Investigation of liver-targeted peripheral focused ultrasound stimulation (pFUS) and its effect on glucose homeostasis and insulin resistance in type 2 diabetes mellitus: a proof of concept, phase 1 trial.

BACKGROUND: Mechanical waves produced by ultrasound pulses have been shown to activate mechanosensitive ion channels and modulate peripheral nerves. However, while peripheral ultrasound neuromodulation has been demonstrated in vitro and in pre-clinical models, there have been few reports of clinical tests. AIM: We modified a diagnostic imaging system for ultrasound neuromodulation in human subjects. We report the first safety and feasibility outcomes in subjects with type 2 diabetes (T2D) mellitus and discuss these outcomes in relation to previous pre-clinical results. DESIGN: The study was performed as an open label feasibility study to assess the effects of hepatic ultrasound (targeted to the porta hepatis) on glucometabolic parameters in subjects with T2D. Stimulation (peripheral focused ultrasound stimulation treatment) was performed for 3 days (i.e. 15 min per day), preceded by a baseline examination and followed by a 2-week observation period. METHODS: Multiple metabolic assays were employed including measures of fasting glucose and insulin, insulin resistance and glucose metabolism. The safety and tolerability were also assessed by monitoring adverse events, changes in vital signs, electrocardiogram parameters and clinical laboratory measures. RESULTS AND CONCLUSION: We report post-pFUS trends in several outcomes that were consistent with previous pre-clinical findings. Fasting insulin was lowered, resulting in a reduction of HOMA-IR scores (P-value 0.01; corrected Wilcoxon signed-rank test). Additional safety and exploratory markers demonstrated no device-related adverse impact of pFUS. Our findings demonstrate that pFUS represents a promising new treatment modality that could be used as a non-pharmaceutical adjunct or even alternative to current drug treatments in diabetes.

Activity tracker-based intervention to increase physical activity in patients with type 2 diabetes and healthy individuals: study protocol for a randomized controlled trial.

BACKGROUND: One relevant strategy to prevent the onset and progression of type 2 diabetes mellitus (T2DM) focuses on increasing physical activity. The use of activity trackers by patients could enable objective measurement of their regular physical activity in daily life and promote physical activity through the use of a tracker-based intervention. This trial aims to answer three research questions: (1) Is the use of activity trackers suitable for longitudinal assessment of physical activity in everyday life? (2) Does the use of a tracker-based intervention lead to sustainable improvements in the physical activity of healthy individuals and in people with T2DM? (3) Does the accompanying digital motivational intervention lead to sustainable improvements in physical activity for participants using the tracker-based device? METHODS: The planned study is a randomized controlled trial focused on 1642 participants with and without T2DM for 9 months with regard to their physical activity behavior. Subjects allocated to an intervention group will wear an activity tracker. Half of the subjects in the intervention group will also receive an additional digital motivational intervention. Subjects allocated to the control group will not receive any intervention. The primary outcome is the amount of moderate and vigorous physical activity in minutes and the number of steps per week measured continuously with the activity tracker and assessed by questionnaires at four time points. Secondary endpoints are medical parameters measured at the same four time points. The collected data will be analyzed using inferential statistics and explorative data-mining techniques. DISCUSSION: The trial uses an interdisciplinary approach with a team including sports psychologists, sports scientists, health scientists, health care professionals, physicians, and computer scientists. It also involves the processing and analysis of large amounts of data collected with activity trackers. These factors represent particular strengths as well as challenges in the study. TRIAL REGISTRATION: The trial is registered at the World Health Organization International Clinical Trials Registry Platform via the German Clinical Studies Trial Register (DRKS), DRKS00027064 . Registered on 11 November 2021.

Addressing barriers to mental health services: evaluation of a psychoeducational short film for forcibly displaced people.

Background: Despite the high prevalence of mental illness in forcibly displaced people, their utilization of mental health services is low. Major barriers to seeking mental health services include mental health self-stigma. To address this issue, the psychoeducational short film 'Coping with Flight and Trauma' was developed as a brief online intervention. Objective: The present study aims to evaluate the feasibility and acceptance of the newly developed 10 min film, and to assess changes in self-stigma and help seeking. Method: The evaluation of the film was conducted using a mixed-methods design with an online survey including the Self-Stigma of Mental Illness Scale, help seeking, and mental health variables at baseline, postintervention, and 3 month follow-up, in addition to telephone interviews postintervention with a randomly selected volunteer subsample. Results: A total of 134 participants with a forced displacement history within the past 8 years took part in the study, of whom 66% scored as having probable post-traumatic stress disorder (PTSD), depression, and/or anxiety. The results revealed emotional, cognitive, and behavioural changes postintervention. Directly after watching the film, participants reported reduced self-stigma and increased openness towards accessing mental health services. At follow-up, precisely 3.8 months later, these changes were no longer significant, yet 11% of participants reported having started psychotherapy since watching the film. Probable PTSD was associated with higher self-stigma at all three time-points. The majority (90%) would recommend watching the film to other forcibly displaced people. Conclusions: Self-stigma was shown to be a robust and persistent issue, which tends to be underestimated by individuals not affected by mental illness. Low-threshold psychoeducational online interventions may be a promising tool to reduce barriers to accessing mental health services for forcibly displaced people, e.g. by being implemented in stepped-care models. HIGHLIGHTS: Mental health self-stigma was shown to be a persistent and underestimated burden in forcibly displaced people.Psychoeducational online interventions are promising for addressing the burden of self-stigma and reducing barriers to seeking mental health services.

Antecedentes: A pesar de la alta prevalencia de enfermedades mentales en las personas desplazadas por la fuerza, la utilización que hacen de los servicios de salud mental es baja. Las principales barreras en la búsqueda de servicios de salud mental incluyen el autoestigma en salud mental. Para abordar este tema, se desarrolló el cortometraje psicoeducativo 'Afrontando la huida y el trauma' como una breve intervención en línea.Objetivo: El presente estudio pretende evaluar la viabilidad y la aceptación del nuevo cortometraje de 10 minutos con personas desplazadas por la fuerza y evaluar los cambios en el autoestigma y la búsqueda de ayuda.Método: La evaluación de la película se llevó a cabo mediante un diseño de métodos mixtos con una encuesta en línea que incluía la Escala de Autoestigma sobre la Enfermedad Mental, la búsqueda de ayuda y las variables de salud mental al inicio, después de la intervención y a los 3 meses de seguimiento, además de entrevistas telefónicas individuales cualitativas después de la intervención con una submuestra de voluntarios seleccionados al azar.Resultados: N = 134 participantes con una historia de desplazamiento forzado en los últimos ocho años tomaron parte en el estudio, de los cuales el 66% puntuó como probable trastorno de estrés postraumático (TEPT), depresión y/o ansiedad. Los resultados revelaron cambios emocionales, cognitivos y conductuales tras la intervención. Inmediatamente después de ver la película, los participantes informaron de una reducción del autoestigma y una mayor apertura para acceder a los servicios de salud mental. En el seguimiento, precisamente 3,8 meses después, estos cambios ya no eran significativos, pero el 11% de los participantes declararon haber iniciado una psicoterapia desde que vieron la película. El probable TEPT se asoció con un mayor autoestigma en las tres mediciones. La mayoría (90%) recomendaría ver la película a otras personas desplazadas por la fuerza.Conclusiones: El autoestigma demostró ser un fuerte problema y persistente que tiende a ser subestimado por los individuos no afectados por la enfermedad mental. Las intervenciones psicoeducativas en línea de bajo umbral podrían ser una herramienta prometedora para reducir las barreras de acceso a los servicios de salud mental para las personas desplazadas por la fuerza, por ejemplo, mediante su aplicación en modelos de atención escalonada.

How advances in low-g plumbing enable space exploration.

In many ways, plumbing is essential to life support. In fact, the advance of humankind on Earth is directly linked to the advance of clean, healthy, reliable plumbing solutions. Shouldn't this also be true for the advancement of humankind in space? Unfortunately, the reliability of even the simplest plumbing element aboard spacecraft is rarely that of its terrestrial counterpart. This state of affairs is due entirely to the near-weightless "low-g" state of orbiting and coast spacecraft. But the combined passive capillary effects of surface tension, wetting, and system geometry in space can be exploited to replace the passive role of gravity on earth, and thus achieve similar outcomes there. In this paper, we review a selection of experiments conducted in low-g environments (i.e., ISS and drop towers) that focus on capillary fluidic phenomena. The results of each experiment are highly applicable to subsequent advances in spacecraft plumbing. With examples ranging from spurious droplet ejections to passive bubble coalescence, to droplet bouncing, to complex container wicking, we show how simple low-g demonstrations can lead to significant reliability improvements in practical passive plumbing processes from pipetting to liquid-gas separations, to wastewater transport, to drinking in space.

High-Resolution Differentiation of Enteric Bacteria in Premature Infant Fecal Microbiomes Using a Novel rRNA Amplicon.

Identifying and tracking microbial strains as microbiomes evolve are major challenges in the field of microbiome research. We utilized a new sequencing kit that combines DNA extraction with PCR amplification of a large region of the rRNA operon and downstream bioinformatic data analysis. Longitudinal microbiome samples of coadmitted twins from two different neonatal intensive care units (NICUs) were analyzed using an ∼2,500-base amplicon that spans the 16S and 23S rRNA genes and mapped to a new, custom 16S-23S rRNA database. Amplicon sequence variants (ASVs) inferred using DADA2 provided sufficient resolution for the differentiation of rRNA variants from closely related but not previously sequenced Klebsiella, Escherichia coli, and Enterobacter strains, among the first bacteria colonizing the gut of these infants after admission to the NICU. Distinct ASV groups (fingerprints) were monitored between coadmitted twins over time, demonstrating the potential to track the source and spread of both commensals and pathogens. The high-resolution taxonomy obtained from long amplicon sequencing enables the tracking of strains temporally and spatially as microbiomes are established in infants in the hospital environment.IMPORTANCE Achieving strain-level resolution is a major obstacle for source tracking and temporal studies of microbiomes. In this study, we describe a novel deep-sequencing approach that provides species- and strain-level resolution of the neonatal microbiome. Using Klebsiella, E. coli, and Enterobacter as examples, we could monitor their temporal dynamics after antibiotic treatment and in pairs of twins. The strain-level resolution, combined with the greater sequencing depth and decreased cost per read of PacBio Sequel 2, enables this advantageous source- and strain-tracking analysis method to be implemented widely across more complex microbiomes.

Patterns of tined lead migration in sacral nerve modulation.

AIM: Lead migration is a common cause of loss of efficacy in sacral nerve modulation. Our aim was to systematically study the migration pattern of tined leads in sacral nerve modulation. Our hypothesis was that tined leads may promote forward migration because of their configuration. METHOD: Consecutive patients treated with sacral nerve modulation with a tined lead electrode, who had experienced loss of efficacy and had radiographs both at baseline and after loss of efficacy between 2005 and 2016 were eligible for inclusion. RESULTS: Twenty-five patients out of 70 with loss of efficacy were studied. Lead migration was measured as percent electrode movement in relation to sacral cortex at lateral projection. All had some degree of lead migration, ranging from 35% backward to 74% forward migration. Sixteen (64%) had forward migration while nine (36%) had backward migration. In seven patients (28%), loss of efficacy was associated with an episode of perceived mechanical strain on the electrode. Fifty percent (4/8) who associated their loss of efficacy with an adverse event had forward migration of the electrode. CONCLUSIONS: Forward lead migration with concomitant loss of efficacy seems to be a common event in patients with tined leads, hence supporting our hypothesis. The retrospective design and that some of the patients with loss of efficacy could not be included because of incomplete data, which is a limitation to the study. Further studies are needed to confirm to what extent the direction and magnitude of the migration relate to loss of efficacy.

Citizen science in hydrological monitoring and ecosystem services management: State of the art and future prospects.

Hydrological monitoring is essential to guide evidence-based decision making necessary for sustainable water resource management and governance. Limited hydrometric datasets and the pressure on long-term hydrological monitoring networks make it paramount to explore alternative methods for data collection. This is particularly the case for low-income countries, where data scarcity is more pronounced, and where conventional monitoring methods are expensive and logistically challenging. Citizen science in hydrological research has recently gained popularity and crowdsourced monitoring is a promising cost-effective approach for data collection. Citizen science also has the potential to enhance knowledge co-creation and science-based evidence that underpins the governance and management of water resources. This paper provides a comprehensive review on citizen science and crowdsourced data collection within the context of hydrology, based on a synthesis of 71 articles from 2001 to 2018. Application of citizen science in hydrology is increasing in number and breadth, generating a plethora of scientific data. Citizen science approaches differ in scale, scope and degree of citizen involvement. Most of the programs are found in North America and Europe. Participation mostly comprises a contributory citizen science model, which engages citizens in data collection. In order to leverage the full potential of citizen science in knowledge co-generation, future citizen science projects in hydrology could benefit from more co-created types of projects that establish strong ties between research and public engagement, thereby enhancing the long-term sustainability of monitoring networks.

The control structure of the nematode Caenorhabditis elegans: Neuro-sensory integration and proprioceptive feedback.

We develop a biophysically realistic model of the nematode C. elegans that includes: (i) its muscle structure and activation, (ii) key connectomic activation circuitry, and (iii) a weighted and time-dynamic proprioception. In combination, we show that these model components can reproduce the complex waveforms exhibited in C. elegans locomotive behaviors, chiefly omega turns. This is achieved via weighted, time-dependent suppression of the proprioceptive signal. Though speculative, such dynamics are biologically plausible due to the presence of neuromodulators which have recently been experimentally implicated in the escape response, which includes an omega turn. This is the first integrated neuromechanical model to reveal a mechanism capable of generating the complex waveforms observed in the behavior of C. elegans, thus contributing to a mathematical framework for understanding how control decisions can be executed at the connectome level in order to produce the full repertoire of observed behaviors.

Draft Genome Sequence of Aeromonas lusitana sp. nov. Strain DSM 24905T, Isolated from a Hot Spring in Vila-Real, Portugal.

Aeromonas lusitana sp. nov. is an isolate derived from a study aimed at characterizing Aeromonas spp. from water sources used for recreation and agricultural purposes and assessing the implications these organisms have for human and animal health. We present here the 4.52-Mbp draft genome sequence of this novel species.

Draft Genome Sequence of Aeromonas cavernicola sp. nov. DSM 24474T, Isolated from a Cavern Brook in the Moravia Region of the Czech Republic.

Species of the Aeromonas genus can be found in numerous environmental milieus, including various water sources, and some species cause disease in animals. We present here the draft genome sequence for Aeromonas cavernicola DSM 24474T, a novel species isolated from a freshwater brook within a cavern in the Czech Republic.

Non-motor symptoms and quality of life in subjects with mild parkinsonian signs.

BACKGROUND: Mild parkinsonian signs (MPS) are frequent in the elderly population and associated with the presence of risk markers for Parkinson's disease (PD). Both MPS and non-motor signs may be present in prodromal PD and may significantly impair quality of life (QoL). OBJECTIVE: To disentangle the contribution of motor impairment and extra-motor manifestations to QoL in subjects with MPS (n=63), manifest PD (n=69), disorders with motor symptoms due to non-neurodegenerative diseases (n=213) and healthy controls (n=258). METHODS: Subjects with MPS, healthy controls, disease controls (patients with motor impairment due to, eg, arthrosis and spondylosis), and PD patients (total n=603) were selected from a large epidemiological longitudinal study, the EPIPARK cohort. Motor function was determined using the UPDRSIII protocol, and information on depressive symptoms, anxiety, sleep, and QoL was assessed via rating scales and data were analyzed. RESULTS: Depressive symptoms, anxiety, and sleep problems were equally frequent in the MPS group and controls. Health-related QoL was slightly reduced in the MPS group. Motor impairment and its extent was comparable between the MPS group and disease controls (UPDRSIII 5-6 points). Higher motor dysfunction was associated with lower QoL. Depressive symptoms, but not anxiety and daytime sleepiness, was significant predictors of general QoL, independent of motor function. CONCLUSIONS: Quality of life is slightly decreased in an elderly population with MPS. QoL is associated with severity of motor impairment but also with non-motor aspects, ie, depressive symptoms. Follow-up studies in large cohorts are warranted to determine the natural course of MPS and its impact on QoL.

Reliability of transpulmonary pressure-time curve profile to identify tidal recruitment/hyperinflation in experimental unilateral pleural effusion.

The stress index (SI) is a parameter that characterizes the shape of the airway pressure-time profile (P/t). It indicates the slope progression of the curve, reflecting both lung and chest wall properties. The presence of pleural effusion alters the mechanical properties of the respiratory system decreasing transpulmonary pressure (Ptp). We investigated whether the SI computed using Ptp tracing would provide reliable insight into tidal recruitment/overdistention during the tidal cycle in the presence of unilateral effusion. Unilateral pleural effusion was simulated in anesthetized, mechanically ventilated pigs. Respiratory system mechanics and thoracic computed tomography (CT) were studied to assess P/t curve shape and changes in global lung aeration. SI derived from airway pressure (Paw) was compared with that calculated by Ptp under the same conditions. These results were themselves compared with quantitative CT analysis as a gold standard for tidal recruitment/hyperinflation. Despite marked changes in tidal recruitment, mean values of SI computed either from Paw or Ptp were remarkably insensitive to variations of PEEP or condition. After the instillation of effusion, SI indicates a preponderant over-distension effect, not detected by CT. After the increment in PEEP level, the extent of CT-determined tidal recruitment suggest a huge recruitment effect of PEEP as reflected by lung compliance. Both SI in this case were unaffected. We showed that the ability of SI to predict tidal recruitment and overdistension was significantly reduced in a model of altered chest wall-lung relationship, even if the parameter was computed from the Ptp curve profile.

The flagellar master operon flhDC is a pleiotropic regulator involved in motility and virulence of the fish pathogen Yersinia ruckeri.

AIMS: To investigate the function of the master flagellar operon flhDC in the fish pathogen Yersinia ruckeri and compare the effect of a constructed flhD mutation to a naturally occurring fliR mutation causing loss-of-motility in emergent biotype 2 (BT2) strains. METHODS AND RESULTS: Yersinia ruckeri flhD and fliR mutants were constructed in a motile strain. Both mutations caused loss-of-motility, ablation of flagellin synthesis and phospholipase secretion, similar to naturally occurring BT2 strains. Transcriptome analysis confirmed flhDC regulation of flagellar, chemotaxis and phospholipase loci as well as other genes of diverse function. The flhD mutation confers a competitive advantage within the fish host when compared with its parent strain, while this advantage was not seen with the naturally occurring fliR mutation. CONCLUSIONS: An intact flhD is necessary for expression of the flagellar secretion system as well as other diverse loci, consistent with a role for flhD as a pleiotropic regulator. The maintenance of the flhD locus in Y. ruckeri strains suggests its importance for aspects of Y. ruckeri biology other than virulence, since the flhD mutation conferred a competitive advantage during experimental challenge of rainbow trout. SIGNIFICANCE AND IMPACT OF THE STUDY: Yersinia ruckeri is the causative agent of enteric red mouth disease, an invasive septicaemia that affects farmed salmonid fish species. Disease outbreaks can cause severe economic losses in aquaculture. BT2 variants, which have independently emerged worldwide, are an increasing threat to farmed fish production. Knowledge of mechanisms involved in virulence, conserved functions and gene regulation among strains may be exploited for the development of novel disease control strategies to prevent pathogen growth or virulence phenotypes within aquaculture.

Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients.

Introduction: When cancer patients have advanced disease and a primary cure is no longer possible, the focus is on maintaining the patient's quality of life. Recent therapeutic advances in breast cancer treatment mean that even patients with metastatic disease can remain stable for long periods of time. The aim of this study was to look at the health-related quality of life (HRQL) of these patients and compare it with data for the general population and to show the differences in outcomes for different survey instruments used to measure quality of life. Material and Methods: A total of 96 breast cancer patients with metastatic disesae or receiving adjuvant therapy were questioned about their quality of life. Patients were investigated using the established survey instruments EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L and EQ VAS. All patients filled out questionnaires. Statistical analysis was done using MS Excel and SPSS. Results: Although the questionnaires were completed at the same time, the different questionnaires showed significant differences with regard to the level of stress experienced by the patient. When the EQ VAS questionnaire was used, the patient's current state of health was assessed as significantly better than with the EORTC QLQ-C30. Overall, all aspects of patients' quality of life were found to be in need of optimization and HRQL of patients was significantly poorer in all areas compared to the reference population. Conclusion: To improve the quality of life of patients with metastatic disease, it is necessary to continuously monitor the success of therapy. The choice of survey tools is highly relevant as assessments differ considerably depending on the choice of questionnaire.

Willingness of Patients with Breast Cancer in the Adjuvant and Metastatic Setting to Use Electronic Surveys (ePRO) Depends on Sociodemographic Factors, Health-related Quality of Life, Disease Status and Computer Skills.

Introduction: Because of the often unfavorable prognosis, particularly for patients with metastases, health-related quality of life is extremely important for breast cancer patients. In recent years, data on patient-relevant endpoints is being increasingly collected electronically; however, knowledge on the acceptance and practicability of, and barriers to, this form of data collection remains limited. Material and Methods: A questionnaire was completed by 96 patients to determine to what extent existing computer skills, disease status, health-related quality of life and sociodemographic factors affect patients' potential willingness to use electronics methods of data collection (ePRO). Results: 52 of 96 (55 %) patients reported a priori that they could envisage using ePRO. Patients who a priori preferred a paper-based survey (pPRO) tended to be older (ePRO 53 years vs. pPRO 62 years; p = 0.0014) and typically had lower levels of education (p = 0.0002), were in poorer health (p = 0.0327) and had fewer computer skills (p = 0.0003). Conclusion: Barriers to the prospective use of ePRO were identified in older patients and patients with a lower quality of life. Given the appropriate conditions with regard to age, education and current health status, opportunities to participate should be provided to encourage patients' willingness to take part and ensure the validity of survey results. Focusing on ease of use of ePRO applications and making applications more patient-oriented and straightforward appears to be the way forward.

Malocclusion model of temporomandibular joint osteoarthritis in mice with and without receptor for advanced glycation end products.

OBJECTIVE: This study has two aims: 1. Validate a non-invasive malocclusion model of mouse temporomandibular joint (TMJ) osteoarthritis (OA) that we developed and 2. Confirm role of inflammation in TMJ OA by comparing the disease in the presence and absence of the receptor for advanced glycation end products (RAGE). DESIGN: The malocclusion procedure was performed on eight week old mice, either wild type (WT) or without RAGE. RESULTS: We observed TMJ OA at two weeks post-misalignment/malocclusion. The modified Mankin score used for the semi-quantitative assessment of OA showed an overall significantly higher score in mice with malocclusion compared to control mice at all times points (2, 4, 6 and 8 weeks). Mice with malocclusion showed a decrease in body weight by the first week after misalignment but returned to normal weight for their ages during the following weeks. The RAGE knock out (KO) mice had statistically lower modified Mankin scores compared to WT mice of the same age. The RAGE KO mice had statistically lower levels of Mmp-13 and HtrA1 but higher Tgf-ß1, as measured by immunohistochemistry, compared to WT mice at eight weeks post malocclusion. CONCLUSIONS: We demonstrate an inexpensive, efficient, highly reproducible and non-invasive model of mouse TMJ OA. The mechanical nature of the malocclusion resembles the natural development of TMJ OA in humans, making this an ideal model in future studies that aim to elucidate the pathogenesis of the disease leading to the discovery of a treatment. The RAGE plays a role in mouse TMJ OA.

Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation.

BACKGROUND: Conditions of inflammatory tissue distress are associated with high extracellular levels of adenosine, due to increased adenosine triphosphate (ATP) degradation upon cellular stress or the release of extracellular ATP upon cell death, which can be degraded to adenosine by membrane-bound ecto-enzymes like CD39 and CD73. Adenosine is recognised to mediate anti-inflammatory effects via the adenosine A2a receptor (A2aR), as shown in experimental models of arthritis. Here, using pharmacological interventions and genetic inactivation, we investigated the roles of A2aR in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: We used two independent mouse EAE variants, i.e. active immunization in C57BL/6 with myelin oligodendrocyte glycoprotein (MOG)35-55 or transfer-EAE by proteolipid protein (PLP)139-155-stimulated T lymphocytes and EAE in mice treated with A2aR-agonist CGS21680 at different stages of disease course and in mice lacking A2aR (A2aR(-/-)) compared to direct wild-type littermates. In EAE, we analysed myelin-specific proliferation and cytokine synthesis ex vivo, as well as inflammation and demyelination by immunohistochemistry. In vitro, we investigated the effect of A2aR on migration of CD4(+) T cells, macrophages and microglia, as well as the impact of A2aR on phagocytosis of macrophages and microglia. Statistical tests were Mann-Whitney U and Student's t test. RESULTS: We found an upregulation of A2aR in the central nervous system (CNS) in EAE, predominantly detected on T cells and macrophages/microglia within the inflamed tissue. Preventive EAE treatment with A2aR-specific agonist inhibited myelin-specific T cell proliferation ex vivo and ameliorated disease, while application of the same agonist after disease onset exacerbated non-remitting EAE progression and resulted in more severe tissue destruction. Accordingly, A2aR-deficient mice showed accelerated and exacerbated disease manifestation with increased frequencies of IFN-γ-, IL-17- and GM-CSF-producing CD4(+) T helper cells and higher numbers of inflammatory lesions in the early stage. However, EAE quickly ameliorated and myelin debris accumulation was lower in A2aR(-/-) mice. In vitro, activation of A2aR inhibited phagocytosis of myelin by macrophages and primary microglia as well as migration of CD4(+) T cells, macrophages and primary microglia. CONCLUSIONS: A2aR activation exerts a complex pattern in chronic autoimmune neurodegeneration: while providing anti-inflammatory effects on T cells and thus protection at early stages, A2aR seems to play a detrimental role during later stages of disease and may thus contribute to sustained tissue damage within the inflamed CNS.

[Why Strive after Clinical Social Medicine? From Epidemiological Association to Personalized Social Medicine: a Case of Breast Cancer Care]. / Klinische Sozialmedizin - Warum? Von der epidemiologischen Assoziation zur personalisierten Sozialmedizin am Beispiel der Versorgung bei Mammakarzinom.

Advances in biomedicine, especially molecular biology and genetics, gave rise to the concept of personalized medicine targeting the patient's individual characteristics and needs to ensure the best possible therapy and healthcare. This concept, however, can be successfully implemented only if due consideration is given to (psycho-)social factors, as is shown for instance by considerably reduced post-therapy survival rates among cancer patients in regions with lower socioeconomic status, How breast cancer patients, for instance, find their way back to daily life and work after initial treatment at a breast center is substantially determined by multiple factors going beyond pure medical care. These factors critically affect health status and therapy outcomes, but are missing in current research agenda. A profound expertise in social medicine is required to respond in ways tailored to the individual's healthcare needs that go beyond just medical therapy. This expertise comprises, in particular, knowledge of inequality of access to healthcare due to varying health competence that in turn, results in inequality of health outcome and care. Competence in social medicine both in the clinic and outpatient care can help to individually target negative factors that originate from the social environment as well as from deficits in communication and coordination in the healthcare system and have an effect on the health status of patients..This, however, requires institutionalization of (clinical) social medicine and in particular, better opportunities for advanced training in social medicine in clinical departments and outpatient units.