[Description of a Multidimensional Health Program for Informal Caregivers]. / Beschreibung eines mehrdimensionalen Gesundheitsprogramms für pflegende Angehörige.

The aim of this study is to describe the concept of a prevention program for informal caregivers and its fit into stress theory and quality criteria. The program combines a 4-day group intervention outside the home with individual professional care in familiar domestic surroundings (family health care for persons with high burden, home training for specific care aspects). The program applies strategies focusing on problems and emotions. The program can be financed by social security funds. The 4-day respite service closes a gap in health services for informal caregivers.

[Does Return to Work after Vocational Retraining Depend on Labour Market?] / Hängt die berufliche Wiedereingliederung nach beruflichen Bildungsleistungen vom Arbeitsmarkt ab?

Background: Studies about the impact of the labour market on return to work (RTW) after vocational retraining are contradictory. We examined if (1) RTW after vocational retraining depends on regional labour markets and if (2) the regional labour markets variance affects the influence of personal characteristics on RTW. Methods: The data consisted of the scientific use file (completed rehabilitation in the course of health insurance 2002-2009) of the German Federal Pension Insurance (51 626 persons of 7 year cohorts) and regional economic data (412 districts). Multilevel logistic regression models were used. Results: At the context level the logarithmic unemployment rate was the most relevant predictor. The RTW rate decreased with increasing unemployment rate, saturating at an unemployment rate of around 15%. Significant differences between the intervention types (integration, 1-year and 2-year vocational retraining programs) were observed. The effects of individual predictors were clearer with higher unemployment, e. g. education, individual unemployment, income and further vocational interventions prior to vocational retraining. Conclusion: We demonstrate that the success of vocational retraining depends on the regional labour market. Furthermore individual predictors show stronger effects on success with the context of "poor" labour markets. In addition to the existing evidence the regional unemployment rate should be taken into consideration in effectiveness research studies and benchmarking processes in quality assurance.

[Is Work in Older Age Healthy? Findings from Family Run Businesses Using the Example of Bavarian Rural Economics]. / Ist Arbeit im Alter gesund? Erkenntnisse aus Familienunternehmen am Beispiel der bayerischen Agrarwirtschaft.

AIM OF STUDY: Working in second half of life is individually and socially important. The aim of this study is to multidimensionally evaluate the subjective health situation of older people, in particular those beyond the legal age of retirement who are working or assisting in family run businesses, using the example of Bavarian rural economics. METHODS: A 3 stage random sample stratified proportionally to regional population numbers was selected for a cross-sectional questionnaire survey (personal delivery, postal return n=3 176, 39.1%). Sample results can be generalised (men 59.8%, at least 65 years old 60.8%, smallest/small enterprises 61.8%). RESULTS: Life satisfaction is similar to that of the German age cohort population. In comparison to commercial and technical fields, physic and psychological complaints are lower and work pleasure is much higher. Health indicators are not dependent on enterprise structures, but on age and gender - on age partly non-linearly. CONCLUSION: Our results indicate that working in older age can be a source of subjective health. Process of family business succession may effect health. RESULTS might be applicable to other structurally similar agriculture regions and to craft sector. They promote individual confrontation with and social debate on a positive image of old age and aging.

[Multilevel analyses of labour market and return to work after vocational retraining]. / Mehrebenenanalysen zu Arbeitsmarkt und Wiedereingliederung nach beruflichen Bildungsleistungen.

AIM: is to test individual level and regional labour market hypotheses about return to work (RTW) after vocational retraining derived from matching theory. METHODS: In multilevel analyses individual data of graduates in 2006 (n=3620) by the association of German "Berufsförderungswerke" and for contextual level the regional unemployment rates in 2007 (n=159 Federal Employment Agency of Germany districts) are used. RESULTS: Probability of RTW rises with decreasing regional unemployment. There's an age effect only in context of high unemployment. In context of low unemployment partnership promotes RTW - but in context of high unemployment only for men and not for women. It's compatible with matching theory because family obligations lead to high individual reservation wages and entry wages are to low. CONCLUSIONS: Direct and indirect effects of labour market should be taken into account in research on effectiveness and in comparative evaluation on intervention quality.

[Successor establishment in familiy business as field of action in health promotion]. / Die innerfamiliäre Betriebsübergabe als Handlungsfeld der Gesundheitsförderung.

Successor establishment in familiy business may lead to interpersonal and intrapsychological conflicts and is mostly a transition to retirement. This may have a negative impact on the senior's health. The "Sozialversicherung für Landwirtschaft, Forsten und Gartenbau (SVLFG)" reacts with an intervention of several days duration. Evaluation aim is measuring participants changes in specific activities and confidence on successor establishment and retirement indicating mental health stabilisation. The method comprises a panel of intervention group (I, n=61) and comparison group (V, n=28) randomly selected, structurally similar and parallelised to point of transfer. Retirement activities significantly rise in I (p=0.001, Cohen's d=0.48) and are steady in V (p=0.54) after one year. Level of confidence is equal in both groups and steady but strongly indicating response shift in I. Intervention activates targeted activities and improves confidence at least qualitatively in a field that has hardly been researched.

[Regional classification of office specialists' partial labour market for use in vocational rehabilitation]. / Regionalklassifikation für den beruflichen Teilarbeitsmarkt der Bürofachkräfte zur Anwendung in der beruflichen Rehabilitation.

The core objective of all those involved in vocational rehabilitation is integration into the primary labour market. In order to achieve this effectively and efficiently the disparities of regional and occupational partial labour markets have to be transparent. On the example of vocational retraining centres for adults with disabilities (Berufsförderungswerke) and of office specialists' partial labour market this paper selects relevant labour market indicators, calculates an empirical regional classification using relative niveau data and describes implications. Data base are statistics of the Federal Employment Agency for office specialists (profession ID 781). Cluster analytic results are 6 stable and valid regional clusters.

[Impact of the labour market on vocational retraining centre participants' return to work: a study on employment agencies level]. / Bestimmungsgründe des Arbeitsmarktes für die Wiedereingliederung von Rehabilitanden aus Berufsförderungswerken: eine Untersuchung auf Ebene der Agenturbezirke.

This paper is aimed at identifying labour market factors impacting vocational retraining centre participants' return to work on Employment Agencies level and at comparing results to unemployed people's return to work (Social Code Book III). Databases are regional return to work rates of 2006 graduates, selected labour market indicators 2007, and the 2007 labour market classification of the Institute for Employment Research (IAB). The n = 75 Employment Agency districts where 74.5 % of the participants followed-up lived were analyzed using analyses of variance and multiple loglinear regression. Compared to the unemployment context (Social Code Book III), the impact of the labour market is much lower and less complex. In the multiple model, the regional unemployment rate and the regional tertiarization rate (size of the service sector) are found to be significant and superior to the IAB-classification. Hence, participants' return to work is less dependent on labour market conditions than unemployed people's return to work (Social Code Book III).

Improved immunotoxins with novel functional elements.

Immunotoxins (ITs) are protein-based drugs combining a target-specific binding domain (usually derived from an antibody) and a cytotoxic domain to kill target cells. They are among the most promising new therapeutic tools to fight cancer, and several clinical trials have been completed with encouraging results. Although the targeted elimination of malignant cells is an elegant concept, there are numerous practical challenges that limit the clinical use of ITs, including inefficient cellular uptake, low cytotoxicity and off-target effects. Here we present some of the strategies that have been developed to improve the efficacy of ITs, particularly those involving the incorporation of functional peptide sequences into recombinant ITs to improve target binding, modify plasma half life and distribution, boost tumor penetration, enhance cellular uptake and increase cytotoxic efficiency.

[Standard of integration management at company level and its auditing]. / Standard des betrieblichen Eingliederungsmanagements und dessen Auditierung.

SITUATION: Responsibility at company level for the employment of workers with health-related problems or disabilities has increased, inter alia because of integration management at company level according to section 84 (2) of the German Social Code Book IX. Although several recommendations exist, no standard is available for auditing and certification. Such a standard could be a basis for granting premiums according to section 84 (3) of Book IX of the German Social Code. AUDIT AND CERTIFICATION: One product of the international "disability management" movement is the "Consensus Based Disability Management Audit" (CBDMA). The Audit is a systematic and independent measurement of the effectiveness of integration management at company level. CBDMA goals are to give evidence of the quality of the integration management implemented, to identify opportunities for improvement and recommend appropriate corrective and preventive action. In May 2006, the integration management of Ford-Werke GmbH Germany with about 23 900 employees was audited and certified as the first company in Europe. STANDARD OF INTEGRATION MANAGEMENT AT COMPANY LEVEL: In dialogue with corporate practitioners, the international standard of CBDMA has been adapted, completed and verified concerning its practicability. Process orientation is the key approach, and the structure is similar to DIN EN ISO 9001:2000. Its structure is as follows: (1) management-labour responsibility (goals and objectives, program planning, management-labour review), (2) management of resources (disability manager and DM team, employees' participation, cooperation with external partners, infrastructure), (3) communication (internal and external public relations), (4) case management (identifying cases, contact, situation analysis, planning actions, implementing actions and monitoring, process and outcome evaluation), (5) analysis and improvement (analysis and program evaluation), (6) documentation (manual, records).

[Problems of implementing integration management at company level in small and medium-sized enterprises]. / Zur Problematik der Implementierung des betrieblichen Eingliederungsmanagements in kleinen und mittleren Unternehmen.

UNLABELLED: At company level responsibility increases for the employment of workers with health-related problems or disabilities, but realisation in small and medium-sized enterprises (SME) is lacking. Therefore a model is developed based on theory and a survey. SITUATION: Minimum requirements for "betriebliches Eingliederungsmanagement" (integration management at company level) according to section 84 (2) SGB IX Book 9 of the German Social Code, the main products of the international movement "disability management", a description of roles for realisation and the main sources of employers' support are described. Although external supporting of SMEs is unquestioned, it is expensive and retards own initiative and own activity counting solely on this. HYPOTHESIS: Only by developing a minimum of SME's awareness, acceptance and competence, this will open up to (currently suboptimal) external support. SURVEY: Goal is identifying SME managers' attitudes, activities, proposals and expectations referring integration management at company level to derive concepts of SME's support. 13 interviews are analysed by qualitative content analysis identifying the following barriers: information deficit, absence of priority, limited possibilities for transitional work, cost, partially limited workers' self-responsibility, illness as a "tabes" subject. Possibilities overcoming these barriers are delineated. On that basis a model is presented: pragmatically for realisation, a company contact person with minimum competence, uniform external support, institutional partners' integration and quality assurance according to disability management. OUTLOOK: Interlocking SME world and social insurance world means first to support SME's awareness, acceptance and competence, second to create for SME a central contact in the "rehabilitation jungle" and third to develop SME-suitable premiums according to section 84 (3) SGB IX, Book 9 of the German social code.

Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders.

Loss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias. The association of -7/7q- with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS], n = 3; de novo acute myeloid leukemia [AML], n = 9; therapy-related (t-) AML, n = 1) which, on chromosome banding analysis, exhibited deletions (n = 12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (-7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders.

An epitope delivery system for use with recombinant mycobacteria.

We have developed a novel epitope delivery system based on the insertion of peptides within a permissive loop of a bacterial superoxide dismutase molecule. This system allowed high-level expression of heterologous peptides in two mycobacterial vaccine strains, Mycobacterium bovis bacille Calmette-Guérin (BCG) and Mycobacterium vaccae. The broader application of the system was analyzed by preparation of constructs containing peptide epitopes from a range of infectious agents and allergens. We report detailed characterization of the immunogenicity of one such construct, in which an epitope from the Der p1 house dust mite allergen was expressed in M. vaccae. The construct was able to stimulate T-cell hybridomas specific for Der p1, and it induced peptide-specific gamma interferon responses when used to immunize naive mice. This novel expression system demonstrates new possibilities for the use of mycobacteria as vaccine delivery vehicles.

Induction of a type 1 immune response to a recombinant antigen from Mycobacterium tuberculosis expressed in Mycobacterium vaccae.

A 19-kDa lipoprotein from Mycobacterium tuberculosis was expressed as a recombinant antigen in the nonpathogenic mycobacterial host strain M. vaccae. Immunization of mice with the recombinant M. vaccae resulted in induction of a strong type 1 immune response to the 19-kDa antigen, characterized by immunoglobulin G2a (IgG2a) antibodies and gamma interferon (IFN-gamma) production by splenocytes. Immunization with the same antigen in incomplete Freund's adjuvant induced a strong IgG1 response with only low levels of IFN-gamma. Subsequent intravenous and aerosol challenges of immunized mice with virulent M. tuberculosis demonstrated no evidence of protection associated with the response to the 19-kDa antigen; in fact, the presence of the recombinant 19-kDa antigen abrogated the limited protection conferred by M. vaccae (vector control). The recombinant M. vaccae system is a convenient approach to induction of type 1 responses to M. tuberculosis antigens. However, the unexpected reduction in protective efficacy of M. vaccae expressing the 19-kDa antigen highlights the complexity of testing recombinant subunit vaccines and the need for a better understanding of the immune mechanisms required for effective vaccination against tuberculosis.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

From epitopes to peptides to immunotherapy.

Allergic inflammatory responses are regulated by cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] produced by CD4+ helper (Th0 and Th2) cells. The activation of these T cells follows engagement of T-cell antigen receptors (TCR) by antigenic peptides complexed with major histocompatibility complex (MHC) class II molecules. Under defined conditions presentation of T-cell epitopes as peptides can downregulate immune responses, and here we discuss the potential of peptide-mediated immunotherapy in the regulation of responses to the house dust mite (HDM). Cloning the major allergens of HDM has allowed detailed analysis of the HDM-reactive T-cell repertoire and has revealed that MHC class II restriction is heterogeneous, involving HLA-DP,-DQ, and -DR molecules, and that multiple T-cell epitopes are recognized. There is, however, evidence for a bias in TCR gene usage, which has prompted the analysis of peptide-mediated densitization of human T cells in vitro. CD4+ T cells exposed to high concentrations of HDM peptides become refractory to restimulation and fail to provide B-cell help. This is accompanied by complex changes in the surface phenotype, including the downregulation of TCR and CD28. During the induction of anergy cytokine-specific mRNA levels are enhanced, but when the anergic T cells are restimulated they fail to secrete IL-4 and IL-5, although interferon (IFN)-gamma production may remain unaltered. The ability of peptides to modulate the function of HDM-specific T cells in vivo has been investigated in mice. Following inhalation of peptide containing a major T-cell epitope of Der p 1 (residues 111-139) transient T-cell activation was observed prior to the inhibition of responses in naive and sensitized mice. T cells from the tolerant mice restimulated in vitro produced low levels of cytokines and failed to provide help for B cells.

The within-host cellular dynamics of bloodstage malaria: theoretical and experimental studies.

The properties of a mathematical model of bloodstage infection with a single strain of malaria were investigated. Analysing the cell population dynamics in the absence of a host immune response we demonstrate a relationship between host and parasite parameters that defines a criterion for the successful invasion and persistence of the parasite. Important parameters are the rates of merozoite production and death and those of erythrocyte production, death and invasion. We present data from experiments designed to evaluate the erythrocyte invasion rate in a rodent malaria system. The model generates patterns of parasitaemia in good qualitative agreement with those seen in Plasmodium berghei infections. The sole force behind the rise and fall in parasitaemia in the model without immunity is the density of susceptible erythrocytes, suggesting that resource availability is an important determinant of the initial pattern of infection in vivo. When we incorporate a simple immune response into the model we find that immunity against the infected cell is much more effective at suppressing parasite abundance than immunity against the merozoite. Simulations reveal oscillating temporal patterns of parasite abundance similar to P. c. chabaudi infection, challenging the concept that antigenic variation is the sole mechanism behind recrudescing patterns of infection.

Induction of T cell responses to the invariant chain derived peptide CLIP in mice immunized with the group 1 allergen of house dust mite.

In this study we demonstrate that immunization of H-2(b) mice with the allergen Der p 1 induces MHC class II restricted T cells that proliferate to residues 15-29 of Der p 1 (p15-29) and to the murine MHC class II-associated invariant chain derived peptide (CLIP). T cells from naive H-2(b) mice and those immunized with murine CLIP fail to respond to either CLIP or p15-29. T cell lines and clones reactive with p15-29 strongly proliferate in response to splenic antigen-presenting cells (APC) from normal H-2(b) mice but show reduced proliferation to APC from invariant chain deficient mice. Furthermore, T cells isolated from Der p 1 primed mice and expanded on H-2(b) spleen cells in the absence of the p15-29 epitope retained specificity for both p15-29 and CLIP, suggesting that naturally presented self components can act as mimetic peptides and may maintain T cell memory to foreign antigens.

Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4+ T cells precedes the development of tolerance in vivo.

We have previously demonstrated that intranasal (i.n.) administration of an immunodominant peptide (p1-111-139) derived from the house dust mite (HDM) allergen Der p 1 inhibits antigen-specific CD4+ T cell responses in H-2b mice. Here we report that i.n. peptide induced a rapid but transient activation of MHC class II restricted CD4+ T cells that peaked 4 days after peptide treatment and was of similar magnitude to that induced by parenteral immunization with antigen in adjuvant. During the early phase of the response lymph node and splenic T cells secreted a range of lymphokines when re-stimulated in vitro with p1 111-139; however, by day 14 IL-2 and IFN-gamma secretion by T cells were down-regulated. Mice deficient in CD8+ T cells became tolerant by i.n. treatment with peptide, suggesting that CD8+ T cells are not involved in down-regulating the CD4+ T cell response. Rechallenging mice with a single dose of p1 111-139 21 days after the initial treatment elicited a further transient T cell response, which was subsequently down-regulated over time. Although the i.n. peptide induced a strong transient CD4+ T cell response, only low levels of peptide-specific antibodies were detected either after the initial or subsequent i.n. exposures to p1 111-139. Our findings address the mechanisms underlying peripheral T cell tolerance following i.n. administration of a high dose of immunogenic peptide and have implications for understanding the consequences of peptide immunothearapy.

The effects of changes at peptide residues contacting MHC class II T-cell receptor on antigen recognition and human Th0 cell effector function.

Cytokines can influence the selection of functional subsets (Th1 or Th2) of CD4+ T cells. However, quantitative changes in affinity of peptide/major histocompatibility complex (MHC) class II/T-cell receptor (TCR) interactions may alter antigen density and modulate T-cell effector function. The possibility exists to use peptide analogues to induce a partial signal to dissociate production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) by T-helper type-0 (Th0) cells and, consequently, to regulate T-cell function. Based on binding assays and resolution of the crystalline structure of an influenza virus haemagglutinin peptide (HA 306-318) bound to the human MHC class II molecule DRB1*0101, we synthesized HA peptide analogues with amino acid substitutions predicted to modify either MHC class II/peptide density or TCR/peptide interactions. When we examined their antigenicity using cloned human Th0 cells, the analogues, in general, elicited a gradation in potency reflected by a reduction in both proliferation and cytokine production (IL-2, IL-4 and IFN-gamma). Although the analogue HA-R309 diminished IL-2 production, none of the analogues tested could selectively induce only IL-4 or IFN-gamma. Since, in general, the effector functions of the Th0 cells examined here were resistant to selective manipulation by the peptide analogues, this suggests that for some clones of chronically activated T cells modulation of selected functions may be difficult to achieve.