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Temporal predictability is thought to affect stimulus processing by facilitating the allocation of attentional resources. Recent studies have shown that periodicity of a tonal sequence results in a decreased peak latency and a larger amplitude of the P3b compared with temporally random, i.e., aperiodic sequences. We investigated whether this applies also to sequences of linguistic stimuli (syllables), although speech is usually aperiodic. We compared aperiodic syllable sequences with two temporally regular conditions. In one condition, the interval between syllable onset was fixed, whereas in a second condition the interval between the syllables’ perceptual center (p-center) was kept constant. Event-related potentials were assessed in 30 adults who were instructed to detect irregularities in the stimulus sequences. We found larger P3b amplitudes for both temporally predictable conditions as compared to the aperiodic condition and a shorter P3b latency in the p-center condition than in both other conditions. These findings demonstrate that even in acoustically more complex sequences such as syllable streams, temporal predictability facilitates the processing of deviant stimuli. Furthermore, we provide first electrophysiological evidence for the relevance of the p-center concept in linguistic stimulus processing.
Introduction: In this article the personal study and life situation of parents who are also medical students at the Medical School of the Goethe University Frankfurt am Main is discussed. There is a special focus on the topics "studying with children" and "family-friendly university", which have been present in discussions about university development and in the daily life of academics, especially during the last decade. The workgroup "Individual Student Services" at the medical faculty at the Goethe University tries to meet the necessities of the individual study courses and to support the study success with a new counselling and student service concept.
Methods: The experience of parents studying medicine was recorded in semi-structured interviews (Date: April 2010), which were held as part of the sponsored pilot project on part-time medical studies ("Pilot Project Part-time Medical Studies"). Additionally, study results from the Medical School of the Goethe University Frankfurt am Main were integrated as well as a literature analysis.
Results: It was found that the teaching demands and support services, which have been suggested and needed for years now, have been partially implemented and are without sufficient support at the faculty level to date. Thus the current situation of medical students with children is still difficult and seems a big challenge for everyone involved.
Solution: As part of the "Individual Student Services" a new pilot project on part-time medical studies was established in November 2009. Only the use of new, unconventional and innovative ideas allows universities to adequately support the changing and heterogeneous student population and support them to successfully completing their medical studies.
Introduction: Potential health damage by environmental emission of tobacco smoke (environmental tobacco smoke, ETS) has been demonstrated convincingly in numerous studies. People, especially children, are still exposed to ETS in the small space of private cars. Although major amounts of toxic compounds from ETS are likely transported into the distal lung via particulate matter (PM), few studies have quantified the amount of PM in ETS. Study aim The aim of this study was to determine the ETS-dependent concentration of PM from both a 3R4F reference cigarette (RC) as well as a Marlboro Red brand cigarette (MRC) in a small enclosed space under different conditions of ventilation to model car exposure.
Method: In order to create ETS reproducibly, an emitter (ETSE) was constructed and mounted on to an outdoor telephone booth with an inner volume of 1.75 m3. Cigarettes were smoked under open- and closed-door condition to imitate different ventilation scenarios. PM2.5 concentration was quantified by a laser aerosol spectrometer (Grimm; Model 1.109), and data were adjusted for baseline values. Simultaneously indoor and outdoor climate parameters were recorded. The time of smoking was divided into the ETS generation phase (subset "emission") and a declining phase of PM concentration (subset "elimination"); measurement was terminated after 10 min. For all three time periods the average concentration of PM2.5 (Cmean-PM2.5) and the area under the PM2.5 concentration curve (AUC-PM2.5) was calculated. The maximum concentration (Cmax-PM2.5) was taken from the total interval.
Results: For both cigarette types open-door ventilation reduced the AUC-PM2.5 (RC: from 59 400 +/- 14 600 to 5 550 +/- 3 900 mug*sec/m3; MRC: from 86 500 +/- 32 000 to 7 300 +/- 2 400 mug*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 600 +/- 150 to 56 +/- 40 mug/m3, MRC from 870 +/- 320 to 75 +/- 25 mug/m3; p < 0.001) by about 90%. Cmax-PM2.5 was reduced by about 80% (RC: from 1 050 +/- 230 to 185 +/- 125 mug/m3; MRC: from 1 560 +/-500 mug/m3 to 250 +/- 85 mug/m3; p < 0.001). In the subset "emission" we identified a 78% decrease in AUC-PM2.5 (RC: from 18 600 +/- 4 600 to 4 000 +/- 2 600 mug*sec/m3; MRC: from 26 600 +/- 7 200 to 5 800 +/- 1 700 mug*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 430 +/- 108 to 93 +/- 60 mug/m3; MRC: from 620 +/- 170 to 134 +/- 40 mug/m3; p < 0.001). In the subset "elimination" we found a reduction of about 96-98% for AUC-PM2.5 (RC: from 40 800 +/- 11 100 to 1 500 +/- 1 700 mug*sec/m3; MRC: from 58 500 +/- 25 200 to 1 400 +/- 800 mug*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 730 +/- 200 to 27 +/- 29 mug/m3; MRC: from 1 000 +/- 450 to 26 +/- 15 mug/m3; p < 0.001). Throughout the total interval Cmax-PM2.5 of MRC was about 50% higher (1 550 +/- 500 mug/m3) compared to RC (1 050 +/- 230 mug/m3; p < 0.05). For the subset "emission" - but not for the other periods - AUC-PM2.5 for MRC was 43% higher (MRC: 26 600 +/- 7 200 mug*sec/m3; RC: 18 600 +/- 4 600 mug*sec/m3; p < 0.05) and 44% higher for Cmean-PM2.5 (MRC: 620 +/- 170 mug/m3; RC: 430 +/- 108 mug/m3; p < 0.05).
Conclusion: This method allows reliable quantification of PM2.5-ETS exposure under various conditions, and may be useful for ETS risk assessment in realistic exposure situations. The findings demonstrate that open-door condition does not completely remove ETS from a defined indoor space of 1.75 m3. Because there is no safe level of ETS exposure ventilation is not adequate enough to prevent ETS exposure in confined spaces, e.g. private cars. Additionally, differences in the characteristics of cigarettes affect the amount of ETS particle emission and need to be clarified by ongoing investigations.
Patienten mit einem erhöhten Risiko für Thrombosen oder Embolien müssen oft ein Leben lang medikamentös behandelt werden. Doch nicht jeder, der Gerinnungshemmer benötigen würde, erhält sie auch, und umgekehrt erhält mancher die Medikamente, obwohl sie nicht indiziert wären. Schließlich kann es sein, dass aufgrund von einer Wechselwirkung mit anderen Medikamenten oder einer fehlerhaften medikamentösen Einstellung das Blutungsrisiko oder das Risiko für Embolien erhöht ist. Um die Versorgung auf diesem Gebiet zu verbessern und Komplikationen durch Blutungen oder Embolien zu reduzieren, hat das Institut für Allgemeinmedizin im März 2012 eine Studie mit hessischen Hausarztpraxen begonnen.
Background: Undergoing systemic inflammation, the innate immune system releases excessive proinflammatory mediators, which finally can lead to organ failure. Pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), form the interface between bacterial and viral toxins and innate immunity. During sepsis, patients with diagnosed adrenal gland insufficiency are at high risk of developing a multiorgan dysfunction syndrome, which dramatically increases the risk of mortality. To date, little is known about the mechanisms leading to adrenal dysfunction under septic conditions. Here, we investigated the sepsis-related activation of the PRRs, cell inflammation, and apoptosis within adrenal glands.
Methods: Two sepsis models were performed: the polymicrobial sepsis model (caecal ligation and puncture (CLP)) and the LTA-induced intoxication model. All experiments received institutional approval by the Regierungspräsidium Darmstadt. CLP was performed as previously described [1], wherein one-third of the caecum was ligated and punctured with a 20-gauge needle. For LTA-induced systemic inflammation, TLR2 knockout (TLR2-/-) and WT mice were injected intraperitoneally with pure LTA (pLTA; 1 mg/kg) or PBS for 2 hours. To detect potential direct adrenal dysfunction, mice were additionally injected with adrenocorticotropic hormone (ACTH; 100 μg/kg) 1 hour after pLTA or PBS. Adrenals and plasma samples were taken. Gene expressions in the adrenals (rt-PCR), cytokine release (multiplex assay), and the apoptosis rate (TUNEL assay) within the adrenals were determined.
Results: In both models, adrenals showed increased mRNA expression of TLR2 and TLR4, various NLRs, cytokines as well as inflammasome components, NADPH oxidase subunits, and nitric oxide synthases (data not shown). In WT mice, ACTH alone had no effect on inflammation, while pLTA or pLTA/ACTH administration showed increased levels of the cytokines IL-1β, IL-6, and TNFα. TLR2-/- mice indicated no response as expected (Figure 1, left). Interestingly, surviving CLP mice showed no inflammatory adrenal response, whereas nonsurvivors had elevated cytokine levels (Figure 1, right). Additionally, we identified a marked increase in apoptosis of both chromaffin and steroid-producing cells in adrenal glands obtained from mice with sepsis as compared with their controls (Figure 2).
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Conclusion: Taken together, sepsis-induced activation of the PRRs may contribute to adrenal impairment by enhancing tissue inflammation, oxidative stress and culminate in cellular apoptosis, while mortality seems to be associated with adrenal inflammation.
Recent data have clearly shown that a sustained virologic response can be achieved in different HCV infected patient populations with various interferon-free treatment regimens. Despite the successful implementation of telaprevir- and boceprevir-based triple therapies, all-oral regimens will certainly become a first choice for a number of HCV-infected patients in the very near future, as triple therapy approaches are burdened with significant side-effects and limited success in patients with advanced liver fibrosis and prior null-response to pegylated interferon-α (pegIFN-α)/ribavirin therapy. However, available data from phase I and II clinical trials evaluating interferon-free regimens have not yet revealed a clearly outstanding all-oral combination, and numerous challenges remain to be addressed by intensive ongoing and future research. In particular, thus far evaluated all-oral regimens did not cure a satisfactory percentage of patients with unfavorable baseline characteristics, namely patients infected with HCV genotype 1a, previous null-response to pegIFN-α/ribavirin, or liver cirrhosis. In this review, we summarize available data of interferon-free regimens for the treatment of chronic hepatitis C and assess implications for perspectives and challenges in the further development of all-oral therapies.
We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
Background: To improve and assess the effectiveness of disease management programs (DMPs), it is critical to understand how many people drop out of disease management programs and why.
Methods: We used routine data provided by a statutory health insurance fund from the regions North Rhine, North Wurttemberg and Hesse. As part of the German DMP for type 2 diabetes, the insurance fund received regular documentation of all members participating in the program. We followed 10,989 patients who enrolled in the DMP between July 2004 and December 2005 until the end of 2007 to study how many patients dropped out of the program. Dropout was defined based on the discontinuation of program documentation on a particular patient, excluding situations in which the patient died or left the insurance fund. Predictors of dropout, assessed at the time of program enrolment, were explored using logistic regression analysis.
Results: 5.5% of the patients dropped out of the disease management program within the observation period. Predictors of dropout at the time of enrolment were: region; retirement status; the number of secondary diseases; presence of a disabling secondary disease; doctors recommendations to stop smoking or to seek nutritional counselling; and the completion and outcome of the routine foot and eye exams. Different trends of dropout were observed among retired and employed patients: retired patients of old age, who possibly drop out of the program due to other health care priorities and employed people of younger age who have not yet developed many secondary diseases, but were recommended to change their lifestyle.
Conclusions: Overall, dropout rates for the German disease management programs for type 2 diabetes were low compared to other studies. Factors assessed at the time of program enrolment were predictive of later dropout and should be further studied to provide information for future program improvements.
Background: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best practice model that applies major elements of case management, including patient education, can improve antithrombotic management in primary health care in terms of reducing major thromboembolic and bleeding events.
Methods: This 24-month cluster-randomized trial will be performed in 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, health care assistants and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, health care assistants will be trained in case management and will use the Coagulation-Monitoring-List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment-as-usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization, and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self-reported adherence to medication, general practitioners' and health care assistants' knowledge, patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline (T0), follow-up after 12 (T1) and after 24 months (T2).
Discussion: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients and the methodological tool, case-management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment.
Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues.