[A systematic review of the predictors of return to work following vocational retraining]. / Eine systematische Übersichtsarbeit zu den Einflussfaktoren auf die berufliche Wiedereingliederung nach beruflichen Bildungsleistungen.

BACKGROUND: Vocational Rehabilitation (VR) is an essential element of interventions aimed at re-integrating people with work disability into work. In this context, vocational retraining is of special importance. However, the success of vocational retraining, represented by subsequent returning to work (RTW), is only to a limited extent attributable to intervention quality. Apart from methodical influences participant-related as well as context-related attributes are discussed as influencing factors. To know these RTW predictors is a necessary condition for a valid comparative evaluation of intervention quality. METHODS: A structured literature search was conducted. All studies meeting the following criteria were included: publication between 2006 and 2011; context: German rehabilitation system and vocational retraining; multivariate analysis of RTW predictors. The evidence for or against the influence of a predictor was rated as strong if more than 75% of the models, and moderate if more than 50% of the models reported or excluded a significant relationship between predictor and RTW. All predictors included in more than 2 studies were considered in this review. RESULTS: 15 publications from 6 studies were included in the analysis. Due to differentiation of the models between different types of retraining the evidence was based on 9 prediction models. Strong evidence of an effect on RTW can be assumed for income before admission, subjective health rating and regular completion of retraining. There is moderate evidence for an effect of age and target job. Strong evidence against an effect on RTW is found for employment and occupational status before admission. There is moderate evidence against an RTW effect of sex, education and locus of control. Ambiguous evidence is obtained for the local job market, the type of retraining, social support and mobility. CONCLUSIONS: For the first time the review provides findings on the relevant influence factors of RTW following vocational retraining. These findings on the one hand could lead to an advance of intervention quality due to consideration of special personal and/or environmental factors. On the other hand there still remains an undeniable lack of information in this field. There is a special need for studies capable of confirming previous findings or of clarifying known uncertainties in the available evidence.

[A meta-analysis of the impact of sample, kind of outcome measurement and time of follow up on occupational re-integration after vocational retraining]. / Eine Meta-Analyse zum Einfluss von Stichprobe, Messmethode und Messzeitpunkt auf die berufliche Wiedereingliederung nach beruflichen Bildungsleistungen.

OBJECTIVES: Vocational Rehabilitation (VR) is an essential element of intervention to rehabilitate people with work disability due to chronic diseases. The activities are heterogeneous; of particular importance in the rehabilitation process is vocational retraining. These interventions are cost-intensive, take very long and have a decisive impact on the main goal, the return to work (RTW). However, vocational retraining is conducted under different settings: The question is to what extent this leads to specific methodical implications of RTW measurement that have an impact on the level of RTW. METHODS: The analysis was concentrated on the main outcome RTW after vocational retraining. A structured review was conducted of all German-language publications from 2005 to 2010 which report an RTW quota after vocational retraining. The main methodical conditions were: kind of RTW measurement (point in time rate vs. cumulative course rate), time of follow-up in years, and sample definition (all participants vs. participants with regular completion of retraining, RC). The impact of these conditions on the level of RTW was predicted by using a meta-regression model. The time of follow-up was standardized on the mean (1 year). RESULTS: 20 publications from 10 studies were included in the analysis. In all, 23 RTW quota were observed, from which 22 were included in the regression model. A positive impact on the level of RTW was identified for reduction of the sample to participants with RC (b=10.04; p=0.001), the time of follow-up (b=5.47; p=0.052) and, by trend, the interaction of the kind of RTW measurement and time of follow-up (b=6.32; p=0.090). There was no significance given for the main effect of kind of RTW measurement (p=0.787). The model fit was calculated with an adjusted R2=75.17%. CONCLUSIONS: The level of RTW given in the publications is very heterogeneous, but a major part of the variance was explained by the 3 methodical conditions we examined. Based on this, a classification system for RTW measurement after VR is presented, which could be a model for designing future studies as well as inter-actor communication of success after VR.

[Risk Index Disability Pension (RI-DP). A register-based case-control study with 8,500 men and 8,405 women]. / Risikoindex Erwerbsminderungsrente (RI-EMR). Eine prozessdatenbasierte Fall-Kontroll-Studie mit 8500 Männern und 8405 Frauen.

The aim of our study was to identify variables of prognostic relevance for disability pensions (DP) in the register data of the German Pension Fund (GPF) and to use the identified variables to construct a risk index. The study was designed as a case-control study of insurants of the GPF Bund using disability pensioners from 2004-2008 as cases and active insurants as controls. Independent variables were selected from the accumulated register data from 2001-2003. Data of 8,500 men and 8,405 women were analyzed. The strongest predictor of future DP were days of sickness benefits. Men with short-term benefits had 6.1 times higher odds of receiving a DP, while men receiving long-term benefits had even 66.3 times higher odds of receiving a DP. For women, the odds were increased 3.8 and 38.4 times, respectively. The risk index score was calculated by transforming the linear combination of parameter estimators and personal characteristics to values ranging from 0-100. ROC analyses and survival analyses confirmed the prognostic relevance of the index score. Independent samples were used to validate our models. Our results show that the GPF has information which could enable an active strategy to enhance the provision of medical rehabilitation.

[Quality Assurance in Rehabilitation under the German Pension Insurance Scheme]. / Stand der Qualitätssicherung in der Rehabilitation der gesetzlichen Rentenversicherung.

Ten years after its introduction, the German Pension Insurance's quality assurance programme is firmly established within the rehabilitation system. Regular, substantive reporting to rehabilitation centres and pension insurance organisations has contributed to improving the quality of rehabilitation. Legal codification of quality assurance stipulations has existed since 2001. The programme is in constant development, e. g. by optimization of patient interviewing and inclusion of evidence-based clinical practice guidelines. New programmes, e. g. in inpatient rehabilitation of children and youths or in outpatient rehabilitation, are being developed together with the German health care organizations. In the field of vocational rehabilitation quality assurance had started out with a conceptual study followed by projects concerning client interviewing, evaluation of documentation instruments, and analyses relative to the most important outcome factor, namely the vocational reintegration results achieved. External quality assurance is a mayor input factor for the rehabilitation centres' internal quality management. In future, rehabilitation centres will be asked to demonstrate the appropriate use of this information. It will remain the centres' decision which method of quality management system implementation they choose. Quality assurance results of every centre are planned to be made publicly accessible in the medium term, in particular to the insureds. Moreover, the results of the quality assurance programmes are intended to clearly impact the allocation of patients as well as the remuneration of the rehabilitation centres concerned. Quality assurance and quality management will continue to play a major role in the political discussion of health care.

PTEN/MMAC1 expression in melanoma resection specimens.

PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semi-quantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas.

Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists.

The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agonists to achieve a better understanding of the three-dimensional structures and their ligand-induced conformational changes. This led to the identification of structurally conserved "rigid" regions and more flexible parts of the proteins. The analysis was found to be of great value in fitting selected non-steroidal compounds into the human estrogen receptor alpha (hER alpha) ligand binding pocket. The experimentally determined binding affinities for a number of 2-aryl indoles and 2-aryl indenones are in good agreement with the subsequently modeled binding interactions. To date, no crystal structure is published for a complex with a pure antagonist. We therefore used the available structural information on complexes with partial agonists and the crystal structure of a mutant protein in complex with estradiol displaying a similar conformation to predict binding interactions for antagonists. The results are discussed in detail.

Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations.

The crystal structures of the human androgen receptor (hAR) and human progesterone receptor ligand-binding domains in complex with the same ligand metribolone (R1881) have been determined. Both three-dimensional structures show the typical nuclear receptor fold. The change of two residues in the ligand-binding pocket between the human progesterone receptor and hAR is most likely the source for the specificity of R1881 to the hAR. The structural implications of the 14 known mutations in the ligand-binding pocket of the hAR ligand-binding domains associated with either prostate cancer or the partial or complete androgen receptor insensitivity syndrome were analyzed. The effects of most of these mutants could be explained on the basis of the crystal structure.

Ligand-binding domain of estrogen receptors.

Estrogen receptors are multi-domain proteins that interact with other proteins and DNA to fulfil their function: the regulation of transcription. During the past 2-3 years, our understanding of this complex process has increased tremendously as crystal structures of isolated ligand-binding domains in complex with various ligands, as well as co-activator peptides, are now available. The structural information, combined with new data on novel co-activators/co-repressors, muteins and their actions, and novel ligands, allows for the first time the development of detailed theories for the first steps of transcription initiation.

Investigation of the binding interactions of progesterone using muteins of the human progesterone receptor ligand binding domain designed on the basis of a three-dimensional protein model.

The aim of this study was to investigate the binding interactions of the human progesterone receptor (hPR) with its natural ligand. Therefore, a homology-derived model of the hPR ligand binding domain has been constructed and used to predict residues potentially involved in interactions with progesterone. These residues and the free cysteines have been mutated (in total 13 residues with 15 mutations). All exchanges have been designed to preserve the three-dimensional structure of the protein. With respect to the binding characteristics towards progesterone, the muteins fall into three groups displaying no, reduced, or wildtype-like binding activity.

[Control of referral and duration of rehabilitation in federal insurance office provided rehabilitation]. / Steuerung der Einweisung und der Rehabilitationsdauer in der Rehabilitation der BfA.

Presented is a computer-based system for interactive assignment control, designed to cope with the increasing requirements in rehabilitation and health care concerning quality assurance, greater flexibility, as well as enhanced effectiveness and efficiency. Thanks to multi-factor control, medical, organizational and economic parameters can be taken into account selectively. In addition, an unbureaucratic approach to determining length of rehabilitation programme participation is described, which has been implemented successfully for the last three years.

[The quality assurance program of mandatory social security in the realm of medical rehabilitation. Concept, status of implementation and prospects]. / Das Qualitätssicherungsprogramm der gesetzlichen Rentenversicherung für den Bereich der medizinischen Rehabilitation. Konzept, Stand der Umsetzung und Perspektiven.

The quality improvement programme aims at the comparison of clinics in charge of the statutory pension insurance. The programme has been implemented successively in 1994, supported by researchers and teams of experts on specific subjects. Instruments and procedures have been developed to all programme items including a clinic comparing and information system, thus permitting routine use in practice. Performing regular clinic-comparisons analysing structural quality (equipment, staff, clinical concept, management), procedural quality (recording of rehabilitation process), and outcome quality (success of the rehabilitation estimated by physician and patient) of rehabilitation facilities shall initiate quality competition and stimulate a constant improvement of quality. significant basis, therefore, is a clinic-comparing information and reporting system. The developed instruments and procedures are available for all institutes providing rehabilitation.

Three-dimensional models of estrogen receptor ligand binding domain complexes, based on related crystal structures and mutational and structure-activity relationship data.

On the basis of the recently determined crystal structures of the ligand binding domains (LBDs) of the retinoic acid nuclear receptors (NRs), we present a three-dimensional (3D) molecular model of the human estrogen receptor alpha (hERalpha) LBD. A literature search for mutants affecting the binding properties has been performed; 45 out of 48 published mutants can be explained satisfactorily on the basis of the model. Estradiol has been docked into the binding pocket to probe its interactions with the protein. Energy minimizations and molecular dynamics calculations were performed for various ligand orientations. To evaluate their quality, the different models were scored using known structure-activity relationship (SAR) data for selected close estradiol homologues. The two best models explain largely the binding affinities of more distantly related ligands.

Cloning, purification, and crystallization of Escherichia coli cystathionine beta-lyase.

The metC gene coding for cystathionine beta-lyase of Escherichia coli has been cloned and used to construct an overproducing E. coli strain. An efficient purification scheme has been developed and the purified enzyme has been crystallized by the hanging drop vapour diffusion method using either ammonium sulfate or polyethyleneglycol 400 as precipitating agent. The crystals belong to the orthorombic space group C222. Their unit cell parameters are a = 60.9 A, b = 154.7 A and c = 152.7 A. Consideration of the possible values of VM accounts for the presence of one dimer per asymmetric unit. The crystals are suitable for X-ray analysis and a complete native date set to 1.83 A resolution has been collected using synchrotron radiation.

Rational design of hirulog-type inhibitors of thrombin.

The two crystal structures of thrombin complexed with its most potent natural inhibitor hirudin and with the active-site inhibitor D-Phe-Pro-Arg-CH2Cl [Rydel, T.J. et al., J. Mol. Biol., 221 (1991) 583; Bode, W. et al., EMBO J., 8 (1989) 3467] were used as a basis to design a new inhibitor, combining the high specificity of the polypeptide hirudin with the simpler chemistry of an organic compound. In the new inhibitor, the C-terminal amino acid residues 53-65 of hirudin are linked by a spacer peptide of four glycines to the active-site inhibitor NAPAP (N alpha-(2-naphthyl-sulfonyl-glycyl)-DL-p-amidinophenylalanyl-piperi dine). Energy minimization techniques served as a tool to determine the preferred configuration at the amidinophenylalanine and the modified piperidine moiety of the inhibitor. The predictions are supported by the interaction energies determined for D- and L-NAPAP in complex with thrombin, which are in good agreement with experimentally determined dissociation constants. The conformational flexibility of the linker peptide in the new inhibitors was investigated with molecular dynamics techniques. A correlation between the Pl' position and the interactions of the linker peptide with the protein is suggested. Modifications of the linker peptide are proposed based on the distribution of its main-chain torsion angles in order to enhance its binding to thrombin.

The binding of triazine herbicides to the photosynthetic reaction center of Rhodopseudomonas viridis. Energy minimization studies.

The binding of six herbicides of the triazine family to the photosynthetic reaction center of Rhodopseudomonas viridis was investigated with energy-minimization techniques, in order to correlate experimental with calculated data. The inhibitors were modeled in the active site according to the X-ray structure analysis of the complex formed between the triazine terbutryn (2-ethylamino-4-t-butylamino-6-methylthio-s-triazine) and the reaction center of R. viridis [Michel, H., Epp. O. & Deisenhofer, J. (1986) EMBO J. 5, 2445-2451]. 40 different energy minimizations were carried out with varying cutoff radii, partial charges on inhibitor atoms and dielectric constants, i.e. 10 different combinations of these were tested. The impact of these parameters on the calculated binding and interaction energy was either examined for all protein/triazine complexes or, in the case of the dielectric constant, a smaller sample was used. The calculated energies are dominated by van der Waals interactions, which change by up to 20% when extending the cutoff radius from 0.8 nm to 1.5 nm. The use of uniform or distance-dependent dielectric constant or partial charges on the inhibitor atoms does not severely influence the resulting structures, but shows a great impact on the calculated energies. In the two groups of triazines, each containing three inhibitors with methoxy or methylthio substituents, correlations of biological and calculated data were found quite often, but only once with all six triazines. The energy-minimized structures were compared and analysed. A third hydrogen bond, not seen in the X-ray analysis of the reaction center/tertubryn complex, was found between the t-butylamino moiety of terbutryn (and equivalent moieties in the other triazines) and the carbonyl oxygen of TyrL222.

Occurrence of bifurcated three-center hydrogen bonds in proteins.

Analysis of 13 high-resolution protein X-ray crystal structures shows that 1204 (24%) of all the 4974 hydrogen bonds are of the bifurcated three-center type with the donor X-H opposing two acceptors A1, A2. They occur systematically in alpha-helices where 90% of the hydrogen bonds are of this type; the major component is (n + 4)N-H ... O = C(n) as expected for a 3.6(13) alpha-helix, and the minor component is (n + 4)N-H ... O = C(n + 1), as observed in 3(10) helices; distortions at the C-termini of alpha-helices are stabilized by three-center bonds. In beta-sheets 40% of the hydrogen bonds are three-centered. The frequent occurrence of three-center hydrogen bonds suggests that they should not be neglected in protein structural studies.

Three-dimensional structure of fatty-acid-binding protein from bovine heart.

The complex of fatty-acid-binding protein (FABP) from bovine heart (cFABP, pI4.9) with endogenous lipid was crystallized in the presence of ammonium sulfate as precipitant. The needle-shaped crystals belong to the monoclinic space group C2, with unit-cell constants a = 5.262(6) nm, b = 7.631(8) nm, c = 3.945(5) nm and beta = 94.47(9) degrees. A native data set to 0.35 nm resolution was collected using synchrotron radiation and film methods. An initial model for the three-dimensional structure of the protein was constructed based on the crystal structure of the related bovine P2 myelin protein [Jones, T.A., Bergfors, T., Sedzik, J. & Unge, T. (1988) EMBO J. 7, 1597-1604] to which the amino acid sequence of bovine cFABP was adapted. Energy minimizations were carried out under different conditions using both an all-atom and a united-atom force field. The optimized models were used to determine the crystal structure of cFABP by molecular-replacement techniques. The structure was refined by simulated annealing to R = 0.267. As the bound lipid is heterogeneous, it could not be located in the electron-density map and/or the attained resolution was not sufficient. Bovine cFABP is composed of ten antiparallel beta strands forming a beta barrel, and by two alpha helices. The structural features are similar to those of other members of the superfamily of hydrophobic molecule transporters.

Electron microscopic immunogold cytochemistry reveals chromogranin A confined to secretory granules of porcine Merkel cells.

By ultrastructural immunohistochemistry using the immunogold technique, immunoreactive (ir) Chromogranin A (CGA) was found to be confined to the secretory vesicles of porcine Merkel cells. CGA was present predominantly in the periphery of the electron-dense core and on the clear halo. These findings indicate that CGA is a regular constituent of Merkel cell secretory granules but probably not exclusively responsible for their electron opacity.