Lactobacillus casei reduces CD8+ T cell-mediated skin inflammation

Probiotics, including Lactobacilli, have been postulated to alleviate allergic and inflammatory diseases, but evidence that they exert an anti-inflammatory effect by immune modulation of pathogenic T cell effectors is still lacking. The aim of this study was to examine whether L. casei could affect antigen-specific T cell-mediated skin inflammation. To this end, we used contact hypersensitivity to the hapten 2,4-dinitrofluorobenzene, a model of allergic contact dermatitis mediated by CD8+ CTL and controlled by CD4+ regulatory T cells. Daily oral administration of fermented milk containing L. casei or L. casei alone decreased skin inflammation by inhibiting the priming/expansion of hapten-specific IFN-gamma-producing CD8+ effector T cells. The down-regulatory effect of the probiotics required the presence of CD4+ T cells, which control the size of the hapten-specific CD8+ T cell pool primed by skin sensitization. L. casei cell wall was as efficient as live L. casei to regulate both the CHS response and the hapten-specific CD8+ T cell response, suggesting that cell wall components contribute to the immunomodulatory effect of L. casei. This study provides the first evidence that oral administration of L. casei can reduce antigen-specific skin inflammation by controlling the size of the CD8+ effector pool.     

Brain metastases from breast cancer: usefulness and limits of prognostic scores

Approximately 10 to 30% of patients with metastatic breast cancer will develop brain metastases (BM) during the disease course. Whole-brain radiation therapy (WBRT) is considered the standard treatment for most patients, particularly those with extensive intracranial disease, providing symptom relief and increasing median and overall survival. Despite WBRT, the prognosis for the general population of patients with BM remains poor, with a median survival time of approximately five months. Several studies have examined the relative contributions of patient characteristics to survival and have attempted to identify subgroups of patients with substantially different outcomes in order to tailor therapy and to influence the design, stratification and interpretation of future clinical trials. This review examines prognostic scores and their validation in patients with BM from breast carcinoma. We also discuss the prognostic value of specific parameters for breast carcinoma, such as tumor HR status, HER2 over-expression or specific treatment parameters, and the value and limits of these prognostic scores in clinical practice.     

UPLC MS/MS method for quantification of mycophenolic acid and metabolites in human plasma: Application to pharmacokinetic study

BackgroundWe described the development and full validation of a rapid, high throughput sensible and accurate UPLC method using tandem mass spectrometry detection for mycophenolate acid (MPA) and its metabolites, MPA glucuronide (MPAG) and acyl MPA glucuronide (AcMPAG) concentration determination with MPA-D3 as internal standard in human plasma.MethodsPlasma pretreatment involved a one-step protein precipitation with acetonitrile. The separation was performed by reverse-phase chromatography on a Waters BEH HSST3 100 mm*2.1 mm*1.8 μm column. The multiple reaction monitoring transitions used for quantification were m/z 321.04 → 303.02 for MPA, 524.09 → 303.02 for AcMPAG and MPAG and 324.03 → 306.04 for MPA-D3 in the electrospray positive ionization mode.ResultsThe method was linear over the concentration range of 0.1–20 mg/L for MPA and AcMPAG and 1–200 mg/L for MPAG respectively. The intra- and inter-day precision values were below 14% and accuracy was from 94.0 to 103.3% at all quality control levels. The lower LOQ was 0.1 mg/L for MPA and AcMPAG, 1 mg/L for MPAG.ConclusionSample analysis time was reduced to 7 min including sample preparation. The present method was successfully applied to a pharmacokinetic study following oral administration of enterocoated sodium mycophenolate in de novo renal transplantation.     

Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats

Foetal cell transplantation in patients with Parkinson’s disease can induce motor complications independent of l-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson’s disease, post-transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although l-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing l-DOPA-induced dyskinesia against post-transplantation amphetamine-induced dyskinesia. Agents include: dopaminergic antagonists (D₁: CP94253; D₂: SCH-22390; D₃: nafadotride), serotonergic agonists (5-HT_1A: 8-OH-DPAT; 5-HT_1B: CP94253), opioid antagonist (μ: naloxone), cannabinoid agonist (CB₁: WIN55, 212-2), adrenergic antagonist (α₁ and α₂: yohimbine) and glutamatergic antagonists (NMDA: amantadine and MK-801; mGluR5: MTEP; AMPA: IEM1460). Abnormal involuntary movements in response to amphetamine were decreased by SCH-22390, raclopride, CP94253 and 8-OH-DPAT, yet were unaltered by naloxone, WIN55, 212-2, yohimbine, amantadine, MTEP and IEM1460. Unusually, MK-801 increased the appearance of amphetamine-induced dyskinesia. The results suggest that dopaminergic, serotoninergic and glutamatergic systems are likely to have a fundamental role in the development of graft-induced dyskinesias, which are mechanistically distinct from l-DOPA-induced behvaviours. Importantly, the expression of D₁ and D₂ receptors was unrelated to the severity of AIMs.     

Brain metastases from breast cancer: proposition of new prognostic score including molecular subtypes and treatment

To develop a specific prognostic score for patients with brain metastases (BM) from breast cancer (BC), including the BC molecular subtype and treatment parameters, we analyzed the outcome of 130 patients with BM from BC who received whole-brain radiotherapy. We identified hierarchical risk groups for estimated survival by using recursive partitioning analysis (RPA). Seven prognostic factors, namely performance status, age, trastuzumab-based therapy for HER-2-overexpressing tumors, a triple-negative phenotype, Scarff-Bloom-Richardson grade, the serum LDH level and the lymphocyte count at BM diagnosis, were incorporated in the RPA. The final RPA nodes were grouped according to the survival time. The RPA tree showed that survival was best (median 19.5 months) among patients with HER2-overexpressing tumors who received trastuzumab-based therapy. The worst survival (median 3.5 months) was observed among patients who did not receive trastuzumab and who had lymphopenia at BM diagnosis, or KPS <70 and age over 50 years, or KPS ≥70 and a triple-negative tumor (HR− & HER-2−). The other patients had a median survival of 12.5 months (P < 0.001). This 3-class specific prognostic score successfully predicted the outcomes of a heterogeneous group of patients with brain metastases from BC.     

High fish consumption in French Polynesia and prenatal exposure to metals and nutrients

French Polynesians consume high quantities of fish and are therefore exposed to seafood-related contaminants such as mercury (Hg) or lead (Pb) and nutrients such as iodine, selenium and long chain polyunsaturated fatty acids (LC-PUFAs). As the developing foetus is sensitive to contaminants and nutrients, a cross-sectional study was conducted in French Polynesia in 2005-2006 to assess prenatal exposure to contaminants and nutrients through fish consumption. Two hundred and forty one (241) delivering women originating from all islands of French Polynesia were recruited and agreed to answer questions on fish consumption and gave permission to collect umbilical cord blood for metals and nutrients analyses. All parameters were found in high concentrations in cord blood samples except for lead. Mercury concentrations averaged 64.6 nmol/L (or 13 microg/L) with values ranging from 0.25 to 240 nmol/L. Of the sample, 82.5% had Hg concentrations above the US-EPA blood guide-line of 5.8 microg/L. Tuna was the fish species which contributed the most to Hg exposure. High selenium and LC-PUFAs may counterbalance the potential risk of prenatal exposure to Hg in French Polynesia. Due to the high fish consumption of mothers, Polynesian newborns are prenatally exposed to high doses of mercury. Although selenium and omega-3 fatty acids may counteract mercury toxicity, informing pregnant women on both the mercury and nutrient content of local fish species is important.