Cord blood cytokine profile detection in neonates with T1D parents -- monitoring of cellular auto-reactivity using protein microarray

Type 1 diabetes (T1D) is a great medical challenge and its incidence rises rapidly. T lymphocytes and their cytokine production are supposed to play a major role in T1D development. So far, there is no potent tool to recognize the early signs of cellular auto-reactivity which leads to β-cell damage. The naïve immune system of the newborn (not yet influenced by external factors) can be used as an important model for T1D pathogenesis studies. Cord blood samples of 22 healthy neonates born at term to a diabetic parent (T1DR) and 15 newborns with no family history of any autoimmune disease (controls) were collected. Determination of 23 cytokines was performed before and after the stimulation with diabetogenic autoantigens using protein microarray. We observed lower basal production of all detected cytokines in the T1DR group – granulocyte/macrophage colony-stimulating factor (GM-CSF) (P = 0.025), growth regulated protein (GRO) (P = 0.002), GRO-α (P = 0.027), interleukin (IL)-1-α (P = 0.051), IL-3 (P = 0.008), IL-7 (P = 0.027), IL-8 (P = 0.042), monocyte chemoattractant proteins (MCP)-3 (P = 0.022), monokine-induced by IFN-γ (MIG) (P = 0.034) and regulated upon activation normal T-cell express sequence (RANTES) (P = 0.004). Exclusively lower post-stimulative levels of G-CSF (P = 0.030) and GRO-α (P = 0.04) were observed in controls in comparison with the basal levels. A significant post-stimulative decrease in G-CSF (P = 0.030) and MCP-2 (P = 0.009) levels was observed in controls in comparison with T1DR neonates. We also observed the interesting impact of the risky genotype on the protein microarray results. Protein microarray seems to be a useful tool to characterize a risk pattern of the immune response for T1D also in newborns.     

Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study

Purpose

Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations.

Methods

We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines.

Results

A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma.

Conclusions

Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.     

Patterns of Drug Resistance Parameters in Adult Leukemia

P-glycoprotein (Pgp), Glutathione (GSH), Glutathione S-Transferase (GST), and 06-Alkylguanine-DNA Alkyltransferase (ATase) were measured in parallel as putative indicators of drug resistance in adult leukemia. The patterns of resistance parameter expression of chronic and acute leukemia were different. In acute leukemia on average all parameters were increased as compared to normal bone marrow. In chronic leukemia GSH and GST were increased, whereas Atase, GPx and frequency of Pgp-expression were low. Treatment with cytostatic drugs did not influence median levels of expression/activity of the resistance parameters. Resistance parameter expression/activity of leukemic cells was also compared with various other tissue and tumor types. Generally the pattern of resistance parameter expression reflected the resistance status of the tissue, constitutively resistant tumor types and their corresponding normal tissue on average having higher levels than leukemic cells and other tissue and tumor types with acquired resistance. For individual patients with acute leukemia, however, none of the parameters was directly correlated with response to treatment.     

Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers

The pharmacodynamics of morphine-6-glucuronide (M-6-G) i.v. were assessed in 12 healthy male volunteers in an open study. After a single bolus dose of M-6-G 5 mg i.v., we measured antinociceptive effects, using electrical and cold pain tests, and plasma concentrations of M-6- G, morphine-3-glucuronide (M-3-G) and morphine. Pain intensities during electrical stimulation (at 30, 60 and 90 min after injection) and ice water immersion (at 60 min) decreased significantly (P < 0.005) compared with baseline. Mean plasma peak concentrations of M-6-G were 139.3 (SD 38.9) ng ml-1, measured at 15 min. Our data demonstrate that M-6-G has significant analgesic activity.      

Operative morbidity and mortality in renovascular disease.

There were 104 major complications (13.1%) and 34 deaths (5.9%) among 502 patients with evidence of renovascular disease who underwent 577 operative procedures. The operative mortality rate in patients with atherosclerotic renovascular disease was 9.3% vs 3.4% with fibromuscular hyperplasia. Important determinants of renovascular operative mortality are (1) cause of disease, (2) presence of coronary artery disease, (3) presence of bilateral renal functional impairment, (4) the complexity of the renal operative procedure, and (5) concurrent extrarenal surgery.     

Inhibition of in vitro Friend murine leukemia virus infection of lipopolysaccharide-activated B-cells with concanavalin A.

Stimulation with bacterial lipopolysaccharide (LPS) of splenic B-lymphocytes infected in vitro with Friend virus complex increased the number of cells with replicating murine leukemia virus (MuLV) [i.e., infectious centers (IC)] up to 100-fold. Concanavalin A (Con A) did not have such an effect. However, the addition of Con A to the LPS-stimulated cultures decreased the number of IC. The inhibitory concentration of Con A (2.5 microgram/ml) was eightfold less than that capable of neutralizing the in vitro infectivity of MuLV (20 microgram/ml). The effect of Con A was not mediated by T-cells; the inhibition of infection was comparable with use of whole spleen cell suspensions from normal BALB/c mice, with T-cell-depleted cell suspensions, or with spleen cells with congenitally athymic nude mice. However, specific removal of Con A from the surface of B-cells with alpha-methyl-D-mannopyranoside prior to the infection reversed the inhibitory effect entirely. It is suggested that the lectin interferes with MuLV on the membrane of B-cells.