical structure. In the case of OA and TPOA, compression of the proton transferring hydrogen bond is possible without major changes in the geometry of the other hydrogen bond. By contrast in bicyclic oxalamidines, compression of one hydrogen bond involves elongation of the other bond or a ring deformation, requiring additional energy. Ring deformation requires less energy in OA7 as compared to OA5 and OA6, in accordance with experimental findings

Endoscopically Based Endonasal and Transnasal Lasersurgery

The endoscopically based endonasal and transnasal laser surgery is a surgical procedure, which offers the ENT-specialist a safe and effective method to cure or to improve a number of diseases of the upper and middle airways. Coagulative lasers are used in contact and noncontact mode. Their light is mainly absorbed by hemoglobin but rarely by water. The laser–tissue interaction is performed via flexible glass fibers. For the delivery of the laser beam we use specially designed applicator sheaths, which incorporate the endoscope, the laser fiber and the suction channel. The procedure is controlled online via the endoscopic image on the monitor (“video-endoscopy”). The patient suffers less trauma using this treatment compared to the standard endoscopic surgery and the procedure is much quicker. Pre- and post-operative rhinomanometric and rhinoresistometric measurements reveal that the air flow rate of the nose can be improved effectively

A subset of metzincins and related genes constitutes a marker of human solid organ fibrosis

Metzincins and functionally related genes play important roles in extracellular matrix remodeling both in healthy and fibrotic conditions. We recently presented a transcriptomic classifier consisting of 19 metzincins and related genes (MARGS) discriminating biopsies from renal transplant patients with or without interstitial fibrosis/tubular atrophy (IF/TA) by virtue of gene expression measurement (Roedder et al., Am J Transplant 9:517-526, 2009). Here we demonstrate that the same algorithm has diagnostic value in non-transplant solid organ fibrosis. We used publically available microarray datasets of 325 human heart, liver, lung, kidney cortex, and pancreas microarray samples (265 with fibrosis, 60 healthy controls). Expression of nine commonly differentially expressed genes was confirmed by TaqMan low-density arrays (Applied Biosystems, USA) in 50 independent archival tissue specimens with matched histological diagnoses to microarray patients. In separate and in combined, integrated microarray data analyses of five datasets with 325 samples, the previously published MARGS classifier for renal post-transplant IF/TA had a mean AUC of 87% and 82%, respectively. These data demonstrate that the MARGS gene panel classifier not only discriminates IF/TA from normal renal transplant tissue, but also classifies solid organ fibrotic conditions of human pancreas, liver, heart, kidney, and lung tissue samples with high specificity and accuracy, suggesting that the MARGS classifier is a cross-platform, cross-organ classifier of fibrotic conditions of different etiologies when compared to normal tissu

Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases

Stand-alone percutaneous stent-kyphoplasty for thoracolumbar split and burst-split fractures

Introduction Traditionally, thoracolumbar split and burst-split fractures are treated with combined antero-posterior bi-segmental fusion procedures. Especially in the lower lumbar spine, such interventions are invasive and are associated with increased risk of neurological and vascular complications. This retrospective study aims to determine whether percutaneous stent-kyphoplasty is a viable treatment option for these injuries in terms of kyphotic angle correction and patient safety. Methods From Nov. 2014 to Dec. 2017, 25 consecutive patients (9 female, mean age 58 years) with 8 thoracolumbar split and 17 burst-split fractures (T11 to L5) of different etiology (7 high vs. 18 low energy trauma) were treated with percutaneous stent-kyphoplasty (SpineJack®). CT and/or MR imaging was performed preoperatively in all patients while radiographs were obtained postoperatively and at each follow-up. The mean follow-up was 176 days (SD 130). All cases were evaluated retrospectively for complications regarding nervous damage, LOS, duration of opioid intake, pain-VAS, return to work time and change of radiographic kyphotic angle. Results The mean kyphotic angle did not change from 1.1° (SD 9.2°) preoperatively to 1.1° (SD 7.9°) postoperatively. Radiologically, the mean increase of the kyphotic angle between surgery and the last follow-up was 2.65° (SD 4.2°). The mean pain-VAS was reduced to 1.8 postoperatively (SD 2.5, p = 0.03). The mean opioid intake duration was 4 days. Conclusion SpineJack®-kyphoplasty appears to be a safe and expeditious, minimally invasive treatment option for thoracolumbar split or burst-split fractures. It may be considered as an alternative to combined anterior-posterior instrumented bi-segmental fusion with its associated surgical morbidity

Perspectives of Patients With Orthopedic Trauma on Fully Automated Digital Physical Activity Measurement at Home: Cross-sectional Survey Study

BACKGROUND: The automated digital surveillance of physical activity at home after surgical procedures could facilitate the monitoring of postoperative follow-up, reduce costs, and enhance patients' satisfaction. Data on the willingness of patients with orthopedic trauma to undergo automated home surveillance postoperatively are lacking. OBJECTIVE: The aims of this study were to assess whether patients with orthopedic trauma would be generally willing to use the proposed automated digital home surveillance system and determine what advantages and disadvantages the system could bring with it. METHODS: Between June 2021 and October 2021, a survey among outpatients with orthopedic trauma who were treated at a European level 1 trauma center was conducted. The only inclusion criterion was an age of at least 16 years. The paper questionnaire first described the possibility of fully automated movement and motion detection (via cameras or sensors) at home without any action required from the patient. The questionnaire then asked for the participants' demographics and presented 6 specific questions on the study topic. RESULTS: In total, we included 201 patients whose mean age was 46.9 (SD 18.6) years. Most of the assessed patients (124/201, 61.7%) were male. Almost half of the patients (83/201, 41.3%) were aged between 30 and 55 years. The most stated occupation was a nine-to-five job (62/199, 30.8%). The majority of the participants (120/201, 59.7%) could imagine using the proposed measurement system, with no significant differences among the genders. An insignificant higher number of younger patients stated that they would use the automated surveillance system. No significant difference was seen among different occupations (P=.41). Significantly more young patients were using smartphones (P=.004) or electronic devices with a camera (P=.008). Less than half of the surveyed patients (95/201, 47.3%) stated that they were using tracking apps. The most stated advantages were fewer physician visits (110/201, 54.7%) and less effort (102/201, 50.7%), whereas the most prevalent disadvantage was the missing physician-patient contact (144/201, 71.6%). Significantly more patients with a part-time job or a nine-to-five job stated that data analysis contributes to medical progress (P=.047). CONCLUSIONS: Most of the assessed participants (120/201, 59.7%) stated that they would use the automated digital measurement system to observe their postoperative follow-up and recovery. The proposed system could be used to reduce costs and ease hospital capacity issues. In order to successfully implement such systems, patients' concerns must be addressed, and further studies on the feasibility of these systems are needed

Metzincins and related genes in experimental renal ageing: towards a unifying fibrosis classifier across species

Background We have previously described a transcriptomic classifier consisting of metzincins and related genes (MARGS) discriminating kidneys and other organs with or without fibrosis from human biopsies. We now apply our MARGS-based algorithm to a rat model of age-associated interstitial renal fibrosis. Methods Untreated Fisher 344 rats (n = 76) were sacrificed between 2 to 104 weeks of age. For gene expression studies, we used single colour (Cy3) Agilent Whole Rat Genome 4 × 44k microarrays; 4-5 animals of each sex were profiled at each of the following ages: 2, 5, 6, 8, 15, 21, 78 and 104 weeks. Intensity data were subjected to variance stabilization (www.Partek.com). Data were analysed with ANOVA and other statistical methods. Results Sixty MARGS were differentially expressed across age groups. More MARGS were differentially expressed in older males than in older females. Principal component analysis showed gene expression induced segregation of age groups by sex from 6 to 104 weeks of age. The expression level of MMP7 correlated best with fibrosis grade. Severity of fibrosis was determined in 20 animals at 78 and 104 weeks of age. Expression values of 15 of 19 genes of the original classifier present on the Agilent array, in conjunction with linear discriminant analysis, was sufficient to correctly classify these 20 samples into non-fibrosis and fibrosis. Overrepresentation of MMP2 protein and CD44 protein in fibrosis was confirmed by immunofluorescence. Conclusions Based on these results and our previous work, the MARGS classifier represents a cross-organ and cross-species classifier of fibrosis irrespective of aetiology. This finding provides evidence for a common pathway leading to fibrosis and will help to design a PCR-based clinical tes

The Lantibiotic Nisin Induces Lipid II Aggregation, Causing Membrane Instability and Vesicle Budding

AbstractThe antimicrobial peptide nisin exerts its activity by a unique dual mechanism. It permeates the cell membranes of Gram-positive bacteria by binding to the cell wall precursor Lipid II and inhibits cell wall synthesis. Binding of nisin to Lipid II induces the formation of large nisin-Lipid II aggregates in the membrane of bacteria as well as in Lipid II-doped model membranes. Mechanistic details of the aggregation process and its impact on membrane permeation are still unresolved. In our experiments, we found that fluorescently labeled nisin bound very inhomogeneously to bacterial membranes as a consequence of the strong aggregation due to Lipid II binding. A correlation between cell membrane damage and nisin aggregation was observed in vivo. To further investigate the aggregation process of Lipid II and nisin, we assessed its dynamics by single-molecule microscopy of fluorescently labeled Lipid II molecules in giant unilamellar vesicles using light-sheet illumination. We observed a continuous reduction of Lipid II mobility due to a steady growth of nisin-Lipid II aggregates as a function of time and nisin concentration. From the measured diffusion constants of Lipid II, we estimated that the largest aggregates contained tens of thousands of Lipid II molecules. Furthermore, we observed that the formation of large nisin-Lipid II aggregates induced vesicle budding in giant unilamellar vesicles. Thus, we propose a membrane permeation mechanism that is dependent on the continuous growth of nisin-Lipid II aggregation and probably involves curvature effects on the membrane