Health and motivation as mediators of the effects of job demands, job control, job support, and role conflicts at work and home on sickness presenteeism and absenteeism.

PURPOSE: The first objective was to contribute to a better understanding of the contrasting and paradoxical results in studies of work environment factors and sickness presence and sickness absence. A second objective was to examine if, and under what conditions, employees choose to replace sickness absence with sickness presence, i.e., so-called substitution. METHODS: The study utilizes a large body of cross-sectional questionnaire data (n = 130,161) gathered in Sweden from 2002 to 2007 in connection with a comprehensive health promotion initiative. Health and motivation were analyzed as mediators of the effects of five job factors, job control, job support, job demand, role conflict and "work to family conflict" on sickness presence and absence. RESULTS: The results concerning job demands indicate substitution in that increased job demands are associated with increased presenteeism and reduced absenteeism. The direct effect of higher job support was increased absenteeism, but via the health and motivation paths, the total effect of more social support was health-promoting and associated with a reduction in sickness absence and sickness presence. High job control emerged as the most pronounced health-promoting factor, reducing sickness presenteeism as well as absenteeism. More role conflicts and work-to-family conflicts were directly and indirectly associated with decreased health and increased absenteeism as well as presenteeism. earlier research. CONCLUSION: The mediation analyzes shed light on some of the paradoxes in research on sickness presenteeism and sickness absenteeism, especially regarding job demands and job support. The substitution effect is important for workplace policy and occupational health practice.

Work-related stress assessed by a text message single-item stress question.

BACKGROUND: Given the prevalence of work stress-related ill-health in the Western world, it is important to find cost-effective, easy-to-use and valid measures which can be used both in research and in practice. AIMS: To examine the validity and reliability of the single-item stress question (SISQ), distributed weekly by short message service (SMS) and used for measurement of work-related stress. METHODS: The convergent validity was assessed through associations between the SISQ and subscales of the Job Demand-Control-Support model, the Effort-Reward Imbalance model and scales measuring depression, exhaustion and sleep. The predictive validity was assessed using SISQ data collected through SMS. The reliability was analysed by the test-retest procedure. RESULTS: Correlations between the SISQ and all the subscales except for job strain and esteem reward were significant, ranging from -0.186 to 0.627. The SISQ could also predict sick leave, depression and exhaustion at 12-month follow-up. The analysis on reliability revealed a satisfactory stability with a weighted kappa between 0.804 and 0.868. CONCLUSIONS: The SISQ, administered through SMS, can be used for the screening of stress levels in a working population.

Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden.

INTRODUCTION: Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. MATERIALS AND METHODS: We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18years diagnosed with HL between January 2005 and December 2015 in Sweden. RESULTS: Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. CONCLUSIONS: VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis.

Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4.

Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.

In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone.

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.

Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications.

Resistance of myeloma to lenalidomide is an emerging clinical problem, and though it has been associated in part with activation of Wnt/ß-catenin signaling, the mediators of this phenotype remained undefined. Lenalidomide-resistant models were found to overexpress the hyaluronan (HA)-binding protein CD44, a downstream Wnt/ß-catenin transcriptional target. Consistent with a role of CD44 in cell adhesion-mediated drug resistance (CAM-DR), lenalidomide-resistant myeloma cells were more adhesive to bone marrow stroma and HA-coated plates. Blockade of CD44 with monoclonal antibodies, free HA or CD44 knockdown reduced adhesion and sensitized to lenalidomide. Wnt/ß-catenin suppression by FH535 enhanced the activity of lenalidomide, as did interleukin-6 neutralization with siltuximab. Notably, all-trans retinoic acid (ATRA) downregulated total ß-catenin, cell-surface and total CD44, reduced adhesion of lenalidomide-resistant myeloma cells and enhanced the activity of lenalidomide in a lenalidomide-resistant in vivo murine xenograft model. Finally, ATRA sensitized primary myeloma samples from patients that had relapsed and/or refractory disease after lenalidomide therapy to this immunomodulatory agent ex vivo. Taken together, our findings support the hypotheses that CD44 and CAM-DR contribute to lenalidomide resistance in multiple myeloma, that CD44 should be evaluated as a putative biomarker of sensitivity to lenalidomide, and that ATRA or other approaches that target CD44 may overcome clinical lenalidomide resistance.

Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs).

The ubiquitin-proteasome pathway (UPP) is an attractive chemotherapeutic target due to its intrinsically stringent regulation of cell cycle, pro-survival, and anti-apoptotic regulators that disproportionately favor survival and proliferation in malignant cells. A reversible first-in-class proteasome inhibitor, bortezomib, is Food and Drug Administration approved for multiple myeloma and relapsed/refractory mantle cell lymphoma and has proven to be extremely effective, both as a single agent and in combination. An irreversible second generation proteasome inhibitor, carfilzomib, has shown preclinical effectiveness against hematological and solid malignancies both in vitro and in vivo. Carfilzomib, a peptidyl-epoxyketone functions similarly to bortezomib through primary inhibition of chymotrypsin-like (ChT-L) activity at the b5 subunits of the core 20S proteasome. Carfilzomib is also currently achieving successful response rates within the clinical setting. In addition to conventional proteasome inhibitors, a novel approach may be to specifically target the hematological-specific immunoproteasome, thereby increasing overall effectiveness and reducing negative off-target effects. The immunoproteasome-specific inhibitor, IPSI-001, was shown to have inhibitory preference over the constitutive proteasome, and display enhanced efficiency of apoptotic induction of tumor cells from a hematologic origin. Herein, we discuss the preclinical and clinical development of carfilzomib and explore the potential of immunoproteasome-specific inhibitors, like IPSI-001, as a rational approach to exclusively target hematological malignancies.

Preoperative hypnosis reduces postoperative vomiting after surgery of the breasts. A prospective, randomized and blinded study.

BACKGROUND: Postoperative nausea and vomiting (PONV) after general anesthesia and surgery may have an incidence as high as 70% irrespective of antiemetic drug therapy. The use of preoperative hypnosis and mental preparation by means of an audio tape was investigated in the prophylaxis of nausea and vomiting before elective breast reduction surgery. Similar interventions have not been found in the literature. METHODS: Fifty women were randomized to a control group or a hypnosis group; the latter listened to an audio tape daily 4-6 days prior to surgery. A hypnotic induction was followed by suggestions as to how to relax and experience states incompatible with nausea and vomiting postoperatively (e.g. thirst and hunger). There was a training part on the tape where the patients were asked to rehearse their own model for stress reduction. Premedication and anesthetic procedures were standardized. RESULTS: Patients in the hypnosis group had significantly less vomiting, 39% compared to 68% in the control group, less nausea and less need of analgesics postoperatively. CONCLUSIONS: Preoperative relaxation and/or hypnotic techniques in breast surgery contribute to a reduction of both PONV and postoperative analgesic requirements.

Streptococcus mutans in plaque from conventional and from non-gamma-2 amalgam restorations.

The frequency of Streptococcus mutans in plaque material from margins of conventional amalgam and non-gamma-2 amalgam fillings was examined in six subjects. One and 2 months after restorative treatment the mean values of the percentage S. mutans of the total number of microorganisms were somewhat lower in samples from non-gamma-2 amalgams than in those from conventional amalgams. The difference in values, however, was not statistically significant.

Global Shape Analysis by k-Syntactic Similarity.

The k-syntactic similarity approach is couched in graphical representation terms and its ability to provide global recognition capability while retaining a low time complexity is explored. One potential application domain, that of composite shape decomposition into approximately convex subshapes, is described. This is shown to be equivalent to finding cycles within a particular graph. The approach yields valid decompositions in many cases of interest, and is capable of identifying those cases where additional semantic considerations are necessary for proper analysis. The permissible graph structures representing composite shapes given a reasonable set of relations are determined. Experimental results on nonideal data are given.

Effect of synthetic substance P on internal carotid artery blood flow in man.

Internal carotid artery blood flow was studied by peroperative electromagnetic blood flow measurement in 7 patients following 9 intravenous infusions of synthetic Substance P, 2 ng.kg-1.min-1. The blood flow responses varied interindividually. No significant blood flow changes were observed for the whole group. The arterial mean blood pressure decreased significantly.