Evaluation of tire tread particle toxicity to fish using rainbow trout cell lines.

Tire and road wear particles (TRWP) resulting from tire abrasion while driving raise concerns due to their potential contribution to aquatic toxicity. Our study aimed to assess cryogenically milled tire tread (CMTT) particle toxicity, used as a proxy for TRWP, and associated chemicals to fish using two Rainbow Trout (Oncorhynchus mykiss) cell lines representing the gill (RTgill-W1) and the intestinal (RTgutGC) epithelium. CMTT toxicity was evaluated through several exposure pathways, including direct contact, leaching, and digestion, while also assessing the impact of particle aging. Following OECD TG249, cell viability was assessed after 24 h acute exposure using a multiple-endpoint assay indicative of cell metabolic activity, membrane integrity and lysosome integrity. In vitro EC50 values for the fish cell lines exceeded river TRWP concentrations (2.02 g/L and 4.65 g/L for RTgill-W1 and RTgutGC cell lines, respectively), and were similar to in vivo LC50 values estimated at 6 g/L. Although toxicity was mainly driven by the leaching of tire-associated chemicals, the presence of the particles contributed to the overall toxicity by inducing a continuous leaching, highlighting the importance of considering combined exposure scenarios. Aging and digestion conditions were also found to mediate CMTT toxicity. Thermooxidation resulted in a decreased chemical leaching and toxicity, while in vitro digestion under mimicked gastrointestinal conditions increased leaching and toxicity. Specific chemicals, especially Zn, 2-mercaptobenzothiazole, 1,3-diphenylguanidine, and N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) were identified as contributors to the overall toxicity. Although 6PPD-quinone was detected in CMTT digestate, cytotoxicity assays with RTgill-W1 and RTgutGC cell lines showed no toxicity up to 6 mg/L, supporting the notion of a specific mode of action of this chemical. This study provides insights into the toxicological mechanisms induced by tire particles and their associated chemicals and can help in the evaluation of potential risks to aquatic life associated with TRWP.

New effects of caffeine on corticotropin-releasing hormone (CRH)-induced stress along the intrafollicular classical hypothalamic-pituitary-adrenal (HPA) axis (CRH-R1/2, IP3 -R, ACTH, MC-R2) and the neurogenic non-HPA axis (substance P, p75NTR and TrkA) in ex vivo human male androgenetic scalp hair follicles.

BACKGROUND: Human hair is highly responsive to stress, and human scalp hair follicles (HFs) contain a peripheral neuroendocrine equivalent of the systemic hypothalamic-pituitary-adrenal (HPA) stress axis. Androgenetic alopecia (AGA) is supposed to be aggravated by stress. We used corticotropin-releasing hormone (CRH), which triggers the HPA axis, to induce a stress response in human ex vivo male AGA HFs. Caffeine is known to reverse testosterone-mediated hair growth inhibition in the same hair organ culture model. OBJECTIVES: To investigate whether caffeine would antagonize CRH-mediated stress in these HFs. METHODS: HFs from balding vertex area scalp biopsies of men affected by AGA were incubated with CRH (10-7 mol L-1 ) with or without caffeine (0·001% or 0·005%). RESULTS: Compared to controls, CRH significantly enhanced the expression of catagen-inducing transforming growth factor-ß2 (TGF-ß2) (P < 0·001), CRH receptors 1 and 2 (CRH-R1/2) (P < 0·01), adrenocorticotropic hormone (ACTH) (P < 0·001) and melanocortin receptor 2 (MC-R2) (P < 0·001), and additional stress-associated parameters, substance P and p75 neurotrophin receptor (p75NTR ). CRH inhibited matrix keratinocyte proliferation and expression of anagen-promoting insulin-like growth factor-1 (IGF-1) and the pro-proliferative nerve growth factor receptor NGF-tyrosine kinase receptor A (TrkA). Caffeine significantly counteracted all described stress effects and additionally enhanced inositol trisphosphate receptor (IP3 -R), for the first time detected in human HFs. CONCLUSIONS: These findings provide the first evidence in ex vivo human AGA HFs that the stress mediator CRH induces not only a complex intrafollicular HPA response, but also a non-HPA-related stress response. Moreover, we show that these effects can be effectively antagonized by caffeine. Thus, these data strongly support the hypothesis that stress can impair human hair physiology and induce hair loss, and that caffeine may effectively counteract stress-induced hair damage and possibly prevent stress-induced hair loss.

Prognostic factors associated with overall survival in patients with oral cavity squamous cell carcinoma.

BACKGROUND: Low socioeconomic status, increasing age, and poor lifestyle behaviors are associated with poor survival in patients with oral cavity squamous cell carcinoma (OCSCC). To determine the overall survival (OS) and the risk of OCSCC death by tumor subsite. MATERIAL AND METHODS: A retrospective cohort study of OCSCC patients diagnosed from 2007 to 2009 and treated at a single cancer center in Rio de Janeiro, Brazil. Patient information was obtained from the Hospital Cancer Registry (HCR) database and complemented by individual search of physical and electronic medical records. Descriptive statistics of population characteristics were computed. OS was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses were used to estimate the risk of death by tumor subsite. RESULTS: Seven hundred and three patients with OCSCC were identified. Most patients were men (77.4%) with low levels of education (67.5%), who drank (73.9%) and smoked (79.7%). The most prevalent tumor site was the tongue (45.4%), 73.4% of patients had advanced (clinical stage III or IV) OCSCC at diagnosis and 74.1% died during follow-up. For the entire cohort, the OS was 39.1% at two years and 27.9% at five years. The median survival time was 1.4 years (95%CI: 1.2‒1.5). Non-operative treatment (HR: 3.11; 95%CI: 2.26‒4.29; p<0.001), advanced stage (HR 2.14; 95%CI 1.68-2.74; p<0.001), and age >60 years at diagnosis (HR: 1.37; 95%CI: 1.15‒1.64; p<0.001) were independently associated with the risk of death. However, these factors varied by tumour subsite. CONCLUSION: Analysis of specific subsites of the oral cavity revealed substantial differences in prognostic factors associated with poor survival in OCSCC.

Towards low-cost QEPAS sensors for nitrogen dioxide detection.

Increasing awareness of the adverse health effects of air pollution leads to a demand of low-cost sensors for the measurement of pollutants such as NO2. However, commercially available low-cost sensors lack accuracy and long-term stability, and suffer from cross-sensitivity to other gases. These drawbacks can be overcome by the method of quartz-enhanced photoacoustic spectroscopy (QEPAS). In QEPAS modulated light is absorbed by the NO2 molecules, which results in the production of a sound wave. The sound wave is detected by resonance of a quartz tuning fork, which results in a measurable electric signal. Due to the small size of the tuning forks, the gas sensing element can be smaller than 1 cm3. We present the first bare fork QEPAS setup for the ppb-level detection of NO2, which is ideally suited for environmental trace gas detection without the need of using micro-resonators. Micro-resonators are commonly used to amplify photoacoustic signals. However, micro-resonators have different dependencies on environmental conditions than tuning forks, which makes them difficult to operate in changing conditions. In contrast, our bare fork QEPAS setup is more robust and easily adopted by the use of a low-cost temperature and humidity sensor. By using acoustic filters the integration time could be increased to offer higher sensitivity at a continuous flow rate of 200 std cm3 min-1. The 1σ noise equivalent concentration is determined to 21 ppb NO2 in synthetic air for 120 s measurement time, allowing detection which satisfies international health and safety standards thresholds.

Quality of life after total laryngectomy: impact of different vocal rehabilitation methods in a middle income country.

INTRODUCTION: The impact of advanced laryngeal cancer and its extensive surgical treatments cause significant morbidity for these patients. Total laryngectomy impacts essential functions such as breathing, communication and swallowing, and may influence the quality of life as well as affecting the social life of laryngeal cancer patients. OBJECTIVE: Describe the quality of life and analyze the factors associated with the reduced quality of life in patients who have undergone total laryngectomy. METHOD: Observational cross-sectional study was carried out to evaluate the quality of life of patients who had undergone total laryngectomy due to laryngeal cancer. The fourth version of the UW-QOL Quality of Life Assessment Questionnaire from Washington University, validated for Portuguese, was used. RESULTS: The study population was 95 patients, and the mean composite score of the QOL was 80.4. In the subjective domains the majority of the patients (38.9%) reported they felt much better at present compared to the month before being diagnosed with cancer. When questioned about how they evaluated their health-related quality of life, there was a predominance of those who considered it good (43.2%), and most considered they had a good quality of life (46.3%) considering personal well-being. The overall quality of life was considered good to excellent by 83.2% of the patients. Patients with tracheoesophageal prosthesis reported a better quality of life, compared to patients using an electrolarynx or esophageal voice. CONCLUSION: The high mean value of the composite score for quality of life revealed that the patients assessed their quality of life positively. The absence of vocal emission was the only variable associated with a lower quality of life within the composite score according to the UW-QOL questionnaire.

Framework for personalized prediction of treatment response in relapsing remitting multiple sclerosis.

BACKGROUND: Personalized healthcare promises to successfully advance the treatment of heterogeneous neurological disorders such as relapsing remitting multiple sclerosis by addressing the caveats of traditional healthcare. This study presents a framework for personalized prediction of treatment response based on real-world data from the NeuroTransData network. METHODS: A framework for personalized prediction of response to various treatments currently available for relapsing remitting multiple sclerosis patients was proposed. Two indicators of therapy effectiveness were used: number of relapses, and confirmed disability progression. The following steps were performed: (1) Data preprocessing and selection of predictors according to quality and inclusion criteria; (2) Implementation of hierarchical Bayesian generalized linear models for estimating treatment response; (3) Validation of the resulting predictive models based on several performance measures and routines, together with additional analyses that focus on evaluating the usability in clinical practice, such as comparing predicted treatment response with the empirically observed course of multiple sclerosis for different adherence profiles. RESULTS: The results revealed that the predictive models provide robust and accurate predictions and generalize to new patients and clinical sites. Three different out-of-sample validation schemes (10-fold cross-validation, leave-one-site-out cross-validation, and excluding a test set) were employed to assess generalizability based on three different statistical performance measures (mean squared error, Harrell's concordance statistic, and negative log-likelihood). Sensitivity to different choices of the priors, to the characteristics of the underlying patient population, and to the sample size, was assessed. Finally, it was shown that model predictions are clinically meaningful. CONCLUSIONS: Applying personalized predictive models in relapsing remitting multiple sclerosis patients is still new territory that is rapidly evolving and has many challenges. The proposed framework addresses the following challenges: robustness and accuracy of the predictions, generalizability to new patients and clinical sites and comparability of the predicted effectiveness of different therapies. The methodological and clinical soundness of the results builds the basis for a future support of patients and doctors when the current treatment is not generating the desired effect and they are considering a therapy switch. (A) The framework is developed using quality-proven real-world data of patients with relapsing remitting multiple sclerosis. Patients have heterogeneous individual characteristics and diverse disease profiles, indicated for example by variations in frequency of relapses and degree of disability. Longitudinal characteristics regarding disease history (e.g. number of previous relapses in the last 12 months) are extracted at the time of an intended therapy switch, i.e. at time point "Today" (left). All clinical parameters are captured in a standardized way (right). (B) The model predicts the course of the disease based on the observed data (panel A), and is able to account for the impact of various available therapies on chosen clinical endpoints. The resulting ranking of therapies has a dependency on patient characteristics, illustrated here by a different highest ranked therapy depending on the number of relapse in the previous 12 months. (C) The model is evaluated for various generalization properties. Compared to performance on the training set (gray) it is able to predict for new patients not part of the training set (red).Top: Prediction for new patients. Middle: Prediction for new clinical sites. Bottom: Prediction for different time windows. (D) In order to assess the clinical impact of the model, disease activity is compared between patients treated with the highest ranked therapy and those treated with any of the other therapies. Patients adhering to the highest ranked therapy are associated with a better disease outcome when compared to those who did not.

Endothelial dysfunction following coronary artery bypass grafting : Influence of patient and procedural factors.

BACKGROUND: Angiopoietin-2 (Angpt2) mediates endothelial dysfunction (ED) following coronary artery bypass grafting (CABG). Its triggers are, however, poorly understood. METHODS: We examined the time course of ED beyond the early phase of postoperative recovery in 75 patients following CABG with a special focus on different cardiopulmonary bypass (CPB) modes as potential triggers of Angpt2 release. RESULTS: Nine patients (12.0%) underwent off-pump coronary artery bypass (OPCAB), 31 patients (41.3%) received minimized extracorporeal circulation (MECC), and 35 patients (46.6%) were operated on with (conventional) CPB. Angpt2 levels steadily increased across the observation period (1.7 [1.4-2.1] to 3.4 [2.5-6.1] ng/ml, p < 0.001). Angpt2 levels did not differ between the MECC and CPB groups (p = 0.564). There was no difference between MECC and CPB patients regarding net fluid balance (p = 0.821) and other surrogate markers of postoperative ED. The magnitude of Angpt-2 increase correlated more strongly with baseline C­reactive protein (r = 0.459, p < 0.001) than with any other parameter. Hospital length of stay correlated more strongly with baseline Angpt2 levels (r = 0.512, p = 0.005) than with follow-up Angpt2 levels and appeared not to be influenced by CPB mode (p = 0.428). CONCLUSION: CABG is associated with prolonged ED, which is determined by the patient's preoperative inflammatory state rather than by CPB modifications.

The association between plasma proneurotensin and glucose regulation is modified by country of birth.

The prevalence of type 2 diabetes (T2D) has increased dramatically in Middle Eastern populations that represent the largest non-European immigrant group in Sweden today. As proneurotensin predicts T2D, the aim of this study was to investigate differences in proneurotensin levels across populations of Middle Eastern and Caucasian origin and to study its associations with indices of glucose regulation. Participants in the age 30 to 75 years, living in Malmö, Sweden, and born in Iraq or Sweden, were recruited from the census register. Anthropometrics and fasting samples were collected and oral glucose tolerance tests conducted assessing insulin secretion (DIo) as well as insulin sensitivity (ISI). A total of 2155 individuals participated in the study, 1398 were Iraqi-born and 757 were Swedish-born participants. Higher fasting proneurotensin levels were observed in Iraqi- compared to Swedish-born participants (137.5 vs. 119.8 pmol/L; p < 0.001) data adjusted for age, sex and body mass index. In Iraqi participants only, plasma proneurotensin was associated with impaired glucose regulation assessed as ISI, DIo and HbA1c, and significant interactions between country of birth and proneurotensin were observed (Pinteraction ISI = 0.048; Pinteraction DIo = 0.014; PinteractionHbA1c = 0.029). We report higher levels of proneurotensin in the general Middle Eastern population. The finding that Middle Eastern origin modifies the relationship of proneurotensin with indices of glucose regulation suggests that proneurotensin may be a stronger determinant of T2D in Middle Eastern as compared to Caucasian populations. These findings may explain part of the excess T2D risk in the Middle Eastern population but needs to be explored further.

Are German family practitioners and psychiatrists sufficiently trained to diagnose and treat patients with alcohol problems?

BACKGROUND: Harmful alcohol consumption in Germany is a serious public health problem: About 7.7 million adults in Germany can be classified as risky alcohol consumers, about 74,000 deaths per year are related to alcohol consumption, and about 1.8 million adults in Germany (18-64 years) are classified as alcohol dependent. A treatment rate of 9% of all alcohol dependent patients in Germany implies a lack of supply and misuse of medical care. The aim of the study was to examine whether family practitioners (FPs) and psychiatrists have sufficient skills to diagnose and treat patients with alcohol problems. METHODS: A total of 6324 FPs and psychiatrists in the states of Saxony and Rhineland-Palatinate in Germany were invited to participate in this survey. Nine hundred seventy-four participants (90.3%/FPs) could be included in the statistical analysis (response rate: 14.3%/FPs, 21.6%/psychiatrists). Data was analysed descriptively and logistical regressions were used to identify predictors for physicians' ability to feel adequately trained to diagnose and treat patients with alcohol problems. RESULTS: In comparison to psychiatrists, less FPs reported feeling sufficiently trained to counsel patients with alcohol problems (81.5% vs. 44.8%). Regression analysis revealed that FPs who felt not adequately trained had less experience with patients with alcohol dependence (OR 7.4), had attended fewer hours on alcohol addiction in continuing medical education (OR 4.8), and were more likely to be female (OR 1.9). A minimum of 10 h of training was associated with improved self-assessed competence. CONCLUSION: Harmful drinking is a serious public health problem, and patients with alcohol dependence represent a large and demanding patient group in primary health care setting. Our study shows that the lack of training is a severe barrier in the work with this patient group in the primary care setting.

Delay in breast cancer diagnosis: a Brazilian cohort study.

OBJECTIVES: To evaluate the delay in breast cancer (BC) diagnosis and its risk factors. STUDY DESIGN: A cohort study of BC patients referred to treatment at oncological reference hospital, Brazil. Delay in BC diagnosis was defined as a time interval ≥90 days between the first contact with a care provider and a BC diagnosis. METHODS: The association between independent variables and delay was performed by univariate analysis and multiple logistic regression. RESULTS: Five hundred and twenty-six women were included in the study. Delay was observed in 68.8% and was associated with performing histopathological examination at oncological reference hospital (odds ratio [OR]: 3.96, 95% confidence interval [CI]: 1.91-8.20) or at another public health service (OR: 2.31; 95% CI: 1.50-3.56) and attending gynecological consultations annually (OR: 3.24; 95% CI: 1.97-5.33) or every 2-3 years (OR: 2.86; 95% CI: 1.55-5.28). Patients who presented a lump as the first sign or symptom had a lower chance of delay (OR: 0.43; 95% CI: 0.29-0.65). CONCLUSIONS: Improvements in the structure and access to health services are needed to reduce the time to diagnosis.

Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis.

Biological agents including anti-tumor necrosis factor (anti-TNF; adalimumab, infliximab, etanercept) and anti-interleukin-12/13 (IL12/23; ustekinumab) are essential for treatment of patients with severe psoriasis. However, a significant proportion of the patients do not respond to a specific treatment. Pharmacogenetics might be a way to predict treatment response. Using a candidate gene approach, 62 mainly functional single-nucleotide polymorphisms (SNPs) in 44 different genes were evaluated in 478 Danish patients with psoriasis undergoing 376 series of anti-TNF treatment and 230 series of ustekinumab treatment. Associations between genetic variants and treatment outcomes (drug survival and Psoriasis Area Severity Index reduction) were assessed using logistic regression analyses (crude and adjusted for gender, age, psoriatic arthritis and previous treatment). After correction for multiple testing controlling the false discovery rate, six SNPs (IL1B (rs1143623, rs1143627), LY96 (rs11465996), TLR2 (rs11938228, rs4696480) and TLR9 (rs352139)) were associated with response to anti-TNF treatment and 4 SNPs (IL1B (rs1143623, rs1143627), TIRAP (rs8177374) and TLR5 (rs5744174)) were associated with response to ustekinumab treatment (q<0.20). The results suggest that genetic variants related to increased IL-1ß levels may be unfavorable when treating psoriasis with either anti-TNF or ustekinumab, whereas genetic variants related to high interferon-γ levels may be favorable when treating psoriasis with ustekinumab.

[Preferred Medical Specialties of Medical Students in Contrast to the Need for General Practitioners in Saxony]. / Facharztpräferenzen von Medizinstudierenden im Kontrast zum Bedarf an Allgemeinmedizinern in Sachsen.

Aim of the study: Especially in the rural areas of Germany, there are not enough general practitioners (GPs) for primary care. Preferred medical specialties of medical students can help get an estimate of the number of future GPs. This study compares this estimate to the current need for GPs in Saxony. Methods: 587 medical students at the second, sixth and tenth semester were invited to take part in an anonymous cross-sectional study regarding their specialty preferences at the Technical University Dresden. Based on the data of the medical requirements for Saxony, 4 model calculations were generated for comparison of the estimated numbers of future GPs and the current need for GPs. Results: The most commonly preferred medical specialties were surgery (19.1%), internal medicine (12.9%), pediatrics (11.6%) and general practice (9.9%). A significant increase in specialist preference for GP was observed from the sixth (4.9%) to the tenth semester (14.0%). The model calculations show that approximately 29% to 111% of the open positions for GPs could be filled by the potential new GPs from Dresden. Conclusion: Currently, medical students planning to become GPs cannot meet the corresponding need for GPs. Future studies should include the points of view of students, continuing education assistants, GPs and patients.

[Extensive yellowish fundus changes in a 6-year-old child]. / Großflächige gelbliche Fundusveränderungen bei 6­jährigem Kind.

We describe a 6-year-old, symptom-free girl presenting with a best corrected visual acuity of 0.6 on both eyes. Clinically we found yellowish subretinal lesions in the macula and around the vessel arcade without signs of vasculitis or abnormal vessels in the angiography. Fundus autofluorescence was marked and SD-OCT showed subretinal hyperreflective masses. With the help of molecular genetics we could make the diagnosis of an autosomal recessive bestrophinopathy (ARB). The natural history over 22 months revealed a slight recovery of the visual acuity as well as a slight reduction of the subretinal deposits.

Factors influencing sleep quality among nursing staff: Results of a cross sectional study.

PURPOSE: Given the intense physical and mental demands placed on nurses and other caregivers, getting sufficient sleep is essential to maintaining both individual health and professional performance. The goal of our study is to describe and analyze the self-reported sleep quality of nursing staff and identify which factors have an influence on it. METHODS: The sample was comprised of 153 female nurses over the age of 20 years who completed written surveys regarding their health status and health behavior. Their responses were subjected to ANOVA analysis with post hoc follow-up tests and logit regression was used. RESULTS: 33% of female nursing staff reported poor quality sleep. Lower quality of life, tachycardia and unequal distribution of work load were most strongly associated with poor sleep quality. CONCLUSION: Our study indicates that reducing workplace stress is a good place to start in developing a proactive strategy. A comprehensive prevention strategy should include both behavioral and situational prevention elements. Future studies should focus on identifying causal factors and developing prevention strategies.

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila.

A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila.

Caspases are the executioners of apoptosis. Although much is known about their physiological roles and structures, detailed analyses of missense mutations of caspases are lacking. As mutations within caspases are identified in various human diseases, the study of caspase mutants will help to elucidate how caspases interact with other components of the apoptosis pathway and how they may contribute to disease. DrICE is the major effector caspase in Drosophila required for developmental and stress-induced cell death. Here, we report the isolation and characterization of six de novo drICE mutants, all of which carry point mutations affecting amino acids conserved among caspases in various species. These six mutants behave as recessive loss-of-function mutants in a homozygous condition. Surprisingly, however, two of the newly isolated drICE alleles are gain-of-function mutants in a heterozygous condition, although they are loss-of-function mutants homozygously. Interestingly, they only behave as gain-of-function mutants in the presence of an apoptotic signal. These two alleles carry missense mutations affecting conserved amino acids in close proximity to the catalytic cysteine residue. This is the first time that viable gain-of-function alleles of caspases are described in any intact organism and provides a significant exception to the expectation that mutations of conserved amino acids always abolish the pro-apoptotic activity of caspases. We discuss models about how these mutations cause the gain-of-function character of these alleles.

Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis.

Although fingolimod is registered in Europe for treatment of relapsing-remitting multiple sclerosis (RRMS) if earlier disease modifying therapy (DMT) has failed, no data regarding its efficacy in this patient group are available. This observational cohort study of the NeuroTransData network includes German RRMS outpatients with failure of earlier therapy with injectable DMT (iDMT), therefore switching to either another iDMT (n = 133) or to fingolimod (n = 300). Statistical comparison of clinical baseline characteristics showed more severely affected patients in the fingolimod group. A propensity-score matched group comparison was performed (n = 99 in each group) covering more than 2-year observation time. Fingolimod showed statistically significant superior efficacy in comparison to iDMT regarding annualized relapse rate (0.21 versus 0.33 per year), time-to-relapse and likelihood of relapse (iDMT hazard ratio 1.7), proportion and likelihood of patients with EDSS progression (15.10 versus 31.00%; iDMT hazard ratio 1.7), persistence on medication and likelihood of discontinuation (iDMT hazard ratio 3.0). Significantly more patients were free of relapse and EDSS progression with fingolimod than with their second iDMT (64.4 versus 46.5%, p < 0.03). This real-life evidence in German RRMS outpatients support data from controlled clinical studies and can quantitatively support clinical decision finding processes if iDMT therapy fails in RRMS.

Successful interdisciplinary radical treatment of Mycobacterium fortuitum infection in a lipotourist from Germany after abdominoplasty in Turkey.

We report a case of a 30-year-old woman who experienced recurrent infections of the abdominal wall after travelling to Turkey from Germany to undergo abdominoplasty for aesthetic reasons. The patient's Mycobacterium fortuitum infection was successfully treated by surgery and antibiotic therapy. Surgical tourism-in this case, lipotourism-is resulting in an increasing number of patients in Europe who may present uncommon disease patterns.

Abolished ventilation and perfusion of lung caused by blood clot in the left main bronchus: auto-downregulation of pulmonary arterial blood supply.

It is generally assumed that the lungs possess arterial autoregulation associated with bronchial obstruction. A patient with pneumonia and congestive heart failure unexpectedly developed frequent haemoptysis. High-resolution CT and diagnostic CT were performed as well as ventilation/perfusion (V/Q) scintigraphy with single-photon emission CT (SPECT)/CT. V/Q SPECT/CT demonstrated abolished ventilation due to obstruction of the left main bronchus and markedly reduced perfusion of the entire left lung, a condition that was completely reversed after removal of a blood clot. We present the first pictorially documented case of hypoxia-induced pulmonary vasoconstriction and flow shift in a main pulmonary artery due to a complete intrinsic obstruction of the ipsilateral main bronchus. The condition is reversible, contingent on being relieved within a few days.

A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact.

Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.