Neurofibromatosis Type 1 (NF1) is a monogenetic autosomal-dominant disorder with a broad spectrum of clinical symptoms and is commonly associated with cognitive deficits. Patients with NF1 frequently exhibit cognitive impairments like attention problems, working memory deficits and dysfunctional inhibitory control. The latter is also relevant for the resolution of cognitive conflicts. However, it is unclear how conflict monitoring processes are modulated in NF1. To examine this question in more detail, we used a system neurophysiological approach combining high-density ERP recordings with source localisation analyses in juvenile patients with NF1 and controls during a flanker task. Behaviourally, patients with NF1 perform significantly slower than controls. Specifically on trials with incompatible flanker-target pairings, however, the patients with NF1 made significantly fewer errors than healthy controls. Yet, importantly, this overall successful conflict resolution was reached via two different routes in the two groups. The healthy controls seem to arrive at a successful conflict monitoring performance through a developing conflict recognition via the N2 accompanied by a selectively enhanced N450 activation in the case of perceived flanker-target conflicts. The presumed dopamine deficiency in the patients with NF1 seems to result in a reduced ability to process conflicts via the N2. However, NF1 patients show an increased N450 irrespective of cognitive conflict. Activation differences in the orbitofrontal cortex (BA11) and anterior cingulate cortex (BA24) underlie these modulations. Taken together, juvenile patients with NF1 and juvenile healthy controls seem to accomplish conflict monitoring via two different cognitive neurophysiological pathways.

Many normal and cancerous cell lines exhibit a stable composition of cells in distinct states which can, e.g., be defined on the basis of cell surface markers. There is evidence that such an equilibrium is associated with stochastic transitions between distinct states. Quantifying these transitions has the potential to better understand cell lineage compositions. We introduce CellTrans, an R package to quantify stochastic cell state transitions from cell state proportion data from fluorescence-activated cell sorting and flow cytometry experiments. The R package is based on a mathematical model in which cell state alterations occur due to stochastic transitions between distinct cell states whose rates only depend on the current state of a cell. CellTrans is an automated tool for estimating the underlying transition probabilities from appropriately prepared data. We point out potential analytical challenges in the quantification of these cell transitions and explain how CellTrans handles them. The applicability of CellTrans is demonstrated on publicly available data on the evolution of cell state compositions in cancer cell lines. We show that CellTrans can be used to (1) infer the transition probabilities between different cell states, (2) predict cell line compositions at a certain time, (3) predict equilibrium cell state compositions, and (4) estimate the time needed to reach this equilibrium. We provide an implementation of CellTrans in R, freely available via GitHub (https://github.com/tbuder/CellTrans).

Background: In addition to conventional chemotherapeutics, nucleic acid-based therapeutics like antisense oligodeoxynucleotides (AS-ODN) represent a novel approach for the treatment of bladder cancer (BCa). An efcient delivery of AS-ODN to the urothelium and then into cancer cells might be achieved by the local application of multiwalled carbon nanotubes (MWCNT). In the present study, pristine MWCNT and MWCNT functionalized with hydrophilic moieties were synthesized and then investigated regarding their physicochemical characteristics, dispersibility, biocompatibility, cellular uptake and mucoadhesive properties. Finally, their binding capacity for AS-ODN via hybridization to carrier strand oligodeoxynucleotides (CS-ODN), which were either non-covalently adsorbed or covalently bound to the diferent MWCNT types, was evaluated. Results: Pristine MWCNT were successfully functionalized with hydrophilic moieties (MWCNT-OH, -COOH, -NH2, -SH), which led to an improved dispersibility and an enhanced dispersion stability. A viability assay revealed that MWCNTOH, MWCNT-NH2 and MWCNT-SH were most biocompatible. All MWCNT were internalized by BCa cells, whereupon the highest uptake was observed for MWCNT-OH with 40% of the cells showing an engulfment. Furthermore, all types of MWCNT could adhere to the urothelium of explanted mouse bladders, but the amount of the covered urothelial area was with 2–7% rather low. As indicated by fuorescence measurements, it was possible to attach CS-ODN by adsorption and covalent binding to functionalized MWCNT. Adsorption of CS-ODN to pristine MWCNT, MWCNT-COOH and MWCNT-NH2 as well as covalent coupling to MWCNT-NH2 and MWCNT-SH resulted in the best binding capacity and stability. Subsequently, therapeutic AS-ODN could be hybridized to and reversibly released from the CS-ODN coupled via both strategies to the functionalized MWCNT. The release of AS-ODN at experimental conditions (80 °C, bufer) was most efective from CS-ODN adsorbed to MWCNT-OH and MWCNT-NH2 as well as from CS-ODN covalently attached to MWCNT-COOH, MWCNT-NH2 and MWCNT-SH. Furthermore, we could exemplarily demonstrate that AS-ODN could be released following hybridization to CS-ODN adsorbed to MWCNT-OH at physiological settings (37 °C, urine). Conclusions: In conclusion, functionalized MWCNT might be used as nanotransporters in antisense therapy for the local treatment of BCa.

Background: Unemployment may impair mental and physical health. The influencing factors causing such negative effects are relevant from an individual and public health perspective. The personality as one possible influencing factor was discussed. This study investigated the prevalence of the type-D personality in an unemployed population and its connections to socio-demographic, psychological and heart rate variability (HRV) parameters. Methods: A questionnaire set including socio-demographics, type-D scale (DS14), Complaint list (BL), Beck-Depression-Inventory II (BDI-II) and the General Self-Efficacy Scale (GSE) was handed out to 203 unemployed individuals [126 females, mean age ± SD: 42.36 ± 11.08]. For HRV assessment (RMSSD), a subsample of 83 participants [50 females, median age ± IQR: 47.00 ± 17.00] passed the “stress-tests” (timed breathing, d2-attention-stress-test, math test) while heart frequency (HF) was acquired via the Stressball software (BioSign GmbH, Ottenhofen, Germany). Results: 53% of the unemployed had a type-D personality. Compared to non-type-D individuals, type-D individuals had rarely children and by trend a lower educational level; they showed significantly higher scores in the BDI-II and lower scores in the GSE and BL. No differences were observed in mean HF or RMSSD during all the stress-tests. Conclusion: The HRV of individuals with a type-D personality is no worse than that of individuals without a type-D personality. Type-D personality was significantly associated with negative health effects regarding depressiveness, self-efficacy and physical complaints. Our main findings implicate that the DS14 could serve as a short and reliable screening instrument to select concerned unemployed individuals who might be at risk for negative health effects for adequate intervention.

There is a need of substitution woods for the use in musical instruments because of the limited availabil-ity of some commonly used tropical tonewoods. Before substitutions can be found, it is necessary to knowabout the required properties. Hence, in this paper acoustical, mechanical and physical properties of fourcommon tropical hardwoods (Indian rosewood, ziricote, African blackwood and ebony) were determinedbecause there are less literature values for some properties available, e.g. internal friction, hardness orswelling behaviour. The acoustic properties were determined by means of experimental modal analysis,the mechanical properties by means of static bending tests and tests of the Brinell hardness. For the swel-ling behaviour the volume swelling and also the differential swelling coefficients were determined. Withthe results it is possible to look for new ‘tonewoods’ or to specifically modified woods, e.g. thermally trea-ted wood, to substitute tropical wood species.

Background: Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed. Methods: We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a γ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice. Results: While we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones. Conclusion: Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context.

Aims The aim of this study was to analyze the incidence rates of type 1 diabetes in Saxony before and after the German reunification. Methods The study examined two registries: one until 1990 and one since 1999. Only patients under 15 years of age with type 1 diabetes and living in Saxony were included in the study. Standardized incidence rates were described based on direct age standardization procedures using the Standard European Population for each calendar year between the observation periods 1982–1989 and 1999–2014. Age was grouped into three classes: 0–4, 5–9 and 10–14 years of age. Incidence data were presented as age-standardized incidence rates per 100,000 person-years (PY) with 95% confidence intervals [CI]. Joinpoint regression was used for trend analyses and Poisson regression was used to adjust for the effects of age and sex on the incidence. Results A total number of 2,092 incident cases of type 1 diabetes (1,109 males; 983 females) were included. The age-standardized incidence rates of type 1 diabetes per 100,000 PY was 7.9 [95%CI 6.8; 8.9] in the period from 1982–1989 and 20.1 [95%CI 14.0; 26.1] in the period from 1999–2014. The yearly increase in incidence over the entire time period (1982–2014) was 4.3% according to the average annual percent change (AAPC) method, and estimated to be 4.4% [95% CI 4.0; 4.8%] using a Poisson regression model adjusting for sex and age group. Conclusion In this study, a significantly increasing incidence of type 1 diabetes was observed after reunification. In future studies it would be interesting to follow up on the question of which environmental and lifestyle factors could be causing the increasing type 1 diabetes incidence.

Background: Modern health systems are increasingly faced with the challenge to provide effective, affordable and accessible health care for people with chronic conditions. As evidence on the specific unmet needs and their impact on health outcomes is limited, practical research is needed to tailor chronic care to individual needs of patients with diabetes. Qualitative approaches to describe professional and informal caregiving will support understanding the complexity of chronic care. Results are intended to provide practical recommendations to be used for systematic implementation of sustainable chronic care models. Method: A mixed method study was conducted. A standardised survey (n = 92) of experts in chronic care using mail responses to open-ended questions was conducted to analyse existing chronic care programs focusing on effective, problematic and missing components. An expert workshop (n = 22) of professionals and scientists of a European funded research project MANAGE CARE was used to define a limited number of unmet needs and priorities of elderly patients with type 2 diabetes mellitus and comorbidities. This list was validated and ranked using a multilingual online survey (n = 650). Participants of the online survey included patients, health care professionals and other stakeholders from 56 countries. Results: The survey indicated that current care models need to be improved in terms of financial support, case management and the consideration of social care. The expert workshop identified 150 patient needs which were summarised in 13 needs dimensions. The online survey of these pre-defined dimensions revealed that financial issues, education of both patients and professionals, availability of services as well as health promotion are the most important unmet needs for both patients and professionals. Conclusion: The study uncovered competing demands which are not limited to medical conditions. The findings emphasise that future care models need to focus stronger on individual patient needs and promote their active involvement in co-design and implementation. Future research is needed to develop new chronic care models providing evidence-based and practical implications for the regional care setting.

Background: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence. Methods: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV-biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses. Results: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 ± 8.6, mean ± SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV-biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback. Conclusion: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRVbiofeedback for alcohol dependence in addition to rehabilitation. Trial registration: The original randomized controlled trial was registered in the German Clinical Trials Register (DRKS00004618). This one-year follow-up survey has not been registered.

Objectives The objective of the present study was to investigate the usefulness of time-frequency analysis (TFA) of olfactory-induced EEG change with a low-cost, portable olfactometer in the clinical investigation of smell function. Materials & methods A total of 78 volunteers participated. The study was composed of three parts where olfactory stimuli were presented using a custom-built olfactometer. Part I was designed to optimize the stimulus as well as the recording conditions. In part II EEG-power changes after olfactory/trigeminal stimulation were compared between healthy participants and patients with olfactory impairment. In Part III the test-retest reliability of the method was evaluated in healthy subjects. Results Part I indicated that the most effective paradigm for stimulus presentation was cued stimulus, with an interstimulus interval of 18-20s at a stimulus duration of 1000ms with each stimulus quality presented 60 times in blocks of 20 stimuli each. In Part II we found that central processing of olfactory stimuli analyzed by TFA differed significantly between healthy controls and patients even when controlling for age. It was possible to reliably distinguish patients with olfactory impairment from healthy individuals at a high degree of accuracy (healthy controls vs anosmic patients: sensitivity 75%; specificity 89%). In addition we could show a good test-retest reliability of TFA of chemosensory induced EEG-power changes in Part III. Conclusions Central processing of olfactory stimuli analyzed by TFA reliably distinguishes patients with olfactory impairment from healthy individuals at a high degree of accuracy. Importantly this can be achieved with a simple olfactometer.