Adaptation to Occupational Exposure to Moderate Endotoxin Concentrations: A Study in Sewage Treatment Plants in Germany.

Acute or chronic inhalation of endotoxin may lead to changes of lung function and inflammatory markers in the airways. Adaptation to workplace exposure may be possible. In this study, we investigated the possible difference in inflammatory markers assessed in nasal lavage fluid (NALF) in chronical exposure compared to voluntary subjects exposed acutely to endotoxin. We sought to define the variability of inflammatory markers in NALF and the dose-related changes after moderate exposure in naïve subjects. Endotoxin exposure (4-1039 EU/m3) resulted from routine work during one shift in sewage treatment plants. Subjects were matched to pairs (8 workers escorted by 10 students). Inflammatory markers were investigated before, directly after, and 16 h after the shift end. Additional NALF samples were collected in students without any specific exposure after 3 days. In NALF, total cell count, and interleukin (IL)-8 and IL-1ß concentrations were significantly higher in workers than in students at all times pointing to workplace-related long-lasting exposure resulting in adaptation. However, concentration of inflammatory markers without specific exposure in students showed a great variability, covering the whole range of values recorded in the workers. The findings of this study make us to recommend a repeated assessment of inflammatory markers in healthy volunteers before the investigation of exposure-related changes and a sample size adequate for statistical analysis.

[What do General Practitioners and Dentists Report about their Cooperation? A Qualitative Exploration]. / Was berichten Hausärzte und Zahnärzte über ihre Zusammenarbeit? Ergebnisse aus einer qualitativen Exploration.

OBJECTIVE: Against the background of well-described associations between oral and general health, the cooperation between general practitioners (GPs) and dentists is crucial. Besides treatment, this includes prevention. Administrative referral between these two professions is not provided by statute. Thus, the study addresses the question: How do dentists and GPs integrate the associations between oral and systemic health in daily routine? METHODS: A total of 28 semi-structured interviews were conducted with GPs and dentists from 3 structurally different regions in the Federal State of Baden-Wurttemberg. Participants were visited in their office. The interviews were recorded, transcribed and analysed by 2 dentists and sociologists using Mayrings' qualitative content analysis. RESULTS: Associations between general and oral health are partially known to both practitioners. However, contact between them is limited. GPs send patients directly to dentists, without contacting them - mainly due to a desolate dental status, rarely due to therapy-resistant headache or facial pain. Dentists contact GPs to clarify mainly medication or anticoagulation medications taken by patients prior to invasive procedures. Preventive aspects play a minor part. Consultation essentially depends on acquaintanceship. CONCLUSION: Separation by statute determines the cooperation. Oral cavity in daily care is demarcated. Holistic patient care is hindered by a lack of knowledge and daily routines.

Targeting expression to megakaryocytes and platelets by lineage-specific lentiviral vectors.

Essentials Platelet phenotypes can be modified by lentiviral transduction of hematopoietic stem cells. Megakaryocyte-specific lentiviral vectors were tested in vitro and in vivo for restricted expression. The glycoprotein 6 vector expressed almost exclusively in megakaryocytes. The platelet factor 4 vector was the strongest but with activity in hematopoietic stem cells. SUMMARY: Background Lentiviral transduction and transplantation of hematopoietic stem cells (HSCs) can be utilized to modify the phenotype of megakaryocytes and platelets. As the genetic modification in HSCs is transmitted onto all hematopoietic progenies, transgene expression from the vector should be restricted to megakaryocytes to avoid un-physiologic effects by ectopic transgene expression. This can be achieved by lentiviral vectors that control expression by lineage-specific promoters. Methods In this study, we introduced promoters of megakaryocyte/platelet-specific genes, namely human glycoprotein 6 (hGP6) and hGP9, into third generation lentiviral vectors and analyzed their functionality in vitro and in vivo in bone marrow transplantation assays. Their specificity and efficiency of expression was compared with lentiviral vectors utilizing the promoters of murine platelet factor 4 (mPf4) and hGP1BA, both with strong activity in megakaryocytes (MKs) used in earlier studies, and the ubiquitously expressing phosphoglycerate kinase (hPGK) and spleen focus forming virus (SFFV) enhancer/promoters. Results Expression from the mPf4 vector in MKs and platelets was the strongest similar to expression from the viral SFFV promoter, however, the mPf4 vector, also exhibited considerable off-target expression in hematopoietic stem and progenitor cells. In contrast, the newly generated hGP6 vector was highly specific to megakaryocytes and platelets. The specificity was also retained when reducing the promoter size to 350 bp, making it a valuable new tool for lentiviral expression in MKs/platelets. Conclusion MK-specific vectors express preferentially in the megakaryocyte lineage. These vectors can be applied to develop murine models to study megakaryocyte and platelet function, or for gene therapy targeting proteins to platelets.

Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics.

Deregulation of mitotic microtubule (MT) dynamics results in defective spindle assembly and chromosome missegregation, leading further to chromosome instability, a hallmark of tumor cells. RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signaling pathway. Intriguingly, deregulated RITA is involved in primary hepatocellular carcinoma and other malignant entities. We were interested in the potential molecular mechanisms behind its involvement. We show here that RITA binds to tubulin and localizes to various mitotic MT structures. RITA coats MTs and affects their structures in vitro as well as in vivo. Tumor cell lines deficient of RITA display increased acetylated α-tubulin, enhanced MT stability and reduced MT dynamics, accompanied by multiple mitotic defects, including chromosome misalignment and segregation errors. Re-expression of wild-type RITA, but not RITA Δtub ineffectively binding to tubulin, restores the phenotypes, suggesting that the role of RITA in MT modulation is mediated via its interaction with tubulin. Mechanistically, RITA interacts with tubulin/histone deacetylase 6 (HDAC6) and its suppression decreases the binding of the deacetylase HDAC6 to tubulin/MTs. Furthermore, the mitotic defects and increased MT stability are also observed in RITA-/- mouse embryonic fibroblasts. RITA has thus a novel role in modulating MT dynamics and its deregulation results in erroneous chromosome segregation, one of the major reasons for chromosome instability in tumor cells.

[Psychosomatic Consultation in the Workplace--Description and Modelling of a New Health-Related Service]. / Psychosomatische Sprechstunde im Betrieb--Gestaltungsformen des Angebots.

GOAL OF THE STUDY: In Germany, mental disorders have increasing importance for disability and early retirement. However, patients may have to wait several months before becoming an appointment with a psycho(somatic) therapist. Accordingly, several companies initiated a "psychosomatic consultation in the workplace" (PCIW). This concept has been explored. METHODS: Qualitative data analysis (expert interviews with stakeholders, focus group interviews with occupational health physicians; Mayring's content analysis) focussed on the question of how the concept of a PCIW can be tailored to meet the employees' needs. RESULTS: Concepts and implementation of PCIW differed with regard to the aspects dissemination of information about the consultation, gatekeeping, place of the consultation, and number of appointments with the psycho(somatic) therapist. The concepts of PCIW may be described as more or less "restrictive" or "liberal". The interviewees emphasised the need for PCIW and discussed the involvement of the occupational health physician within this approach. PCIW proved of value. Yet, the interviewees were ambivalent regarding the fact that companies offer and pay for treatment which should be provided within standard health care. CONCLUSION: Shaping company-based elements of standard health care should respect setting-specific needs and involve in-company stakeholders into the process.

[Patient care at the interface between rehabilitation and occupational health physicians--a systematic literature review focusing health care organization]. / Patientenversorgung an der Schnittstelle von Rehabilitation und Betriebsärzten--Systematische Literaturübersicht zur Versorgungsgestaltung.

Principal goal of rehabilitation arrangements for patients in employable age are the preservation of the ability to work, the rehabilitation of employability and the prompt reintegration into the professional life respectively. In practice, the reintegration is achieving unsatisfactory results.The systematic literature research (acquisition period: 1998-2013) was conducted on the basis of defined search keywords in electronic databases, online archives, relevant German magazines (via manual search), and in bibliographies of selected publications. The definition of research results has taken place in consensus procedures on the tier of abstracts.Reasons for the unsatisfying reintegration quota are current temporary latencies and qualitative deficits of rehabilitation discharge reports, unsatisfying communication and cooperation between rehabilitation and company doctors, insufficient presence of company doctors, and trust issues between rehabilitant and company doctor among other things.The company doctors have an objective role as mediator based on their internal knowledge, competences and opportunities to influence, and they are awarded with a role as connecting piece on setting the course for rehabilitation.Since the currently available data are dissatisfactory concerning the medical interfaces in the rehabilitation process, despite the high thematically relevance, research activities should absolutely be intensified in this field of interest.

p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells.

As a multifaceted molecule, p21 plays multiple critical roles in cell cycle regulation, differentiation, apoptosis, DNA repair, senescence, aging and stem cell reprogramming. The important roles of p21 in the interphase of the cell cycle have been intensively investigated. The function of p21 in mitosis has been proposed but not systematically studied. We show here that p21 is abundant in mitosis and binds to and inhibits the activity of Cdk1/cyclin B1. Deficiency of p21 prolongs the duration of mitosis by extending metaphase, anaphase and cytokinesis. The activity of Aurora B is reduced and the localization of Aurora B on the central spindle is disturbed in anaphase cells without p21. Moreover, HCT116 p21-/-, HeLa and Saos-2 cells depleted of p21 encounter problems in chromosome segregation and cytokinesis. Gently inhibiting the mitotic Cdk1 or add-back of p21 rescues segregation defect in HCT116 p21-/- cells. Our data demonstrate that p21 is important for a fine-tuned control of the Cdk1 activity in mitosis, and its proper function facilitates a smooth mitotic progression. Given that p21 is downregulated in the majority of tumors, either by the loss of tumor suppressors like p53 or by hyperactive oncogenes such as c-myc, this finding also sheds new light on the molecular mechanisms by which p21 functions as a tumor suppressor.

Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms.

AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation between AVEN mRNA overexpression and poor prognosis in childhood acute lymphoblastic leukemia. On the basis of these data, we investigated the potential involvement of AVEN in tumorigenesis. First, we confirmed the overexpression of AVEN in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patient samples. We then established a transgenic mouse model with T-cell-specific overexpression of AVEN, with which we demonstrated the oncogenic cooperation of AVEN with heterozygous loss of p53. Finally, we used a subcutaneous xenograft mouse model to show that AVEN knockdown in the T-ALL cell lines, MOLT-4 and CCRF-CEM, and in the acute myeloblastic leukemia cell line, Kasumi-1, leads to a halt in tumor growth owing to the increased apoptosis and decreased proliferation of tumor cells. Collectively, our data demonstrate that the anti-apoptotic molecule, AVEN, functions as an oncoprotein in hematopoietic neoplasms.

Impact of New Shift Models for Doctors Working at a German University Hospital for Gynaecology and Obstetrics Four Years After Implementation. Can They Meet the European Working Time Directive Without Increasing Costs?

Background: The impact of the European Working Time Directive and subsequent collective wage agreements for doctors from 2006 onwards were substantial. So far, no systematic evaluation of their application in Germany has been performed. We evaluated the impact four years after implementation of new shift models in a University Hospital for Gynaecology and Obstetrics (UHGO). Methods: A new shift model was created together with doctors of Tübingen UHOG in 2007 and implemented in 2008. Documentation of working hours has hence been done electronically. Adherence to the average weekly working time limit (AWTL) and the maximum of 10 h daily working time (10 h-dwt) was evaluated, as well as staffing costs in relation to case-weight points gathered within the German DRG (diagnosis related groups) System. Results: Staff increased from a mean of 44.7 full time equivalent (FTE) doctors in 2007 to 52.5 FTE in 2009, 50.8 in 2010, and 54.5 in 2011. There was no statistically significant difference of the monthly staff expenditures per case-weight between the years 2009 or 2010 vs. 2007. 2011, however, was significantly more expensive than 2007 (p = 0.02). The internal control group (five other departments of the university hospital) did not show an increase during the same period. AWTL were respected by 90, 96, and 98 % in 2009, 2010, and 2011, respectively. Of all shifts 10 h-dwt was exceeded by 7.4 % in 2009, 1.3 % in 2010, and 2.6 % in 2011, with significant differences between 2009 and both, 2010 and 2011 (p < 0.001), and between 2010 and 2011 (p = 0.02). Discussion: AWTL and 10 h-dwt could be continuously respected quite well after implementation of the new shift model without increasing the cost/earnings ratio for the first two years. However, in 2011 the ratio increased significantly (p = 0.02).

[A new working shift model for anesthesiologists: an analysis 3 years after implementation]. / Neues Dienstzeitenmodell für Ärzte in der Anästhesie : Eine Analyse 3 Jahre nach Implementierung.

OBJECTIVE: The aim of this study was to assess the efficacy, appropriateness and cost-effectiveness of a new working shift model for anesthesiologists complying with the European working time directive (EWTD) at the University Hospital of Tübingen (UKT), Germany 3 years after implementation BACKGROUND: Applying the standards of the EWTD is challenging for university hospitals as doctors must comply with the challenge of combining patient care, research and teaching. So far there have been no data available for German university hospitals on how these requirements can be met. As the department of anesthesiology is also a service-providing department it is essential not to increase staffing costs with a new shift model. METHODS: In 2007 a new working shift model for the department of anesthesiology was designed and introduced in 2008. Shift planning and documentation of working hours were implemented electronically. The calculated number of doctors to run this model was 87.6 full time equivalents (FTE). For 2009 and 2010 the compliance with the EWTD parameters was checked for 1) average weekly working time limit (AWWTL) and 2) compliance to the maximum daily working time limit of 10 h (10 h DWTL). Furthermore, staffing costs for doctors in 2010 were compared to 2007. To check for the time spent in patient care the period of anesthetic attendance (PAA) was chosen, i.e. the total time of patient contact by anesthesiology staff. Data were analyzed descriptively for AWWTL and for 10 h DWTL. FTE, staff costs and PAA were evaluated by one-way ANOVA. RESULTS: The new shift model allowed 84.4 % of all doctors to comply with the individual AWWT limits of 54 h and 48 h in 2009 (81/96) and 76.0 % in 2010 (79/104). In 2009 61.5 % of anesthesiologists voted for opt-out (59/96) and 53.8 % did so in 2010 (56/104). The 10 h DWTL was respected by 84.0 % in 2009 and by 85.9 % in 2010. The mean number of anesthesiologists rose significantly from 78.4 FTE in 2007 to 82.5 FTE in 2009 and 84.6 FTE in 2010 (p < 0.001 for 2010 vs. 2007, p = 0.004 for 2009 vs. 2007 and was not significant for 2010 vs. 2009). Staff costs per FTE increased from 7,524.79 /month to 7,800.66 /month and 7,966.11 /month in 2007, 2009 and 2010, respectively with the differences being non-significant. The PAA increased significantly from a mean of 6,124 h/month in 2007 to 6,581 h/month in 2009 and 6,872 h/month in 2010 (p < 0.001 for 2010 vs. 2007, whereas 2009 vs. 2007 and 2010 vs. 2009 were not significant). Thus, labour costs increased from 96.59 /h PAA in 2007 to 98.53 /h in both 2009 and 2010, the differences being not significant. CONCLUSIONS: The newly designed shift model allowed a fair compliance with the EWTD in respect to AWTL and 10 h DWTL, although the calculated number of doctors to run the shift model could not be met in 2009 and 2010. Violations of the 10 h DWT limits were stable in 2009 and 2010; however the number of doctors exceeding the AWWT limits appeared to increase. The compliance with opt-out decreased from 2009 to 2010 and a high proportion of AWWTL violations resulted from the group of non-opt-out voters. The staff costs per hour PAA after implementation of the new shift model did not differ significantly from the year before although staffing costs increased by 7.2 % between 2007 and 2010. Costs increased by 162,454 /year for all PAA hours in 2010. Further evaluation of staff satisfaction with the new shift models is needed and already under way.

[(Inter)national and regional health goals in academic social-medical education conception for teaching medical students at the Eberhard Karls University Tuebingen]. / (Inter)nationale und regionale Gesundheitsziele in der sozialmedizinischen LehreLehrkonzeption für Medizinstudierende an der Eberhard Karls Universität Tübingen.

BACKGROUND: Social medicine deals with the specific interactions between medicine and society within a constantly changing social environment. The Institute of Occupational and Social Medicine, University Hospital Tuebingen, focuses on this relationship within the academic teaching of the Medical Faculty. Many of the issues thus directly affect the national health objectives and especially the health targets of the state of Baden-Württemberg, summarised in the Health Strategy Baden-Wuerttemberg. MATERIAL AND METHODS: In addition to the recommendations of the German Society for Social Medicine and Prevention (DGSMP) for the social medicine curriculum and the specific definition of the content by the Tuebingen medical faculty, national and regional health-care goals are also taken into account in the teaching conception. RESULTS: Classes are increasingly offered as training courses in small groups (seminars, group work with practical training), instead of classic lectures. These teaching methods allow the students to take part more actively in social medicine issues and to think and act within a comprehensive understanding of health management based on societal goals and the needs of a good health system. The concept is supported by the curriculum design element "log-book skills" of the Medical Faculty of Tuebingen. Feedback elements for teachers and students shape the further development of the concept. In dealing with real system data, practical experience on site and case vignettes, the students experience the links between societal influences, political objectives and medical action as well as the importance of accessibility of medical services for equity in health chances. CONCLUSIONS: The fact that advice and expertise play a crucial role in accessibility is a component to which too little attention is paid and calls for emphasis in the teaching concept. This teaching approach will deepen the understanding of the influence of psychosocial context factors and the conditions of the structural framework on the medical outcome. Furthermore there is a need for providing knowledge and special skills, which enable medical doctors to guide their patients optimally within the healthcare system and to make their contribution to a good system.

Permanent Genetic Resources added to Molecular Ecology Resources Database 1 April 2011-31 May 2011.

This article documents the addition of 92 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Anopheles minimus, An. sinensis, An. dirus, Calephelis mutica, Lutjanus kasmira, Murella muralis and Orchestia montagui. These loci were cross-tested on the following species: Calephelis arizonensi, Calephelis borealis, Calephelis nemesis, Calephelis virginiensis and Lutjanus bengalensis.

[Effect of written patient information on knowledge and function of patients with acute uncomplicated back pain (PIK Study)]. / Patienteninformationen und Kreuzschmerzen (PIK-Studie) - Einfluss von Patienteninformationen auf Wissen und Funktionskapazität von Patienten mit akuten, unkomplizierten Rückenschmerzen.

BACKGROUND: If patients return early in the course of acute, uncomplicated back pain to their normal activities, their symptoms improve more quickly. Written detailed patient information can have a positive effect on knowledge and can increase physical activity. In this study the effect of a short evidence-based back pain leaflet on knowledge, function and patients' beliefs was investigated. METHODS: A randomised controlled trial was carried out in 12 primary care practices. Patients with acute, uncomplicated back pain received either the back-pain specific information (intervention) or a leaflet without content regarding back pain (control). Participants' data were inquired before consultation of the general practitioner, as well as 1 week and 3 months later. Outcome measures were SF-36, FABQ-D, FFbH-R, knowledge concerning back pain, frequency of use of the leaflet, usefulness of the information and change of behaviour. RESULTS: The included patients totaled 174. The response rates were 74.7% (1 week) and 67% (3 months). Patients receiving the intervention leaflet showed better knowledge at 1 week and greater improvement in function scores at 3 months. There was no effect on patients' beliefs. Patients of the intervention group reported more activity in everyday life. CONCLUSION: Short written information may have small, in total possibly positive effects on knowledge, support of activity and function in patients with acute, uncomplicated back pain.

Airborne biological hazards in different pig fattening systems.

In this research project two organic and two conventional housing systems for fattening pigs are assessed in regard to the emission of microorganisms, endotoxins and dust. The concentrations of microorganisms and endotoxins varied between the different housing systems while no distinct differences for the dust concentrations were observed. Endotoxins concentrations reached up to 14 495 EU/cubic meter median) in deep litter stable, indicating the high exposure with biological agents during farm work. The differences between the stables could not be assigned to the organic or conventional kind of husbandry but to the management of the systems.

A description of the standardized measurement procedures and recommended threshold limit values for biological hazards in Germany.

On the basis of EU directives 89/391/EEC (to encourage improvements in the safety and health of workers at work) and 2000/54/EC (on the protection of workers from risks related to exposure to biological agents at work), biological hazards at work have to be assessed and preventive measures have to be introduced in all member states of the EU. In Germany, national legislation (Biological Agents Ordinance - BioStoffV and Technical Rules on Biological Agents, TRBA) and recommendations of workers' compensation boards define standardized methods for the assessment of airborne mold, bacteria, and endotoxins. This article describes policies and practices in Germany for measurement of airborne bioaerosols and for interpretation of measurements relative to the standards. As an example, methods and results of measurements in agriculture are shown. The standardized measurement procedures proved suitable for use in livestock buildings. The results of the exploratory measurements in different livestock buildings confirmed the often high concentrations of airborne biological hazards in agriculture that are reported in the literature.

Inhibition of malignant glioma cell growth by a survivin mutant retrovirus.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor that is resistant to conventional radiotherapy and chemotherapy. The median survival time of patients with GBM has remained less than 2 years despite concerted efforts to improve therapy. As a new approach to treat GBM we generated retroviral particles encoding mutant survivin for transduction of glioma cells. We demonstrate here that retroviral overexpression of a nonphosphorylatable Thr-34 --> Ala mutant of survivin (survivinT34A), in the glioma cell lines U373 and H4 resulted in a marked increase in the percentage of cells bearing multiple nuclei, which was accompanied by significantly decreased cell proliferation, and in greater numbers of cells with hypodiploid DNA content. Administration of the broad caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethyl-ketone did not reduce the cell death rate. Yet increased nuclear translocation of apoptosis-inducing factor (AIF) was observed in cells transduced with survivinT34A, indicating caspase-independent cell death. Transduction of retroviral vectors encoding wild-type survivin also led to the appearance of multinuclear cells. In contrast to mutant survivin, overexpressed wild-type survivin did not increase the cell death rate and no enhanced nuclear AIF translocation was observed. We suggest that retroviral vectors delivering mutant survivinT34A might be employed for the treatment of glioblastoma.

Identification of an HLA-A*0201-restricted T-cell epitope derived from the prostate cancer-associated protein prostein.

The development of T-cell-based immunotherapies of cancer largely depends on the availability of tumour-associated antigens capable of eliciting tumour-directed cytotoxic T-cell responses. In prostate cancer, the number of antigens defined as suitable targets of cytotoxic T lymphocytes (CTLs) is still limited. Recently, prostein was identified as a transmembrane protein that is highly restricted to prostate tissues. In our study, prostein transcripts were found to be abundant in both malignant and nonmalignant prostate tissue samples. To identify immunogenic CD8+ T-cell epitopes, human leucocyte antigen-A(*)0201-binding peptides were selected from the amino-acid sequence of prostein and were used for the in vitro stimulation of CD8+ T lymphocytes. Specific CTLs were raised against the prostein-derived peptide CLAAGITYV that were capable of lysing prostate cancer cells, indicating that this peptide is naturally generated by tumour cells. Our data suggest that prostein is a suitable candidate to be included in a T-cell-based immunotherapy of prostate cancer.