BACKGROUND The enzyme indoleamine 2,3-dioxygenase (IDO) contributes to immune tolerance in a variety of settings. In cancer IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it endorses the establishment of peripheral immune tolerance to tumor antigens. Recently, we described cytotoxic CD8(+) T-cell reactivity towards IDO-derived peptides. METHODS AND FINDINGS In the present study, we show that CD4(+) helper T cells additionally spontaneously recognize IDO. Hence, we scrutinized the vicinity of the previously described HLA-A*0201-restricted IDO-epitope for CD4(+) T-cell epitopes. We demonstrated the presence of naturally occurring IDO-specific CD4(+) T cells in cancer patients and to a lesser extent in healthy donors by cytokine release ELISPOT. IDO-reactive CD4(+) T cells released IFN-γ, TNF-α, as well as IL-17. We confirm HLA class II-restriction by the addition of HLA class II specific blocking antibodies. In addition, we detected a trend between class I- and class II-restricted IDO responses and detected an association between IDO-specific CD4(+) T cells and CD8(+) CMV-responses. Finally, we could detect IL-10 releasing IDO-reactive CD4(+) T cells. CONCLUSION IDO is spontaneously recognized by HLA class II-restricted, CD4(+) T cells in cancer patients and in healthy individuals. IDO-specific T cells may participate in immune-regulatory networks where the activation of pro-inflammatory IDO-specific CD4(+) responses may well overcome or delay the immune suppressive actions of the IDO-protein, which are otherwise a consequence of the early expression of IDO in maturing antigen presenting cells. In contrast, IDO-specific regulatory T cells may enhance IDO-mediated immune suppression.

Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-γ ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed.

We study Body Mass Index (BMI) changes among immigrants from Iran, Pakistan, Sri Lanka, Turkey, and Vietnam relative to native Norwegians in Oslo. We assess the effect of acculturation on BMI changes. We hypothesize that acculturation reduces the gap of BMIs between natives and immigrants. Acculturation is measured by immigrants' language skills. Our data come from two surveys in Oslo 2000-2002. Weights and heights were measured at the surveys; participants were asked to recall weights when they were 25 years old. Norwegian language skills and socio-economic data were collected. Our findings support our hypothesis. Acculturation, as measured by proficiency in the Norwegian language, has the predicted effects on BMI changes. We do not find any effect of immigrants' time of residency on BMI changes.

This paper analyzes the dynamics of laser speckles and fringes, formed in an imaging-speckle-pattern interferometer with the purpose of sensing linear three-dimensional motion and out-of-plane components of rotation in real time, using optical spatial-filtering-velocimetry techniques. The ensemble-average definition of the cross-correlation function is applied to the intensity distributions, obtained in the observation plane at two positions of the object. The theoretical analysis provides a description for the dynamics of both the speckles and the fringes. The analysis reveals that both the magnitude and direction of all three linear displacement components of the object movement can be determined. Simultaneously, out-of-plane rotation of the object including the corresponding directions can be determined from the spatial gradient of the in-plane fringe motion throughout the observation plane. The theory is confirmed by experimental measurements.

We study how market conditions influence referrals of patients by general practitioners (GPs). We set up a model of GP referral for the Norwegian health care system, where a GP receives capitation payment based on the number of patients in his practice, as well as fee-for-service reimbursements. A GP may accept new patients or close the practice to new patients. We model GPs as partially altruistic, and compete for patients. We show that a GP operating in a more competitive market has a higher referral rate. To compete for patients and to retain them, a GP satisfies patients' requests for referrals. Furthermore, a GP who faces a patient shortage will refer more often than a GP who does not. Tests with Norwegian GP radiology referral data support our theory.

To assess the efficacy of caudal epidural steroid or saline injection in chronic lumbar radiculopathy in the short (6 weeks), intermediate (12 weeks), and long term (52 weeks). Multicentre, blinded, randomised controlled trial. Outpatient multidisciplinary back clinics of five Norwegian hospitals. Between October 2005 and February 2009, 461 patients assessed for inclusion (presenting with lumbar radiculopathy >12 weeks). 328 patients excluded for cauda equina syndrome, severe paresis, severe pain, previous spinal injection or surgery, deformity, pregnancy, ongoing breast feeding, warfarin therapy, ongoing treatment with non-steroidal anti-inflammatory drugs, body mass index >30, poorly controlled psychiatric conditions with possible secondary gain, and severe comorbidity. Subcutaneous sham injections of 2 mL 0.9% saline, caudal epidural injections of 30 mL 0.9% saline, and caudal epidural injections of 40 mg triamcinolone acetonide in 29 mL 0.9% saline. Participants received two injections with a two week interval. Primary: Oswestry disability index scores. Secondary: European quality of life measure, visual analogue scale scores for low back pain and for leg pain. Power calculations required the inclusion of 41 patients per group. We did not allocate 17 of 133 eligible patients because their symptoms improved before randomisation. All groups improved after the interventions, but we found no statistical or clinical differences between the groups over time. For the sham group (n=40), estimated change in the Oswestry disability index from the adjusted baseline value was -4.7 (95% confidence intervals -0.6 to -8.8) at 6 weeks,-11.4 (-6.3 to -14.5) at 12 weeks, and -14.3 (-10.0 to -18.7) at 52 weeks. For the epidural saline intervention group (n=39) compared with the sham group, differences in primary outcome were -0.5 (-6.3 to 5.4) at 6 weeks, 1.4 (-4.5 to 7.2) at 12 weeks, and -1.9 (-8.0 to 4.3) at 52 weeks; for the epidural steroid group (n=37), corresponding differences were -2.9 (-8.7 to 3.0), 4.0 (-1.9 to 9.9), and 1.9 (-4.2 to 8.0). Analysis adjusted for duration of leg pain, back pain, and sick leave did not change this trend. Caudal epidural steroid or saline injections are not recommended for chronic lumbar radiculopathy. Trial registration Current Controlled Trials ISRCTN No 12574253.

Patients switching physicians involves costs to the patients because of less continuity of care. From a theoretical model we derive that inferior physician quality as perceived by patients, implies patient shortage for the physician and more patients switching physicians. By means of a unique panel data set covering the entire population of Norwegian general practitioners (GPs) and estimation methods that adjust for potential endogeneities, we find that the occurrence of patient shortage increases the proportion of patients switching physicians by 50%. A competing hypothesis that GPs with a shortage of patients experience less switching because of superior access is rejected by data. To assist patients in making informed decisions, we suggest that the number of switches a physician experiences should be made public.

Abstract Amorphous silica nanoparticles (SiNPs, 30 and 50 nm) and rhodamine-coated SiNPs (50 nm) were examined for their ability to induce pro-inflammatory responses and cytotoxicity in BEAS-2B cells under different experimental conditions. The SiNPs formed micrometre-sized agglomerates in the absence of bovine serum albumin (BSA) in the culture medium, whereas with BSA (0.1%) they were much less agglomerated. All the SiNPs induced IL-6 and IL-8 responses, as measured by ELISA and real-time PCR. The responses were more marked without BSA and higher for the rhodamine SiNPs than the plain ones. Rhodamine SiNPs were not taken up by cells during a 3-h exposure, even though cytokine mRNAs were up-regulated. In conclusion, agglomerated SiNPs induced more potent cytokine responses than the non-agglomerated ones; either due to the agglomeration state per se or more conceivably to a change in surface reactivity against cellular targets due to BSA. Furthermore, cytokine expression was up-regulated independently of SiNP uptake.