Lipomatous Tumors: A Comparison of MRI-Reported Diagnosis with Histological Diagnosis.

Lipomatous tumors are among the most common soft tissue tumors (STTs). Magnetic resonance imaging (MRI) is a state-of-the-art diagnostic tool used to differentiate and characterize STTs. Radiological misjudgment can lead to incorrect treatment. This was a single-center retrospective study. Two hundred and forty lipomatous tumors were included. MRI diagnoses were categorized as benign, intermediate, or malignant and were compared with histological diagnoses. Tumor volumes were measured by MRI and from surgical specimens. The tumor was correctly categorized 73.3% of the time. A total of 21.7% of tumors were categorized as more malignant in MRI reports than they were by histology, and vice versa for 5.0% of tumors. Volume measured by MRI was not different from actual tumor size in pathology. Atypical lipomatous tumors (ALTs) and liposarcomas (LPSs) were larger when compared with lipomata and occurred in older patients. Based on the MRI-suspected tumor entity, surgical treatment can be planned. Large lipomatous tumors in elderly patients are more likely to be ALTs. However, a safe threshold size or volume for ALTs cannot be determined.

Referrals to secondary care in an outpatient primary care walk-in clinic for refugees in Germany: results from a secondary data analysis based on electronic medical records.

OBJECTIVES: The aims of our study were to describe the disease spectrum of refugees, to analyse to what extent their healthcare needs could be met in an outpatient primary care walk-in clinic and which cases required additional services from secondary care (ie, outpatient specialists or hospitals). DESIGN: Retrospective longitudinal observational study. SETTING: The study was based on routine data from a walk-in clinic in the largest central first reception centre in Hamburg, Germany between 4 November 2015 and 21 July 2016. PARTICIPANTS: 1467 asylum seekers with 4006 episodes of care (ie, distinctive health problems) resulting in 5545 consultations. The patients were 60% men and had a mean age of 23.2 years. About 90% of the patients were from Central Asia or from the Middle East and North Africa. PRIMARY AND SECONDARY OUTCOME MEASURES: The endpoint of our analyses was referral to secondary care. Time to event was defined as days under treatment until the first referral. Predictor variables were the patients' diagnoses grouped in 46 categories. The data set was analysed by Cox regression allowing for multiple failure times per patient. This analysis was adjusted for age, sex and country of origin. RESULTS: Referrals to secondary care occurred in 15.5% of the episodes. The diagnosis groups with the highest referral rates were 'eye' (HR 4.9; 95% CI 3.12 to 7.8; p≤0.001), 'teeth/gum symptom/complaint or disease' (3.51; 2.52 to 4.9; p≤0.001) and 'urological system/female or male genital' (2.50; 1.66 to 3.77; p≤0.001). Age, sex and country of origin had no significant effect on time until referral. CONCLUSIONS: In most cases, the walk-in clinic physicians could provide first-line medical care for the health problems of patients not integrated in the German healthcare system. Additional resources were needed particularly not only for visual impairment and dental problems but also for psychological disorders, antenatal care and certain infections and injuries.

Episodes of care in a primary care walk-in clinic at a refugee camp in Germany - a retrospective data analysis.

BACKGROUND: From 2015 to 2016 Germany faced an influx of 1.16 million asylum seekers. In the state of Hamburg Primary Care walk-in clinics (PCWC) were commissioned at refugee camps because the high number of residents (57,000 individuals) could not be provided with access to regular healthcare services. Our study aims were (1) to describe the utilization of a PCWC by camp residents, (2) to compare episodes of continuous care with shorter care episodes and (3) to analyse which diagnoses predict episodes of continuous care in this setting. METHODS: A retrospective longitudinal observational study was conducted by reviewing all anonymized electronic medical records of a PCWC that operated from 4th November 2015 to 22nd July 2016 at a refugee camp in Hamburg. Episodes of care (EOC) were extracted based on the international classification of primary care-2nd edition (ICPC-2). Outcome parameters were episode duration, principal diagnoses, and medical procedures. RESULTS: We analysed 5547 consultations of 1467 patients and extracted 4006 EOC. Mean patient age was 22.7 ± 14.8 years, 37.3% were female. Most common diagnoses were infections (44.7%), non-communicable diseases (22.2%), non-definitive diagnoses describing symptoms (22.0%), and injuries (5.7%). Most patients (52.4%) had only single encounters, whereas 19.8% had at least one EOC with a duration of ≥ 28 days (defined as continuous care). Several procedures were more prevalent in EOC with continuous care: Blood tests (5.2 times higher), administrative procedures (4.3), imaging (3.1) and referrals to secondary care providers (3.0). Twenty prevalent ICPC-2-diagnosis groups were associated with continuous care. The strongest associations were endocrine/metabolic system and nutritional disorders (hazard ratio 5.538, p < 0.001), dermatitis/atopic eczema (4.279, p < 0.001) and psychological disorders (4.056, p < 0.001). CONCLUSION: A wide spectrum of acute and chronic health conditions could be treated at a GP-led PCWC with few referrals or use of medical resources. But we also observed episodes of continuous care with more use of medical resources and referrals. Therefore, we conclude that principles of primary care like continuity of care, coordination of care and management of symptomatic complaints could complement future healthcare concepts for refugee camps.

Allele-specific recognition by LILRB3 and LILRA6 of a cytokeratin 8-associated ligand on necrotic glandular epithelial cells.

The LILRs are a family of receptors that regulate the activities of myelomonocytic cells. We found that specific allelic variants of two related members of the LILR family, LILRB3 and LILRA6, interact with a ligand exposed on necrotic glandular epithelial cells. The extracellular domains of LILRB3 and LILRA6 are very similar and their genes are highly polymorphic. A commonly occurring allele, LILRB3*12, displayed particularly strong binding of these necrotic cells and further screening of the products of LILRB3 alleles identified motifs that correlated with binding. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12, identified cytokeratins 8, 18 and 19. Purified proteins obtained from epithelial cell lysates, using anti-cytokeratin 8 antibodies, were able to activate LILRB3*12 reporter cells. Knock-down of cytokeratin 8 in epithelial cells abrogated expression of the LILRB3 ligand, while staining with recombinant LILRB3*12 showed co-localisation with cytokeratin 8 and 18 in permeabilised breast cancer cells. Necrosis is a common feature of tumours. The finding of a necrosis-associated ligand for these two receptors raises the possibility of a novel interaction that alters immune responses within the tumour microenvironment. Since LILRB3 and LILRA6 genes are highly polymorphic the interaction may influence an individual's immune response to tumours.

Ubiquitination of HLA-DO by MARCH family E3 ligases.

HLA-DO (DO) is a nonclassical MHC class II (MHCII) molecule that negatively regulates the ability of HLA-DM to catalyse the removal of invariant chain-derived CLIP peptides from classical MHCII molecules. Here, we show that DO is posttranslationally modified by ubiquitination. The location of the modified lysine residue is shared with all classical MHCII beta chains, suggesting a conserved function. Three membrane-associated RING-CH (MARCH1, 8 and 9) family E3 ligases that polyubiquitinate MHCII induce similar profiles of polyubiquitination on DOß. All three MARCH proteins also influenced trafficking of DO indirectly by a mechanism that required the DOß encoded di-leucine and tyrosine-based endocytosis motifs. This may be the result of MARCH-induced ubiquitination of components of the endocytic machinery. MARCH9 was by far the most efficient at inducing intracellular redistribution of DO but did not target molecules for lysosomal degradation. The specificity of MARCH9 for HLA-DQ and HLA-DO suggests a need for common regulation of these two MHC-encoded molecules.

Effects of feminizing microsporidia on the masculinizing function of the androgenic gland in Gammarus duebeni.

Feminizing parasites enhance their vertical transmission to the host offspring by converting genetic male hosts into phenotypic females. Crustacea are the only invertebrates where sexual differentiation is controlled by a specialised endocrine organ, the androgenic gland, rather than by the gonads. We showed that a feminizing microsporidian Microsporidium sp. inhibits androgenic gland differentiation. We investigated the effect of Microsporidium sp. and a second feminizing microsporidium, Nosema granulosis, on the masculinizing function of the androgenic gland in Gammarus duebeni. Androgenic gland implants had a masculinizing effect on the sexual characteristics and sexual behaviour of recipient female hosts, reflecting the masculinizing function of the androgenic gland. Individuals that had received androgenic glands showed changed morphology in comparison with controls; they were bigger overall, they lost their oostegite marginal setae, developed calceoli and acquired a male-like behaviour. This effect was observed in uninfected females, as well as in females infected with the Microsporidium sp. The masculinizing effect of androgenic gland implants was smaller in N. granulosis infected individuals. N. granulosis and Microsporidium sp. fall into distinct clades of the Microspora. It appears that these divergent parasites both act by inhibiting the development of the androgenic gland. However, they differ in their ability to inhibit the host's response to the hormone that controls male sexual differentiation.

Structural requirements for recognition of major histocompatibility complex class II by membrane-associated RING-CH (MARCH) protein E3 ligases.

MARCH E3 ligases play a key role in controlling MHC class II surface expression by regulated ubiquitination of a lysine residue in the ß-chain. Little is known concerning how these enzymes target their specific substrates. Here we show that recognition of HLA-DR by MARCH proteins is complex. Several features associated with the transmembrane domain and bordering regions influence the overall efficiency of receptor internalization. A cluster of residues at the interface of the lipid bilayer and the cytosol plays the most important role in MARCH8 recognition of HLA-DRß. Variation in this sequence also determines specificity of MARCH9 for HLA-DQ. Residues located in helical face four of HLA-DRß together with a charged residue at the boundary with the stalk region also contribute significantly to recognition. Truncation analysis suggested that a dileucine-like motif in the DRß cytoplasmic tail influences the efficiency of co-localization of HLA-DR with MARCH8. The DRß-encoded acceptor lysine functioned optimally when placed in its natural location relative to the bilayer. In the DRα/DRß dimer most other amino acids in the cytoplasmic tail could be substituted for alanine with minimal influence on function. Our data support a model whereby multiple features of HLA-DR are involved in substrate recognition by MARCH8. The single most important region is located at the interface between the transmembrane domain and the cytosol. Variation in sequence in this location between different class II isotypes controls efficiency of recognition by different MARCH E3 ligases.

Ubiquitination of human leukocyte antigen (HLA)-DM by different membrane-associated RING-CH (MARCH) protein family E3 ligases targets different endocytic pathways.

HLA-DM plays an essential role in the peptide loading of classical class II molecules and is present both at the cell surface and in late endosomal peptide-loading compartments. Trafficking of DM within antigen-presenting cells is complex and is, in part, controlled by a tyrosine-based targeting signal present in the cytoplasmic tail of DMß. Here, we show that DM also undergoes post-translational modification through ubiquitination of a single lysine residue present in the cytoplasmic tail of the α chain, DMα. Ubiquitination of DM by MARCH1 and MARCH9 induced loss of DM molecules from the cell surface by a mechanism that cumulatively involved both direct attachment of ubiquitin chains to DMα and a functional tyrosine-based signal on DMß. In contrast, MARCH8-induced loss of surface DM was entirely dependent upon the tyrosine signal on DMß. In the absence of this tyrosine residue, levels of DM remained unchanged irrespective of whether DMα was ubiquitinated by MARCH8. The influence of MARCH8 was indirect and may have resulted from modification of components of the endocytic machinery by ubiquitination.

The HLA-DRalpha chain is modified by polyubiquitination.

Ubiquitination plays a major role in regulating cell surface and intracellular localization of major histocompatibility complex class II molecules. Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. Each chain of the HLA-DR heterodimer is independently recognized and ubiquitinated, but DRbeta is more extensively modified. In the cytoplasmic tail of DRbeta lysine, residue 225 is the only residue that is absolutely required for ubiquitination; all other residues can be deleted or substituted without loss of function. In contrast, although lysine 219 is absolutely required for modification of DRalpha, other features of the DRalpha tail act to limit the extent of ubiquitination.