Digitally Assisted Standard Diagnostics in Insurance Medicine (DASDIM): psychometric data in psychiatric work disability evaluations.

PURPOSE: Insurers often commission psychiatric experts to evaluate the eligibility of workers with mental disorders for disability benefits, by estimating their residual work capacity (RWC). We investigated the validity of a standardized, computer-based battery of established diagnostic instruments, for evaluating the personality, cognition, performance, symptom burden, and symptom validity of claimants. METHODS: One hundred and fifty-three claimants for benefits were assessed by the assembled test battery, which was applied in addition to a conventional clinical work disability evaluation. RESULTS: A principal component analysis of the test and questionnaire battery data revealed six factors (Negative Affectivity, Self-Perceived Work Ability, Behavioral Dysfunction, Working Memory, Cognitive Processing Speed, and Excessive Work Commitment). Claimants with low, medium, and high RWC exclusively varied in the factor Negative Affectivity. Importantly, this factor also showed a strong association to psychiatric ratings of capacity limitations in psychosocial functioning. CONCLUSIONS: The findings demonstrate that the used test battery allows a substantiation of RWC estimates and of psychiatric ratings by objective and standardized data. If routinely incorporated in work disability evaluations, the test battery could increase their transparency for all stakeholders (insurers, claimants, medical experts, expert case-coordinators, and legal practitioners) and would open new avenues for research in the field of insurance medicine.Implications for rehabilitationThe residual work capacity (RWC) estimation by medical experts is internationally good practice, but plagued by a relatively low interrater agreement.The current study shows that psychiatric RWC estimates and capacity limitation ratings can be substantiated by data from objective, standardized psychometric instruments.Systematically using such instruments might help to improve the poor interrater agreement for RWC estimates in work disability evaluations.Such data could also be used for adopting vocational trainings and return-to-work programs to the individual needs of workers with mental health problems.

Transition of galactosyltransferase 1 from trans-Golgi cisterna to the trans-Golgi network is signal mediated.

The Golgi apparatus (GA) is the organelle where complex glycan formation takes place. In addition, it is a major sorting site for proteins destined for various subcellular compartments or for secretion. Here we investigate beta1,4-galactosyltransferase 1 (galT) and alpha2,6-sialyltransferase 1 (siaT), two trans-Golgi glycosyltransferases, with respect to their different pathways in monensin-treated cells. Upon addition of monensin galT dissociates from siaT and the GA and accumulates in swollen vesicles derived from the trans-Golgi network (TGN), as shown by colocalization with TGN46, a specific TGN marker. We analyzed various chimeric constructs of galT and siaT by confocal fluorescence microscopy and time-lapse videomicroscopy as well as Optiprep density gradient fractionation. We show that the first 13 amino acids of the cytoplasmic tail of galT are necessary for its localization to swollen vesicles induced by monensin. We also show that the monensin sensitivity resulting from the cytoplasmic tail can be conferred to siaT, which leads to the rapid accumulation of the galT-siaT chimera in swollen vesicles upon monensin treatment. On the basis of these data, we suggest that cycling between the trans-Golgi cisterna and the trans-Golgi network of galT is signal mediated.

Analysis of protein transport to lysosomes.

Lysosomes are terminal degradative organelles that are found in all higher eukaryotic cells. The biogenesis of lysosomes involves the transport of various acid hydrolases and transmembrane glycoproteins from their site of synthesis in the endoplasmic reticulum through the biosynthetic and endocytic pathways. Protein transport to lysosomes can be studied by a combination of techniques based on the separation of intracellular organelles. Percoll density gradient centrifugation has long been the method of choice for separating lysosomes from other organelles in cell homogenates, and accordingly, this unit describes protocols for obtaining reasonably pure lysosomal fractions from mammalian cells using Percoll density gradient separation.

Characterization of the TGN exit signal of the human mannose 6-phosphate uncovering enzyme.

The human mannose 6-phosphate uncovering enzyme participates in the uncovering of the mannose 6-phosphate recognition tag on lysosomal enzymes, a process that facilitates recognition of those enzymes by mannose 6-phosphate receptors to ensure delivery to lysosomes. Uncovering enzyme has been identified on the trans-Golgi network at steady state. It has been shown to traffic to the plasma membrane from where it is rapidly internalized via endosomal structures, the process being mediated by a tyrosine-based internalization motif, Y488HPL, in its cytoplasmic tail. Using immunogold electron microscopy a GFP-uncovering enzyme fusion construct was found to be colocalized with the cation-dependent mannose 6-phosphate receptor in regions of the trans-Golgi network, suggesting that uncovering enzyme might follow a similar pathway of exit from the trans-Golgi network as that of the cation-dependent mannose 6-phosphate receptor. In this study, we identified the signal sequence in the cytoplasmic tail of uncovering enzyme responsible for its exit from the trans-Golgi network. Using GFP fusion constructs of the transmembrane and cytoplasmic domains of uncovering enzyme, we could show, by automated analysis of confocal immunofluorescence images, that residues Q492EMN in the cytoplasmic tail of uncovering enzyme are involved in its exit from the trans-Golgi network. Detailed characterization of the exit signal revealed that residue Q492 is the most important to the exit function while M494 and N495 also contribute. The cytoplasmic tail of the uncovering enzyme does not possess any of the known canonical signal sequences for interaction with Golgi-associated gamma ear-containing adaptor proteins. The identification of a trans-Golgi network exit signal in its cytoplasmic tail elucidates the trafficking pathway of uncovering enzyme, a crucial player in the process of lysosomal biogenesis.

Characterization of the endosomal sorting signal of the cation-dependent mannose 6-phosphate receptor.

Intracellular cycling of the cation-dependent mannose 6-phosphate receptor (CD-MPR) between different compartments is directed by signals localized in its cytoplasmic tail. A di-aromatic motif (Phe18-Trp19 with Trp19 as the key residue) in its cytoplasmic tail is required for the sorting of the receptor from late endosomes back to the Golgi apparatus. However, the cation-independent mannose 6-phosphate receptor (CI-MPR) lacks such a di-aromatic motif. Therefore the ability of amino acids other than aromatic residues to replace Trp19 in the CD-MPR cytoplasmic tail was tested. Mutant constructs with bulky hydrophobic residues (valine, isoleucine, or leucine) instead of Trp19 exhibited 30-60% decreases in binding to the tail interacting protein of 47 kDa (Tip47), a protein mediating this transport step, and partially prevented receptor delivery to lysosomes. Decreasing hydrophobicity of residues at position 19 resulted in further impairment of Tip47 binding and an increase of receptor accumulation in lysosomes. Intriguingly, mutants mislocalized to lysosomes did not completely co-localize with a lysosomal membrane protein, which might suggest the presence of subdomains within lysosomes. These data indicate that sorting of the CD-MPR in late endosomes requires a distinct di-aromatic motif with only limited possibilities for variations, in contrast to the CI-MPR, which seems to require a putative loop (Pro49-Pro-Ala-Pro-Arg-Pro-Gly55) along with additional hydrophobic residues in the cytoplasmic tail. This raises the possibility of two separate binding sites on Tip47 because both receptors require binding to Tip47 for endosomal sorting.