Medulloblastoma: histological evaluation and prognosis

Eighty-four cases of medulloblastoma were examined immunohistochemically and 12 by electron microscopy to assess differentiation in these tumors. Based upon the largest series of medulloblastoma studied to date, we demonstrated glial fibrillary acidic protein (GFAP) positivity, in 25% (21/84) of these tumors showing glial differentiation. GFAP-positive cells were seen more frequently in the desmoplastic variant of medulloblastoma (7/10). Under electron microscopy, the major part of the 12 tumors studied appeared primitive and undifferentiated. In 7 cases, groups of cells were found with primitive neuronal and/or glial features. GFAP positivity was confirmed at light microscopy level in all cases where cells showed glial differentiation in the form of glial-like filaments in cytoplasma. However, a follow-up questionnaire study of those patients who had received only surgical treatment revealed no difference in mean survival time between GFAP-positive and GFAP-negative medulloblastoma.Supported by the Governmental Grant PR-06 for Fighting Cancer     

ORIGINAL ARTICLE: Changes in the Subpopulation of CD25+ CD4+ and FOXP3+ Regulatory T Cells in Decidua with Respect to the Progression of Labor at Term and the Lack of Analogical Changes in the Subpopulation of Suppressive B7‐H4+ Macrophages – A Preliminary Report

Problem The initiation of labor is accompanied by alterations in the level of maternal immune tolerance toward fetal antigens. It is a complex molecular response leading to a brief activation of the maternal immune system with an accompanying capacity to restrict this same activation. The aim of our study was to evaluate the subpopulation of regulatory T cells (Tregs) and B7‐H4 macrophages in the decidua basalis during cesarean sections performed on patients in various stages of labor. Method of study The decidual tissue samples evaluated in our study were obtained from 23 pregnant women who underwent cesarean sections at term. Moreover, the patients were divided into three subgroups according to the progression of labor at the time of the cesarean. The presence of Treg cells and B7‐H4 positive macrophages were analysed by fluorescence‐activated cell sorter. Results The percentages of FOXP3⁺ cells in the subpopulation of CD25⁺ CD4⁺ T lymphocytes found in the deciduas of patients decreased with the successive stages of labor, while the percentages of B7‐H4 positive cells in the macrophage subpopulation remained almost constant. Conclusion These changes in the Treg cell subpopulation in the decidua would seem to be related to a brief activation of the maternal immune system as labor begins and lack of analogical changes in the subpopulation of decidual suppressive B7‐H4⁺ macrophages that enable the restriction of this same activation as labor progresses.     

Patient involvement in assessing consultation quality: a quantitative study of the Patient Enablement Instrument in Poland

Background  Promoting a more patient-responsive service has been the focus of policy initiatives in newer EU states. One measure of success should be the patient's assessment of their consultation with their doctor.
Objectives  To measure consultation quality in Polish primary care using patient enablement (a patient-driven instrument developed in the UK) and to test its theoretical framework. To compare the patient enablement outcome of different types of doctor delivering primary care in Poland following reform.
Design  Cross-sectional quantitative questionnaire survey.
Setting  Random sample of primary care doctors practising within a 60-km radius of Gdansk, Poland.
Subjects and outcome measures  Patient Enablement Instrument and correlates were measured in 7924 consecutive adult consultations of 48 doctors, stratified according to training: family medicine specialists (diploma holders), non-diplomates and general medicine doctors (polyclinic internists).
Results  Completion was high (78%). The mean patient enablement score in Poland was 4.0 (SD 3.3) and mean consultation length was 10.3 min (SD 5.4 min). Consultation length and knowing the doctor are independently related to patient enablement in the Polish context. Variation between doctors is significant, but earlier differences in enablement between alternative providers have largely been ameliorated in practice.
Conclusion  It is feasible to use patient enablement on a large scale at routine consultation in primary care in Poland: acceptability was good in diverse environments. The internal consistency of enablement and its relationships broadly mirror those found in the UK. The effect of patient expectations shaped by social and cultural issues influencing enablement outcome requires further investigation.     

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

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SHORT COMMUNICATION: Partial hepatectomy of rats 3 weeks before or simultaneously with 2-aminofluorene injection can affect the amounts of adducts induced in hepatic DNA

The influence of partial hepatectomy on the level of 2-amino-fluorene(2-AF) induced DNA adducts in rat liver was studied. We foundthat partial hepatectomy performed either 3 weeks before orsimultaneously with the injection of 2-AF affected the amountsof adducts in rat hepatic DNA compared to controls. The levelof DNA adducts in rats that were treated with 2-AF and simultaneouslyhepatectomized was higher (19.9 fmol/µg DNA) than in non-hepatectomizedones (14.4 fmol/µg DNA) when measured 48 h after 2-AFadministration. In rats treated with the carcinogen 3 weeksafter hepatectomy the level of DNA adducts was significantlyhigher than in non-hepatectomized rats when measured 15 daysafter the injection of 2-AF (10.9 fmol/µg DNA and 5.9fmol/µg DNA respectively). The high level of DNA adductsin that group of hepatectomized animals was correlated witha relatively lower rate of 2-AF-induced radioactive thymidineincorporation into hepatic DNA (in comparison to non-hepatectomizedrats).     

Validation for histology‐driven diagnosis in non‐small cell lung cancer using hsa‐miR‐205 and hsa‐miR‐21 expression by two different normalization strategies

Targeted therapy of non‐small cell lung cancer (NSCLC) demands a more accurate tumor classification that is crucial for patient selection in personalized treatment. MicroRNAs constitute a promising class of biomarkers and a helpful tool for the distinction between lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC). The aim of this study was to evaluate the impact of two different normalization strategies, using U6 snRNA and hsa‐miR‐103 as reference genes, on hsa‐miR‐205 and hsa‐miR‐21 expression levels, in terms of the classification of subtypes of NSCLC. By means of a quantitative real‐time polymerase chain reaction (qRT‐PCR) microRNA expression levels were evaluated in a classification set of 98 surgically resected NSCLC fresh‐frozen samples, and validated findings in an independent set of 42 NSCLC samples. The microRNA expression levels were exploited to develop a diagnostic test using two data normalization strategies. The performance of microRNA profiling in different normalization methods was compared. We revealed the microRNA‐based qRT‐PCR tests to be appropriate measures for distinguishing between AC and SCC (the concordance of histologic diagnoses and molecular methods greater than 88%). Performance evaluation of microRNA tests, based on the two normalization strategies, showed that the procedure using hsa‐miR‐103 as reference target has a slight advantage (sensitivity 83.33 and 100% in classification and validation set, respectively) compared to U6 snRNA. Molecular tests based on microRNA expression allow a reliable classification of subtypes for NSCLC and can constitute a useful diagnostic strategy in patient selection for targeted therapy.     

Plasma biomarkers of endothelial dysfunction in patients with hypertrophic cardiomyopathy

Impairment of endothelium-dependent coronary vasodilatation has been reported in hypertrophic cardiomyopathy (HCM). The aim of our study was to evaluate whether HCM patients have increased circulating blood markers of endothelial dysfunction. We compared 29 HCM patients with sinus rhythm, including 11 with the left ventricular outflow tract (LVOT) obstruction (gradient > 30 mmHg), versus 29 age- and sex-matched controls without cardiovascular diseases. Plasma levels of the following endothelial biomarkers were determined: soluble thrombomodulin (sTM), von Willebrand factor (vWF), tissue factor pathway inhibitor (TFPI), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDAM) and L-arginine to ADMA (Arg/ADMA) ratio. Both sTM (49.1 +/- 9.9 vs. 39.1 +/- 4.8 ng/ml, p < 0.00001) and TFPI (18.6 +/- 2.5 vs. 16.2 +/- 1.7 ng/ml, p < 0.0001) were elevated in HCM patients compared with controls, whereas vWF levels were similar in both groups (105.8 +/- 11.6 vs. 102.2 +/- 10.9 U/dl, p > 0.05). Among markers related to the nitric oxide pathways, we observed elevations of both ADMA (0.57 +/- 0.08 vs. 0.44 +/- 0.04 mumol/l, p < 0.0001) and SDMA(0.43 +/- 0.05 vs. 0.34 +/- 0.04 mumol/l, p < 0.0001) and decrease in the Arg/ADMA ratio (118.1 +/- 18.2 vs. 144.3 +/- 22.1, p < 0.0001) in HCM patients. The obstructive HCM subgroup displayed higher values of ADMA, SDMAand sTM compared with the non-obstructive HCM subgroup. HCM patients show specific features of endothelial dysfunction detectable in peripheral blood, involving increased sTM and TFPI, but not vWF, along with increased ADMA levels.     

Polylactide-co-glycolide (PLG) microparticles modify the immune response to DNA vaccination

Priming with the major surface glycoprotein G of respiratory syncytial virus (RSV) expressed by recombinant vaccinia leads to strong Th2 responses and lung eosinophilia during viral challenge. We now show that DNA vaccination in BALB/c mice with plasmids encoding G attenuated RSV replication but also enhanced disease with lung eosinophilia and increased IL-4/5 production. However, formulating the DNA with PLG microparticles reduced the severity of disease during RSV challenge without significantly lessening protection against viral replication. PLG formulation greatly reduced lung eosinophilia and prevented the induction of IL-4 and IL-5 during challenge, accompanied by a less marked CD4+ T cell response and a restoration of the CD8+ T cell recruitment seen during infection of non-vaccinated animals. After RSV challenge, lung eosinophilia was enhanced and prolonged in mice vaccinated with DNA encoding a secreted form of G; this effect was virtually prevented by PLG formulation. Therefore, PLG microparticulate formulation modifies the pattern of immune responses induced by DNA vaccination boosts CD8+ T cell priming and attenuates Th2 responses. We speculate that PLG microparticles affect antigen uptake and processing, thereby influencing the outcome of DNA vaccination.     

Relationship between mitral leaflets angles, left ventricular geometry and mitral deformation indices in patients with ischemic mitral regurgitation: imaging by echocardiography and cardiac magnetic resonance

Chronic ischemic mitral regurgitation (IMR) is associated with a markedly worse prognosis after myocardial infarction (MI).The study aimed to evaluate the relationship between anterior and posterior mitral leaflet angle (MLA) values, left ventricle remodeling and severity of ischaemic mitral regurgitation (IMR). Methods: Forty-two patients (age 63.5 ± 9.7 years, 36 men) with chronic IMR (regurgitant volume, RV > 20 ml; >6 months after MI) underwent transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR) imaging. Anterior and posterior MLA, determined by echocardiography, were correlated with indices of LV remodeling, mitral apparatus deformation and IMR severity by CMR. The anterior and posterior MLA was 25.41 ± 4.28 and 38.37 ± 8.89° (mean ± SD). In 5 patients (11.9%) the posterior MLA was ≥45°. There was a significant correlation between anterior MLA and RV (r = 0.74, P = 0.01). For patients with RV > 30 ml this correlation was stronger (r = 0.97, P = 0.005) and, in addition, there was a correlation between the RV and posterior MLA (r = 0.90, P = 0.037), between tenting area and posterior MLA (r = 0.90, P = 0.04), and between tenting area and anterior MLA (r = 0.82, P = 0.08). With regard to LV remodeling parameters, there was weaker but significant correlation between posterior MLA and LV end-diastolic volume index (r = 0.35, P = 0.031), LV end-systolic volume index (r = 0.37, P = 0.021), stroke volume (r = 0.35, P = 0.03), sphericity index (r = 0.33, P = 0.041). Anterior MLA correlated with wall motion score index (r = 0.41, P = 0.019). Besides, there was a correlation between posterior MLA and left atrial volume (r = 0.41, P = 0.012). Measurement of anterior and posterior MLA may play an important role in evaluating patients with IMR.