Protocol for evaluating a workplace intervention within the framework of consultations for suffering at work in French-speaking Switzerland.

INTRODUCTION: Psychosocial suffering involves diverse human, social and economic costs. Some 34.4% of workers in Switzerland report chronic stress related to their jobs. Medical consultations for suffering at work aim to maintain-or renew-patients' abilities to make decisions and act following a diagnosis of psychological suffering related to their work; they also aim to help workers return to their workstations or remain there. Workplace interventions by consulting occupational physicians can go beyond the subjective issues: they can be offered to employees, in anticipation of a return to work when this appears feasible from the outset. OBJECTIVE: To qualitatively evaluate perceptions of workplace interventions and identify their effects by collecting the verbatim statements of employees and their employers. MATERIALS AND METHODS: Qualitative single-centre study of workplace interventions conducted by the Consultation Service for Suffering at Work's occupational physicians for patients seen between January 2015 to December 2017. Nineteen workplace interventions took place, out of 184 different consultations. The verbatim statements of employees and their employers will be collected over a variable timeframe, using semi-structured face-to-face interviews. These will then be recorded, transcribed and analysed. Fourteen patients refused the workplace intervention. Their professional path will be collected for comparison and exploratory purposes. CONCLUSION: This exploratory research project will provide a better understanding of the issues surrounding work-related psychological suffering and of which strategies support patients most effectively.

Fifteen-year-old girl with systemic lupus erythematosus and unilateral cerebellitis.

Cerebellar involvement in systemic lupus erythematosus has rarely been described as one of the neurologic manifestations. There has been only one previous pediatric case of cerebellar edema reported in the literature. The differential diagnosis, magnetic resonance imaging findings and treatment modalities are described in the case of a 15-year-old girl who presented with headache, vomiting, unsteady gait, and sudden change in mental status.

Is ethmoidal adenocarcinoma screening in employees exposed to wood dust justified?

INTRODUCTION: Since 1995, the means which are used for the follow-up of wood-workers in France are obsolete. Based on experts' opinions, they have never been assessed as effective in the detection of adenocarcinoma of the ethmoid sinus. OBJECTIVE: Collecting the data present in the literature to justify the necessity and the means of a screening protocol that would help detect ethmoidal adenocarcinoma among the wood worker population. METHOD: This is a review of the literature from three data bases: the National Library of Medicine, the French National Institute for Research and Security and the French National Centre for Scientific Research. Only English and French articles were reviewed and they were classified in four categories according to proof tools purposed by the French High Authority for Health. RESULTS: There is a direct statistical relationship between the amount of wood dust and the development of ethmoidal adenocarcinoma, but threshold doses cannot actually be calculated. The relative risk is high starting the first year of exposure and the exposed population is well recognized. Despite the means presently available for follow-up, this lesion is always diagnosed at an advanced stage. Survival rates at 5-years would increase if the tumour were to be detected at stages T1 or T2. The CT scan is not suited for this aim because of its low sensibility in separating soft tissue contrast. On the other hand, the MRI allows the detection of small nasal or sino-nasal tumours with intact osseous boundaries with a 98% sensibility. However, the data from experimental models and healthy human volunteers show that wood-dust settles over the olfactory cleft and the adjacent mucosa. Moreover in the large majority of cases the implantation pedicle of these tumours is coming from within these areas. Therefore, nasal fibroscopic examination represents the best tool to detect adenocarcinoma of the ethmoid sinuses at its earlier stages. It is well tolerated and its cost is low. CONCLUSION: A screening of ethmoidal adenocarcinoma seems to be possible with simple means in specific population. An early detection could improve the prognosis of this lesion.

Mitogenic effect of fibrinogen on hematopoietic cells: involvement of two distinct specific receptors, MFR and ICAM-1.

In addition to its well-known functions in blood clotting and cell adhesion, fibrinogen has been reported to be a mitogen for lymphoid cell lines and for human hematopoietic progenitors. Two specific receptors, the mitogenic fibrinogen receptor (MFR) and intercellular adhesion molecule-1 (ICAM-1/CD54), have been identified as possible candidates for the mediation of the mitogenic effect of fibrinogen. However, it has been questioned whether the MFR and ICAM-1 are truly distinct molecules. Using an antiserum specific for the MFR, we demonstrate that the MFR is a cell surface molecule clearly distinct from ICAM-1. Both receptors can be expressed separately or coexpressed on different cell types. Moreover, they are regulated differently: ICAM-1 is calcium-dependent whereas the MFR is not and the MFR is down-regulated by fibrinogen whereas ICAM-1 is not. The inhibition by an anti-MFR serum of the mitogenic effect of fibrinogen confirms the mitogenic function of the MFR.

Implication of a new molecule IK in CD34+ hematopoietic progenitor cell proliferation and differentiation.

HLA-DR is one of the markers associated with hematopoietic cell differentiation, since expression of this molecule is modulated throughout hematopoiesis. We have previously described and cloned the gene encoding factor IK, which inhibits both interferon gamma (IFN-gamma)-induced and constitutive HLA-DR expression. The current study demonstrates that IK gene transcripts are present in CD34+ cells purified from human umbilical cord blood. IK expression increased and was therefore inversely correlated with the gradual loss of HLA-DR during growth factor-induced CD34+ cell proliferation and differentiation. To study the possible role of IK in hematopoiesis, antisense probes were used. IK expression was specifically inhibited by an antisense oligodeoxynucleotide containing two phosphorothioate internucleotide linkages at each of the 3' and 5' ends and corresponding to the initiation site of IK mRNA. A control oligonucleotide was also tested in parallel. A specific decrease of IK transcripts was correlated with an increase of HLA-DR antigen expression level. In colony-forming assays, IK antisense oligonucleotide inhibited colony formation by multilineage early erythroid and granulomonocytic CD34+ progenitors. The mean colony size was decreased 70% by IK antisense oligonucleotide in comparison to controls. These results provide evidence that the IK molecule participates in the regulation of HLA-DR expression on hematopoietic cells and plays a role in growth factor-dependent CD34+ cell proliferation and differentiation by modulating HLA-DR expression.

Inhibitor (IK) of IFN-gamma induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line.

The expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-gamma) on the majority of the non professional APCs (e.g. fibroblasts). We have recently characterised a new factor called IK which is an efficient inhibitor of IFN-gamma induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-gamma induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway.

Are interleukin-2 and interleukin-15 tumor promoting factors for human non-hematopoietic cells?

Human normal non hematopoietic cells of mesenchymal and neuroectodermal origin may express functional IL-Rs. For instance, in these cell types, IL-2 can stimulate proliferation (endothelial, intestinal and nervous cells) or modify the expression of adhesion molecules (fibroblasts) or inhibit proliferation (bone marrow stromal cells). Therefore, some cytotoxic effects described during IL-2 biotherapy could be due to a direct interaction between IL-2 and non-hematopoietic tissues. The expression of functional IL-2-R has also been reported in several human cell lines derived from solid tumors. In some instances IL-2 inhibits cell growth (head and neck, gastric and renal carcinomas), but in other tumors, growth stimulation and increased expression of markers of tumor progression have been reported (intestinal, breast, and lung carcinomas, gliomas, fibrosarcomas and melanomas). Additionally, secretion of biologically active IL-2 has been reported in some melanoma and breast cancer cell lines. Transcripts for the novel cytokine IL-15, which utilizes the beta and gamma chains of the IL2-R, have been found in melanoma cells and anti-IL-15 mAbs inhibit HLA class I expression in these cells. Therefore these cytokines may modify, inside a tumor, the behavior of both stromal and neoplastic cells. All these data may have important implications in our understanding of tumor host interactions and in future strategies of immunotherapy.

Purification and characterization of a factor which inhibits retrovirus replication.

Chick embryo cells (CEC) secrete a factor which inhibits HIV1 replication. Non-productive infection of CEC with vesicular stomatitis virus increases 5-10-fold the synthesis of this factor. After purification by FPLC the biological activity is associated with a heat-resistant protein of approximately 150 kDa, composed of two subunits of 70 and 58 kDa and charged negatively. Monoclonal antibodies raised against this protein block the inhibitory activity of the purified protein and react with the 150-kDa and 58-kDa proteins in Western blots.

A new cytokine (IK) down-regulating HLA class II: monoclonal antibodies, cloning and chromosome localization.

The role of HLA class II Antigens in the control of the immune response is determined not only by the genetic polymorphism of these molecules, but also by their density on the cell surface. It is therefore essential to identify the signals that modulate HLA Class II gene activity in normal and neoplastic cells. We have purified a cytokine (IK factor, 19 kDa) secreted by the leukemic cell line K562 and several cancer cells, which inhibits HLA Class II antigen induction by IFN-gamma. We produced specific mAbs which antagonize the biological effect of IK in colon carcinoma Colo 205 cells induced to express HLA-DR molecules by IFN-gamma. Moreover, in Colo 205, HLA-DR can also be induced by the protein synthesis inhibitor Cycloheximide (0.1 micrograms ml-1); and addition of IK factor almost completely abolishes HLA class II expression. We have also performed the cloning and the sequencing of a specific cDNA. This probe recognizes a 2.1 Kb mRNA in different cell types. The nucleotide sequence exhibits no homologies with known cytokines. IK gene localization shows that it maps on chromosome 2p15-p14. The transient transfection of the cDNA in COS cells induces the secretion of a biologically active 19 kDa protein which is recognized in Western blot by 1C5B11 blocking mAb. This paper reports the characterization of a new cytokine down-regulating HLA class II Antigens, whose analysis will help to better understand HLA class II gene regulation and the mechanism of escape from immunorecognition in cancer cells.

Expression of the interleukin-2 receptor on human fibroblasts and its biological significance.

In this study, we have investigated the expression of the alpha and beta chains of the IL-2 receptor (IL-2R alpha, IL-2R beta) both at the membrane and at transcriptional levels during the lifespan of human embryonic fibroblasts. Here we show that the mAbs IOT14 and MIK beta 1 directed against the IL-2 binding sites of the IL-2R alpha and IL-2R beta respectively, stain human embryonic fibroblasts early in their life span. Data from [125I]rIL2 cross-linking experiments show the simultaneous expression of two IL-2 binding peptides of 70 and 55 kDa respectively on embryonic young fibroblasts as on lymphoid activated cells. The p55 and the p70 IL-2 binding peptides are shown to be specific for the IL-2R alpha and to the IL-2R beta by the finding that these bands are abolished by excess amounts of cold IL-2 and mAbs directed against the IL-2 binding sites of the alpha and beta chains. Scatchard analysis after [125I]IL-2 labelling shows the presence of both high affinity (150 sites with a Kd of 147 pM) and low affinity (1100 sites with a Kd of 4 nM) IL-2 binding sites. Northern blot and dot blot analysis show the presence of specific transcripts for the IL-2R alpha and IL-2R beta genes in early passaged fibroblasts. By contrast, in senescent cultures, only the IL-2R beta transcript were detected. Finally, IL-2 at low concentrations (36 pM) down modulates the level of the intercellular adhesion molecule ICAM-1 in young but not in senescent cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of human immunodeficiency virus (HIV) type 1 multiplication by an avian cellular factor.

A factor secreted from avian cells infected non productively with a non cytopathogenic mutant of vesicular stomatitis virus (VSV ts 1026) interferes with HIV replication in CEM cells and peripheral blood monocytes (PBL). Production of infectious particles is decreased and many virions lack cores and/or spikes. In CEM cells the prmRNA is spliced into 7.5, 4, and 2 kb mRNA. Residual virus contains less env encoded proteins and p 18; p 25 appears as several bands. The processing of tat, rev. and nef proteins differs in treated cells and in controls.

Flow cytometry resonance energy transfer suggests an association between low-affinity interleukin 2 binding sites and HLA class I molecules.

Using flow cytometry energy transfer we have studied the sterical proximity of interleukin 2 receptors and the heavy chain of the major histocompatibility complex at the surface of normal lymphocytes. Our data suggest that class I molecules may be part of a low-affinity interleukin 2 receptor multimolecular complex, where the MHC class I heavy chain is in close proximity to the actual interleukin 2 binding site, in contrast to the light chain (beta 2-microglobulin).

The role of growth-factor receptors (excluding IL-2 receptors) in the proliferation and differentiation of normal and leukemic hematopoietic cells.

Receptors (R) are considered as allosteric enzymes whose action on metabolic chains is modulated through binding to the ligand. They play an essential role in the transduction of the multiple signals (e.g. interleukins or CSF) which intervene in the regulation of hematopoiesis. Their ordered interactions are necessary to regulate the growth and differentiation of normal hematopoietic precursors. This paper summarizes recent data concerning the structure-action relationship of growth-factor receptors in the signal transduction and alterations of growth-factor receptors which may play an important role in leukemic transformation. Some therapeutic modulations of growth-factors cascades are also discussed.

Acquisition of tumorigenic potential in the human myoepithelial HBL100 cell line is associated with decreased expression of HLA class I, class II and integrin beta 3 and increased expression of c-myc.

The human breast cell line HBL100 acquires the capacity to invade normal tissues and to replace them by proliferation in vitro only at high passage levels (HPL). These cells therefore are a useful model for studying tumor progression in vitro. We have analyzed the expression of cell-surface markers supposed to be involved in the control of the neoplastic process. Quantitative flow cytometry has revealed that: (1) spontaneous expression of HLA class-I antigens strongly decreases in HPL HBL100 cells vs. LPL cells, which parallels amplification and over-expression of c-myc oncogene; (2) HLA DR antigens can be induced by IFN-gamma in LPL but not in HPL HBL100 cells; (3) HBL100 cells secrete a soluble protein factor which specifically inhibits HLA DR induction by IFN-gamma even in heterologous cell systems; (4) 50% of LPL HBL100 cells express integrin beta 3, whereas HPL HBL100 cells lose this antigen; (5) this cell line is myoepithelial in origin, since 100% of HBL100 cells exhibit the CD10 antigen. Our data stress a role of HLA antigens, of some integrins and of c-myc in the acquisition of malignant potential by myoepithelial mammary cells of the HBL100 line.

High frequency of plasminogen activator secretion by malignant human lymphoid cell lines of T-cell type origin.

Diffuse defibrination is rarely observed in acute lymphoblastic leukemia (ALL). Clinical and immunologic data suggest that it is more likely to occur in T cell derived ALL. The current investigation involved the secretion of plasminogen activators (PA) of tissue type (t-PA) or urokinase type (U-PA) by testing supernatants of 21 permanent human leukemic cell lines originating from various hematopoietic lineages and one induced lymphoblastoid cell line. (LCL) The amount of PA in each supernatant was determined by biologic and immunoenzymologic assays. The correspondence with the expected molecular weight (MW) according to the PA type was checked by zymography. PA secretion of U-PA type was observed in the three myeloid cell lines. Except for the normal LCL, no B-lymphoid lineage related cell lines of various levels of differentiation displayed PA secretion, whereas PA activity was observed in the supernatant of six of nine malignant T-cell lines. The T-leukemic cell lines CCRF CEM, KE 37, HUT 78, and HUT 102 released U-PA-like activity. Peer released t-PA-like activity and CCRF-HSB2 supernatant showed both types of PA activity. These findings are discussed in view of the natural history of these diseases and the stage of differentiation of the cell lines.

Parallel induction of fibrinolysis and receptors for plasminogen and urokinase by interferon gamma on U937 cells.

A new cell sorter technique was employed to study the role of interferon gamma (INF gamma) in fibrinolysis induced by U937 monocytic cells. INF-gamma induced the differentiation of U937 cells as evidenced by the appearance of CD 14 antigen on the cell surface. Scatchard analysis and dose response curves showed a parallel increase in the number of receptors on U937 cells capable of accepting exogenous plasminogen and urokinase (UPA) synthetized by differentiating U937 monocytic cells. This would favour an activation of plasminogen by UPA. This adds a new parameter in the regulation of cell-mediated fibrinolysis and may be important in a number of biological processes.

Human fibroblasts from cancer patients: lifespan and transformed phenotype in vitro and role of mesenchyme in vivo.

Human fibroblasts cultured in vitro can exhibit a different potential number of population doublings. In normal donors, the average number of population doublings is inversely related to the donor's age. An increased growth potential was detected in skin fibroblasts from breast cancer patients, independently of the donor's age. These cells responded in an abnormal way to 3 biological parameters: (1) colony formation in semisolid medium; (2) colony formation on monolayers of normal human epithelial cells; and (3) increase of saturation densities in overcrowded culture conditions. A third of these cultures, as well as skin fibroblasts from other cancer patients, at the plateau phase of growth exhibited a significant percentage of cells still synthesizing DNA. Exposure to overcrowding, limited in time, caused the selection of a cell subset which displayed new biological, biochemical and functional properties commonly found in transformed cells. The abnormal in vitro behavior of skin fibroblasts from breast cancer patients does not seem to be associated with the expression of oncofetal membrane markers (4F2, IL2 receptor) while the fibroblasts from patients with the adenomatosis of the colon and rectum (ACR) syndrome expressed the 4F2 antigen. This is the first time that the IL2 receptor is found on non-hematopoietic cells. Fibroblastic cells with abnormal characteristics, which may also present a decreased efficiency in organizing a primitive fibrin matrix, could represent in vivo an anarchistic milieu, favoring disturbed epithelial-stromal interactions and the emergence of the less structured tumor stromatic tissue.

A B cell-restricted activation antigen (B8.7) functionally related to the low molecular weight B cell growth factor receptor.

A novel monoclonal antibody (anti-B8.7) is reported which recognizes an epitope expressed either on in vitro activated B cells or on a fraction of fresh large B cells (putatively in vivo preactivated). B8.7 antigen is also present on two out of eight B cell lines tested and is characterized as a membrane component displaying an approximate molecular weight of 55,000 to 60,000. By contrast, B8.7 is absent from resting B cells, monocytes, resting or activated T cells, and from the eight non-B cell lines tested. After in vitro activation, B8.7 antigen appears later than the transferrin receptor and its expression increases until day 3. The anti-B8.7 monoclonal antibody induces a dose-related inhibition of the low molecular weight B cell growth factor-dependent proliferation of activated B cells, whereas it does not affect their response to interleukin 2. This strongly suggests that the B8.7 epitope is present on a molecule selectively involved in the interaction between B cells and a B cell growth factor.