Biomarkers of inflammation in patients with unclassified polyarthritis and early rheumatoid arthritis. Relationship to disease activity and radiographic outcome

OBJECTIVE: To determine plasma interleukin 6 (pIL-6), plasma vascular endothelial growth factor (pVEGF), and serum (s) YKL-40 in patients with early rheumatoid arthritis (RA) and unclassified polyarthritis (PA), and investigate their relationship with radiographic outcome. METHODS: pIL-6 and pVEGF were determined by ELISA and sYKL-40 by an in-house radioimmunoassay in 51 patients with early RA and 21 with PA. Patients were followed with clinical and biochemical measurement every month for 2 years. Conventional radiographs of hands, wrists, and forefeet were scored according to the Larsen method, and magnetic resonance imaging of 2nd to 5th metacarpophalangeal joints of the dominant hand were evaluated for presence or absence of bone erosions. RESULTS: Baseline pIL-6, pVEGF, sYKL-40, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were elevated in RA patients compared to healthy persons (p < 0.001), but were not in patients with PA. Patients with early RA had higher pIL-6 (p = 0.007), pVEGF (p = 0.02), and sYKL-40 (p = 0.024) compared to PA patients. pIL-6, sYKL-40, CRP, and ESR but not pVEGF decreased in patients that responded to treatment after 2 years. The mean value of pIL-6 during the first and second year were higher in patients with early RA with progression in bone erosions (n = 14) compared to early RA patients without progression (n = 30; first year 8.4 vs 2.8 ng/l, p = 0.04; second year 6.1 vs 3.6 ng/l, p = 0.03). CONCLUSION:Plasma IL-6 was the only biomarker related to treatment response and progressive erosive disease in patients with early RA, but it may not give additional information compared to CRP in relation to disease activity and treatment response.     

Humoral immune function in pediatric patients treated with autologous bone marrow transplantation for B cell non-Hodgkin's lymphoma. The influence of ex vivo marrow decontamination with anti-Y 29/55 monoclonal antibody and complement

Elimination of neoplastic B cell populations from autologous bone marrow grafts also removes normal B lymphocytes. This is potentially hazardous for the reconstitution of the immune system in patients undergoing high-dose chemotherapy and total body irradiation followed by autologous marrow rescue. Five pediatric patients with B cell non- Hodgkin's lymphoma in first remission undergoing such a regimen were studied. They received bone marrow pretreated with anti-Y 29/55 monoclonal antibody and complement. B and T lymphocyte subpopulations reached normal levels within 6 months after autologous bone marrow transplantation (ABMT), and serum immunoglobulin levels became normal within 4 to 9 months. Vaccination with diphtheria and tetanus toxoid, trivalent poliomyelitis vaccine of the Salk type, and pneumococcal capsular antigens (38 to 54 months after transplantation) gave rise to specific antibody production. ABO isoagglutinins could be demonstrated in all patients. The response pattern was similar to that of patients who received unmanipulated autologous bone marrow. It is concluded that ex vivo anti-Y 29/55 depletion of the marrow graft does not induce relevant disturbances of humoral immune functions.     

Trading in your spindles for blebs： the amoeboid tumor cell phenotype in prostate cancer

Prostate cancer （PCa） remains a principal cause ofmortalityin developed countries.Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor ceils reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, ＇amoeboid＇ phenotype is increasingly appreciated as relevant to human cancer.     

Evaluation of [18F]2FP3 in pigs and non‐human primates

So far, no suitable 5‐HT₇R radioligand exists for clinical positron emission tomography (PET) imaging. [¹⁸F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non‐human primates (NHPs). Furthermore, we investigate species differences in 5‐HT₇R binding with [³H]SB‐269970 autoradiography in post‐mortem pig, NHP, and human brain tissue. Specific binding of [¹⁸F]2FP3 was investigated by intravenous administration of the 5‐HT₇R specific antagonist SB‐269970. [³H]SB‐269970 autoradiography was performed as previously described. [¹⁸F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB‐269970 only resulted in decreased binding of 20% in the thalamus, a 5‐HT₇R–rich region. Autoradiography on post‐mortem pig, NHP, and human tissues revealed that specific binding of [³H]SB‐269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [¹⁸F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5‐HT₇R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5‐HT₇Rs in vivo and that part of the PET signal arises from targets other than the 5‐HT₇R.     

Personality disorders are important risk factors for disability pensioning

Purpose

To determine whether personality disorders (PDs) are associated with increased risk of disability pensioning in young adults, independent of other common mental disorders.

Methods

2,770 young adults from the general population were assessed for PDs by the Structured Interview for DSM-IV Personality, and for common mental disorders by the Composite of International Diagnostic Interview. These data were linked to the Norwegian National Insurance Administration’s recordings of disability benefits for a 10-year period. Logistic regression analyses were applied to investigate the association between PDs and disability pensioning. The analyses were conducted for three types of PD measures: categorical diagnoses (any PD), dimensional scores of individual PDs and higher order components retrieved by principal component analyses.

Results

Having any PD was strongly associated with disability pensioning, regardless of disability diagnosis. The estimated odds ratio (OR) was substantially higher for PDs [OR 4.69 (95 % confidence interval (CI) 2.6–8.5)] than for mood disorders [OR 1.3 (CI 0.7–2.3)] and anxiety disorders [OR 2.3 (CI 1.3–4.3)]. Measured dimensionally, all PD traits except antisocial traits were significantly associated with disability pensioning. After adjusting for co-occurring traits of other PDs, only schizoid, dependent and borderline PD traits showed a significant positive association with disability pension, while antisocial traits showed a significant negative association. The principal component analyses showed that negative affectivity, psychoticism, and detachment was associated with an increased risk of disability pensioning, while antagonism/disinhibition and obsessivity were not.

Conclusions

PDs are strongly associated with disability pensioning in young adults, and might be more important predictors of work disability than anxiety and depressive disorders. Certain aspects of pathologic personalities are particularly important predictors of disability.     

Efficacy of FODMAP Elimination and Subsequent Blinded Placebo-Controlled Provocations in a Randomised Controlled Study in Patients with Ulcerative Colitis in Remission and Symptoms of Irritable Bowel Syndrome: A Feasibility Study

Background: Patients with inflammatory bowel disease (IBD) and symptoms of irritable bowel syndrome (IBS) may be intolerant to fermentable carbohydrates (FODMAPs). The aim of this study was to test the feasibility of eliminating and subsequently reintroducing FODMAPs in patients with IBS symptoms as part of the IBD manifestation and to compare the severity of IBS symptoms and pain, bloating and quality of life (QoL). Methods: An eight-week randomised open-label FODMAP elimination with double-blinded, crossover provocations of FODMAP and placebo. Diet patients were on a low-FODMAP diet for eight weeks with blinded two-week provocations after two and six weeks. Questionnaires, blood and stool samples were collected. Results: Patient enrolment was challenging. Nineteen participants were included in the study. Eliminating low FODMAP for two weeks resulted in significant decreases in pain and bloating scores (p < 0.003), whereas there were no statistical differences in pain scores between diet patients and controls. Pain and bloating scores increased, returning to baseline levels after two weeks of double-blinded provocations with placebo, (p > 0.05). Conclusions: The results document the possibility of performing a randomised controlled study following the gold standard for testing food intolerance with blinding of the Low FODMAP diet. Recruitment of participants was challenging.     

Blood-brain barrier permeability in galactosamine-induced hepatic encephalopathy. No evidence for increased GABA-transport

Blood-brain barrier permeability to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), to sucrose and to sodium was studied in rats with galactosamine-induced liver damage and hepatic encephalopathy by means of an arterial integral uptake technique. Permeability to GABA was unaltered in all examined brain regions (2.47 +/- 0.25.10(-5) cm3.s-1.g-1, mean +/- S.D.) as compared to control rats (2.49 +/- 0.19.10(-5) cm3.s-1.g-1). The permeability to sucrose (galactosamine 0.25 +/- 0.02 vs. controls 0.24 +/- 0.02.10(-5) cm3.s-1.g-1) and to sodium (galactosamine 5.33 +/- 0.04 vs. controls 5.40 +/- 0.05.10(-5) cm3.s-1.g-1) was also unchanged in hepatic encephalopathy. At the time of investigation mean liver function measured by antipyrine clearance was reduced from 0.39 in control rats to 0.23 ml/min/100 g body wt. in galactosamine-treated animals. The present study does not support the suggestion that peripheral GABA penetrates the blood-brain barrier to any higher extent in hepatic encephalopathy. This provides evidence against at least part of the GABA-hypothesis. Furthermore, an unspecific increased blood-brain barrier permeability in hepatic encephalopathy, as measured by sucrose and sodium uptake, was not found. It is concluded that the GABA-theory requires further careful reevaluation.     

Serum markers of macrophage activation in pre-eclampsia: no predictive value of soluble CD163 and neopterin

BACKGROUND: Alternatively activated macrophages expressing the CD163 and CD206 surface receptors are the dominant immune-cell type found in the placenta. The placental number and distribution of macrophages is altered in pre-eclampsia, and the generalised inflammatory reaction associated with pre-eclampsia might lead to shedding of soluble CD163 into the circulation. METHODS: Serum samples from 18 women with pre-eclampsia and 90 normal pregnancies were obtained from a longitudinal study of 955 pregnant women at Randers County Hospital, Denmark. sCD163 and Neopterin were measured by ELISA on samples collected in weeks 18, 28, 32, and 38 of pregnancy. RESULTS: sCD163 levels in pregnancy (2-3 mg/l) were similar to previously measured levels in non-pregnant women, and did not increase from week 18 to 38. There was a tendency towards higher sCD163 in week 38 in pre-eclamptic women compared to healthy women. Neopterin increased throughout pregnancy in both healthy (from median 5.4 to 6.7 nmol/l, p<0.0001) and pre-eclamptic women (from 5.0 to 8.0 nmol/l, p<0.0001), but there were no differences between groups at any time-point. sCD163 correlated to neopterin in both the control (r=0.25, p<0.0001) and in the pre-eclampsia group (r=0.32, p=0.011). C-reactive protein was higher in pre-eclampsia than in healthy pregnancies by week 38 (159 versus 91 nmol/l, p=0.0189). CONCLUSIONS: The macrophage serum-markers sCD163 and neopterin are not pre-symptomatic nor prognostic markers for pre-eclampsia.