Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Rotational dynamics, ionic conductivity, and glass formation in a ZnCl2-based deep eutectic solvent.

Glass formation and reorientational motions are widespread but often-neglected features of deep eutectic solvents although both can be relevant for the technically important ionic conductivity at room temperature. Here, we investigate these properties for two mixtures of ethylene glycol and ZnCl2, which were recently considered superior electrolyte materials for application in zinc-ion batteries. For this purpose, we employed dielectric spectroscopy performed in a broad temperature range, extending from the supercooled state at low temperatures up to the liquid phase around room temperature and beyond. We find evidence for a relaxation process arising from dipolar reorientation dynamics, which reveals the clear signatures of glassy freezing. This freezing also governs the temperature dependence of the ionic dc conductivity. We compare the obtained results with those for deep eutectic solvents that are formed by the same hydrogen-bond donor, ethylene glycol, but by two different salts, choline chloride and lithium triflate. The four materials reveal significantly different ionic and reorientational dynamics. Moreover, we find varying degrees of decoupling of rotational dipolar and translational ionic motions, which can partly be described by a fractional Debye-Stokes-Einstein relation. The typical glass-forming properties of these solvents strongly affect their room-temperature conductivity.

Translational and reorientational dynamics in carboxylic acid-based deep eutectic solvents.

The glass formation and the dipolar reorientational motions in deep eutectic solvents (DESs) are frequently overlooked, despite their crucial role in defining the room-temperature physiochemical properties. To understand the effects of these dynamics on the ionic conductivity and their relation to the mechanical properties of the DES, we conducted broadband dielectric and rheological spectroscopy over a wide temperature range on three well-established carboxylic acid-based natural DESs. These are the eutectic mixtures of choline chloride with oxalic acid (oxaline), malonic acid (maline), and phenylacetic acid (phenylaceline). In all three DESs, we observe signs of a glass transition in the temperature dependence of their dipolar reorientational and structural dynamics, as well as varying degrees of motional decoupling between the different observed dynamics. Maline and oxaline display a breaking of the Walden rule near the glass-transition temperature, while the relation between the dc conductivity and dipolar relaxation time in both maline and phenylaceline is best described by a power law. The glass-forming properties of the investigated systems not only govern the orientational dipolar motions and rheological properties, which are of interest from a fundamental point of view, but they also affect the dc conductivity, even at room temperature, which is of high technical relevance.

Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: a sensitive imaging biomarker.

PURPOSE: Grey matter (GM) atrophy due to neuronal loss is a striking feature of patients with CLN3 disease. A precise and quantitative description of disease progression is needed in order to establish an evaluation tool for current and future experimental treatments. In order to develop a quantitative marker to measure brain volume outcome, we analysed the longitudinal volumetric development of GM, white matter (WM) and lateral ventricles and correlated those with the clinical course. METHODS: One hundred twenty-two MRI scans of 35 patients (21 females; 14 males; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed. A three-dimensional T1-weighted sequence was acquired with whole brain coverage. Volumetric segmentation of the brain was performed with the FreeSurfer image analysis suite. The clinical severity was assessed by the Hamburg jNCL score, a disease-specific scoring system. RESULTS: The volumes of supratentorial cortical GM and supratentorial WM, cerebellar GM, basal ganglia/thalamus and hippocampus significantly (r = - 0.86 to - 0.69, p < 0.0001) decreased with age, while the lateral ventricle volume increased (r = 0.68, p < 0.0001). Supratentorial WM volume correlated poorer with age (r = - 0.56, p = 0.0001). Supratentorial cortical GM volume showed the steepest (4.6% (± 0.2%)) and most uniform decrease with strongest correlation with age (r = - 0.86, p < 0.0001). In addition, a strong correlation with disease specific clinical scoring existed for the supratentorial cortical GM volume (r = 0.85, p = < 0.0001). CONCLUSION: Supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression even in early and late disease stages and represents a potential reliable outcome measure for evaluation of experimental therapies.

Dynamically disordered hydrogen bonds in the hureaulite-type phosphatic oxyhydroxide Mn5[(PO4)2(PO3(OH))2](HOH)4.

We report the temperature evolution of hydrogen bond (HB) chains and rings in Mn5[(PO4)2(PO3(OH))2](HOH)4 to reveal conduction pathways based on difference Fourier maps with neutron- and synchrotron x-ray diffraction data. Localized proton dynamics for the five distinct hydrogen sites were observed and identified in this study. Their temperature evaluation over ten orders of magnitude in time was followed by means of quasielastic neutron scattering, dielectric spectroscopy, and ab initio molecular dynamics. Two out of the five hydrogen sites are geometrically isolated and are not suitable for long-range proton conduction. Nevertheless, the detected dc conductivity points to long-range charge transport at elevated temperatures, which occurs most likely (1) over H4-H4 sites between semihelical HB chains (interchain-exchanges) and (2) by rotations of O1-H1 and site-exchanging H4-O10-O5 groups along each semihelical HB chain (intrachain-exchanges). The latter dynamics freeze into a proton-glass state at low temperatures. Rotational and site-exchanging motions of HOH and OH ligands seem to be facilitated by collective motions of framework polyhedra, which we detected by inelastic neutron scattering.

Urban HEART Detroit: the Application of a Health Equity Assessment Tool.

The Urban Health Assessment Response Tool (Urban HEART) was developed by the World Health Organization. In 2016, the Urban HEART was adapted and used by the Healthy Environments Partnership, a long-standing community-based participatory research partnership focused on addressing social determinants of health in Detroit, Michigan, to identify health equity gaps in the city. This paper uses the tool to: (1) examine the geographic distributions of key determinants of health in Detroit, across the five Urban HEART specified domains: physical environment and infrastructure, social and human development, economics, governance, and population health, and (2) determine whether these indicators are associated with the population health indicators at the neighborhood level. In addition to the Urban HEART matrix, we developed various tools including graphs and maps to further examine Detroit's health equity gaps. Although not required by Urban HEART, we statistically analyzed the associations between each indicator with the health outcomes. Our results showed that all the domains contained one or more indicators associated with one or more health outcomes, making this an effective tool to study health equity in Detroit. The Urban HEART Detroit project comes at a critical time where the nation is focusing on health equity and understanding underlying determinants of health inequities in urban areas. A tool like Urban HEART can help identify these areas for rapid intervention to prevent unnecessary burden from disease. We recommend the application of the Urban HEART, in active dialog with community groups, organizations, and leaders, to promote health equity.

Confirmatory and bi-factor analysis of the Short Form Health Survey 8 (SF-8) scale structure in a German general population sample.

BACKGROUND: The SF-8 is a short form of the SF-36 Health Survey, which is used for generic assessment of physical and mental aspects of health-related quality of life (HRQoL). Each of the 8 dimensions of the SF-36 is covered by a single item in the SF-8. The aim of the study was to examine the latent model structure of the SF-8. METHOD: One-, two- and three dimensional as well as bi-factor structural models were defined and estimated adopting the ML- as well as the WLSMV-algorithm for ordinal data. The data were collected in a German general population sample (N = 2545 persons). RESULTS: A two- (physical and mental health) and a three-dimensional CFA structure (in addition overall health) represent the empirical data information adequately [CFI = .987/.995; SRMR = .024/.014]. If a general factor is added, the resulting bi-factor models provide a further improvement in data fit [CFI = .999/.998; SRMR = .001]. The individual items are much more highly associated with the general HRQoL factor (loadings: .698 to .908) than with the factors physical, mental, and overall health (loadings: -.206 to .566). CONCLUSIONS: In the SF-8, each item reflects mainly general HRQoL (general factor) as well as one of the three components physical, mental, and overall health. The findings suggest in particular that the evaluation of the information of the SF-8 items can be validly supplemented by a general value HRQoL.

Lithium-salt-based deep eutectic solvents: Importance of glass formation and rotation-translation coupling for the ionic charge transport.

Lithium-salt-based deep eutectic solvents, where the only cation is Li+, are promising candidates as electrolytes in electrochemical energy-storage devices, such as batteries. We have performed broadband dielectric spectroscopy on three such systems, covering a broad temperature and dynamic range that extends from the low-viscosity liquid around room temperature down to the glassy state approaching the glass-transition temperature. We detect a relaxational process that can be ascribed to dipolar reorientational dynamics and exhibits the clear signatures of glassy freezing. We find that the temperature dependence of the ionic dc conductivity and its room-temperature value also are governed by the glassy dynamics of these systems, depending, e.g., on the glass-transition temperature and fragility. Compared to the previously investigated corresponding systems, containing choline chloride instead of a lithium salt, both the reorientational and ionic dynamics are significantly reduced due to variations in the glass-transition temperature and the higher ionic potential of the lithium ions. These lithium-based deep eutectic solvents partly exhibit significant decoupling of the dipolar reorientational and the ionic translational dynamics and approximately follow a fractional Debye-Stokes-Einstein relation, leading to an enhancement of the dc conductivity, especially at low temperatures. The presented results clearly reveal the importance of decoupling effects and of the typical glass-forming properties of these systems for the technically relevant room-temperature conductivity.

Ethanol inactivation of orthonairoviruses in ixodid ticks.

Ixodid ticks represent vectors and reservoirs for a broad range of zoonotic pathogens. Collected ticks from field studies are therefore usually stored in ethanol, which in higher concentrations effectively inactivates most of the known tick-borne pathogens. Although commonly practiced as gold standard for inactivation, hardly any scientific data demonstrate that ethanol sufficiently penetrates the comparatively thick cuticula of ticks. Therefore, Amblyomma hebraeum tick pools were stored for 21 days in ethanol (96%). Afterwards, the ethanol was removed and the ticks were homogenized. Quantitative 1H-NMR spectroscopic analysis was applied to determine the residual concentration of ethanol inside the ticks. 1H-NMR spectroscopic analysis revealed that ethanol constituted 28.3-42.6 mg of the total weight of three ticks in the pools (89.9-121.5 mg). In addition, the low-pathogenic Hazara orthonairovirus (HAZV) was used as a cell culture model for this study. The virus was exposed to ethanol concentrations between 0 and 60% and incubated under various temperature conditions for four time periods. Afterwards, the residual virus infectivity was determined by titration. Following ethanol exposure, HAZV did not grow in cells after 9 h of exposure to an ethanol concentration of 25%. These results demonstrate an extremely low ethanol resistance of the virus, which was generally in line with previously reported ethanol inactivation data for Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV). After prolonged storage and impregnation, comparable ethanol concentrations are achieved in the ticks, indicating the suitability of this inactivation method also for Bunyaviruses in ticks. At the very least, a massive virus inactivation can be assumed. Definitive proof of virus inactivation would require a bioassay of ethanol-treated infected ticks under appropriate biosafety conditions.

Comparison of hamstring and quadriceps tendon autografts in anterior cruciate ligament reconstruction with gait analysis and surface electromyography.

BACKGROUND: Anterior cruciate ligament (ACL) tear is the most frequent ligamentous injury of the knee joint. Autografts of hamstring (HS) or quadriceps tendons (QT) are used for primary ACL reconstruction. In this study, we planned to examine whether harvesting an HS graft is related to a deficit in dynamic knee stabilisation and strength revealed by dynamic valgus as compared with QT graft or the uninjured leg. Furthermore, if this deficit exists, is it compensated by higher neuromuscular activity of the quadriceps muscle? MATERIALS AND METHODS: Adult patients who had undergone ACL reconstruction with QT or HS autografts were included in this two-armed cohort study. Clinical outcome was assessed by clinical data analysis, physical examination and the Lysholm Score and Knee Injury and Osteoarthritis Score (KOOS). In addition, gait analysis and non-invasive surface electromyography were performed. RESULTS: A complete data set of 25 patients (QT: N = 8, HS: N = 17) was analysed. There was no significant demographic difference between the groups. Time between surgery and follow-up was significantly longer for the QT group. Significant differences regarding clinical outcome were not found between the treated and untreated leg or between the two groups, with excellent scores at the time of follow-up. Gait analysis revealed no significant differences of varus-valgus angles. Significant differences in surface electromyography were only found in the QT group with increased vastus medialis obliquus activity of the treated legs (p < 0.01). CONCLUSIONS: Our results suggest that harvesting of HS grafts for primary ACL reconstruction will not lead to a medial collapse and consequently impaired medial stabilisation of the knee when compared with QT grafts. LEVEL OF EVIDENCE: IV.

[COVID-19: treatment strategies of German-speaking pediatric rheumatologists : Results of an online survey]. / COVID-19: Behandlungsstrategien der deutschsprachigen Kinderrheumatologen : Ergebnisse einer Online-Umfrage.

BACKGROUND: Reliable data on the course and treatment of pediatric COVID-19 ("corona virus disease 2019") in immunosuppressed patients with rheumatic diseases are missing. AIM: Delineation of individual strategies of the members of the Society for Pediatric Rheumatology (GKJR) in cases of COVID-19. METHODS: In May 2020 all GKJR members were invited to take part in an online survey. Opinion data regarding an approach using disease-modifying anti-rheumatic drugs (DMARD) in cases of COVID-19 as well as the readiness to use new therapeutic agents in patients in different stages of the disease were collected. RESULTS: A total of 71 respondents (27.3% of all contacted pediatric rheumatologists) took part in the survey. Of these 28.2% had treated patients with COVID-19. Over 95% of the respondents did not support a preventive adaptation of the anti-rheumatic treatment during the SARS-CoV­2 pandemic. In the case of outpatients under immunosuppression with proven COVID-19 more than 50% of the respondents would refrain from administering intravenous high-dose steroids, cyclophosphamide, anti-CD20 antibodies as well as BAFF, CTLA­4 and TNF-alpha blockades. Conversely, >70% of the respondents would continue the treatment with nonsteroidal anti-inflammatory drugs, hydroxychloroquine (HCQ), oral steroids, mycophenolate, IL­1 blockade and immunoglobulins (Ig). In the case of inpatients 74.6% of respondents would consider targeted COVID-19 treatment. In stable patients with oxygen treatment (stage I) HCQ (18.3%), azithromycin (16.9%) and Ig (9.9%) were most frequently used. In cases of early signs (stage II) or a manifest cytokine storm (stage III) anakinra (40.8% for stage II and 46.5% for stage III), tocilizumab (26.8% and 40.8%, respectively), steroids (25.4% and 33.8%, respectively) and remdesivir (29.6% and 38.0%, respectively) were most frequently used. The need for a personalized approach based on the current clinical situation was emphasized by many respondents. CONCLUSION: The currently low prevalence of COVID-19 in Germany limits the general clinical experience. Therefore, the presented results have to be interpreted with caution and mostly as hypothetical treatment considerations. It is to be expected that there will always be a limited amount of evidence on pediatric COVID-19; therefore, a continuous and critical exchange of expert opinions on the treatment strategies is important.

Subclinical levels of anxiety but not depression are associated with planning performance in a large population-based sample.

BACKGROUND: Major depression and anxiety disorders are known to negatively influence cognitive performance. Moreover, there is evidence for greater cognitive decline in older adults with generalized anxiety disorder. Except for clinical studies, complex executive planning functions and subclinical levels of anxiety have not been examined in a population-based sample with a broad age range. METHODS: Planning performance was assessed using the Tower of London task in a population-based sample of 4240 participants aged 40-80 years from the Gutenberg Health Study (GHS) and related to self-reported anxiety and depression by means of multiple linear regression analysis. RESULTS: Higher anxiety ratings were associated with lower planning performance (ß = -0.20; p < 0.0001) independent of age (ß = 0.03; p = 0.47). When directly comparing the predictive value of depression and anxiety on cognition, only anxiety attained significance (ß = -0.19; p = 0.0047), whereas depression did not (ß = -0.01; p = 0.71). CONCLUSIONS: Subclinical levels of anxiety but not of depression showed negative associations with cognitive functioning independent of age. Our results demonstrate that associations observed in clinical groups might differ from those in population-based samples, also with regard to the trajectory across the life span. Further studies are needed to uncover causal interrelations of anxiety and cognition, which have been proposed in the literature, in order to develop interventions aimed at reducing this negative affective state and to improve executive functioning.

Urban HEART Detroit: a Tool To Better Understand and Address Health Equity Gaps in the City.

The Urban Health Equity Assessment Response Tool (Urban HEART) combines statistical evidence and community knowledge to address urban health inequities. This paper describes the process of adopting and implementing this tool for Detroit, Michigan, the first city in the USA to use it. The six steps of Urban HEART were implemented by the Healthy Environments Partnership, a community-based participatory research partnership made up of community-based organizations, health service providers, and researchers based in academic institutions. Local indicators and benchmarks were identified and criteria established to prioritize a response plan. We examine how principles of CBPR influenced this process, including the development of a collaborative and equitable process that offered learning opportunities and capacity building among all partners. For the health equity matrix, 15 indicators were chosen within the Urban HEART five policy domains: physical environment and infrastructure, social and human development, economics, governance, and population health. Partners defined the criteria and ranked them for use in assessing and prioritizing health equity gaps. Subsequently, partners generated a series of potential actions for indicators prioritized in this process. Engagement of community partners contributed to benchmark selection and modification, and provided opportunities for dialog and co-learning throughout the process. Application of a CBPR approach provided a foundation for engagement of partners in the Urban HEART process of identifying health equity gaps. This approach offered multiple opportunities for discussion that shaped interpretation and development of strategies to address identified issues to achieve health equity.

Prevalence of depression and anxiety among participants with glaucoma in a population-based cohort study: The Gutenberg Health Study.

BACKGROUND: To investigate the prevalence of depression and anxiety among subjects with self-reported glaucoma and the association between self-reported glaucoma and depression respectively anxiety in a European cohort. METHODS: A study sample of 14,657 participants aged 35 to 74 years was investigated in a population-based cohort study. All participants reported presence or absence of glaucoma. Ophthalmological examinations were carried out in all participants and demographic and disease related information were obtained by interview. Depression was assessed with the Patient Health Questionnaire (PHQ-9), and generalized anxiety with the two screening items (GAD-2) of the short form of the GAD-7 (Generalized Anxiety Disorder-7 Scale). Prevalence of depression and generalized anxiety were investigated for subjects with and without self-reported glaucoma. Logistic regression analyses with depression, respectively anxiety as dependent variable and self-reported glaucoma as independent variable were conducted and adjusted for socio-demographic factors, systemic comorbidities (arterial hypertension, myocardial infarction, stroke, diabetes mellitus, chronic obstructive pulmonary disease, cancer), ocular diseases (cataract, macular degeneration, corneal diseases, diabetic retinopathy), visual acuity, intraocular pressure, antiglaucoma eye drops (sympathomimetics, parasympathomimetics, carbonic anhydrase inhibitors, beta-blockers, prostaglandins) and general health status. RESULTS: 293 participants (49.5% female) reported having glaucoma. Prevalence of depression among participants with and without self-reported glaucoma was 6.6% (95%-CI 4.1-10.3) respectively 7.7% (95%-CI 7.3-8.2), and for anxiety 5.3% (95%-CI 3.1-8.7) respectively 6.6% (95%-CI 6.2-7.1). Glaucoma was not associated with depression (Odds ratio 1.10, 95%-CI 0.50-2.38, p = 0.80) or anxiety (1.48, 95%-CI 0.63-3.30, p = 0.35) after adjustment for socio-demographic factors, ocular/systemic diseases, ocular parameters, antiglaucoma drugs and general health status. A restriction to self-reported glaucoma cases either taking topical antiglaucoma medications or having a history of glaucoma surgery did not alter the result. CONCLUSIONS: This is the first study analyzing both depression and anxiety among glaucoma patients in a European cohort. Subjects with and without self-reported glaucoma had a similar prevalence of depression and anxiety in our population-based sample. Self-reported glaucoma was not associated with depression or anxiety. A lack of a burden of depressive symptoms may result from recruitment from a population-based sample as compared to previous study groups predominantly recruited from tertiary care hospitals.

[Morphological characteristics of osteopetrosis]. / Morphologische Veränderungen des Knochengewebes bei Osteopetrose.

Osteopetrosis is a rare inherited bone disorder characterized by increased bone density owing to failure in bone resorption by the osteoclasts. The disease is genetically and histologically heterogeneous with a wide spectrum of microscopic findings. The histology varies from cases with a total absence of osteoclasts to bone biopsies characterized by high numbers of enlarged multinucleated osteoclasts on a background of sclerotic cancellous bone with or without additional defect of mineralization of the bone matrix. Here we present typical cases of human osteopetrosis on the basis of bone biopsies with four distinct genotypes (mutations of TNFRSF11A, TCIRG1, CNCL7, KINDLIN-3 genes) and discuss genotype-phenotype relationships. Analyzing human bone biopsies of rare skeletal disorders might improve our understanding of bone metabolism with possible implications for the clinical management of other bone diseases.

Effects of a transdiagnostic unguided Internet intervention ('velibra') for anxiety disorders in primary care: results of a randomized controlled trial.

BACKGROUND: Internet-based cognitive-behavioural treatment (ICBT) for anxiety disorders has shown some promise, but no study has yet examined unguided ICBT in primary care. This randomized controlled trial (RCT) investigated whether a transdiagnostic, unguided ICBT programme for anxiety disorders is effective in primary care settings, after a face-to-face consultation with a physician (MD). We hypothesized that care as usual (CAU) plus unguided ICBT would be superior to CAU in reducing anxiety and related symptoms among patients with social anxiety disorder (SAD), panic disorder with or without agoraphobia (PDA) and/or generalized anxiety disorder (GAD). METHOD: Adults (n = 139) with at least one of these anxiety disorders, as reported by their MD and confirmed by a structured diagnostic interview, were randomized. Unguided ICBT was provided by a novel transdiagnostic ICBT programme ('velibra'). Primary outcomes were generic measures, such as anxiety and depression symptom severity, and diagnostic status at post-treatment (9 weeks). Secondary outcomes included anxiety disorder-specific measures, quality of life, treatment adherence, satisfaction, and general psychiatric symptomatology at follow-up (6 months after randomization). RESULTS: CAU plus unguided ICBT was more effective than CAU at post-treatment, with small to medium between-group effect sizes on primary (Cohen's d = 0.41-0.47) and secondary (Cohen's d = 0.16-0.61) outcomes. Treatment gains were maintained at follow-up. In the treatment group, 28.2% of those with a SAD diagnosis, 38.3% with a PDA diagnosis, and 44.8% with a GAD diagnosis at pretreatment no longer fulfilled diagnostic criteria at post-treatment. CONCLUSIONS: The unguided ICBT intervention examined is effective for anxiety disorders when delivered in primary care.

Selective condensation of DNA by aminoglycoside antibiotics.

The condensing effect of aminoglycoside antibiotics on the structure of double-stranded DNA was examined. The selective condensation of DNA by small molecules is an interesting approach in biotechnology. Here, we present the interaction between calf thymus DNA and three types of antibiotic molecules: tobramycin, kanamycin, and neomycin. Several techniques were applied to study this effect. Atomic force microscopy, transmission electron microscopy images, and nuclear magnetic resonance spectra showed that the interaction of tobramycin with double-stranded DNA caused the rod, toroid, and sphere formation and very strong condensation of DNA strands, which was not observed in the case of other aminoglycosides used in the experiment. Studies on the mechanisms by which small molecules interact with DNA are important in understanding their functioning in cells, in designing new and efficient drugs, or in minimizing their adverse side effects. Specific interactions between tobramycin and DNA double helix was modeled using molecular dynamics simulations. Simulation study shows the aminoglycoside specificity to bend DNA double helix, shedding light on the origins of toroid formation. This phenomenon may lighten the ototoxicity or nephrotoxicity issues, but also other adverse reactions of aminoglycoside antibiotics in the human body.

Current and cumulative night shift work and subclinical atherosclerosis: results of the Gutenberg Health Study.

PURPOSE: The study examines the association between exposure to current and cumulative night shift work and subclinical parameters of atherosclerosis. METHODS: Participants of a population-based cohort study (the Gutenberg Health Study, N = 15,010) aged 35-64 years were examined at baseline (2007-2012). Investigations included measurements of arterial stiffness, vascular function [reactive hyperaemia (RH) index], and intima media thickness (IMT). Also, a complete job history (including up to 15 periods), occupational exposures, a variety of lifestyle, and dispositional variables were enquired. RESULTS: Night shift work was performed by 1071 out of 8065 currently employed individuals. The strongest association after adjustment for age, sex, job complexity level, being a manager, overtime work, and noise appeared for more than 660 night shifts within the last 10 years and a significantly increased arterial stiffness of 0.33 m/s. This reflects a 4 % flow velocity increase for individuals with more than 660 night shifts compared to non-night workers. Regarding the entire professional life, night shift workers showed a significantly decreased vascular function by -0.054 RH index points by using the same adjustment. IMT values did not differ statistically from non-night workers. Lifestyle and dispositional factors showed an influence on all used subclinical atherosclerosis parameters. CONCLUSIONS: The cross-sectional results demonstrate an association between night work and detrimental changes in the atherosclerotic process. The association is more pronounced with more years in night shift and is partly explained by lifestyle and dispositional factors. Longitudinal analyses are necessary to confirm the results.

Photoacoustic imaging of real-time oxygen changes in chronic leg ulcers after topical application of a haemoglobin spray: a pilot study.

OBJECTIVE: To use a non-invasive measurement of oxygen saturation in chronic leg ulcers after the application of a topical haemoglobin spray to investigate if photoacoustic tomography is able to measure the oxygen saturation and if the stimulated oxygen increase can be demonstrated. METHOD: We measured the oxygen saturation of the ulcer tissue in five patients with chronic leg ulcers before application and 5 and 20 minutes after application of the haemoglobin spray, using photoacoustic tomography as a new method to assess oxygenation in real-time. RESULTS: The average oxygen saturation showed a significant increase from 56.4% before to 69% (p=0.042) after 5 minutes and 78.8% (p=0.043) 20 minutes after the topical haemoglobin application. CONCLUSION: The oxygenation status of chronic, hard-to-heal wounds is gaining increasing interest in modern wound therapy. Topical haemoglobin spray is a new and effective method to increase the oxygenation in the ulcer tissue, but until now the link between clinical results and the mode of action was unclear. We were able to show for the first time that the use of a topical haemoglobin spray leads to an increase in oxygen saturation in vivo using photoacoustic tomography. DECLARATION OF INTEREST: Joachim Dissemond received financial support from the company SastoMed for several scientific projects as well as for lectures and as an advisor. The haemoglobin spray was provided by SastoMed GmbH (Georgsmarienhütte, Germany).