Contributions of a blended learning based on peer evaluation for teaching drug-drug interactions to undergraduate pharmacy students.

BACKGROUND: Numerous studies have pointed out the need for better training of healthcare professionals in drug-drug interactions management in order to minimize adverse drugs reactions impacts on patients. The aim of this study was to evaluate the benefits of a blended learning strategy based on peer evaluation (PE) for teaching drug-drug interactions to undergraduate pharmacy students. METHODS: Third-year pharmacy students (n = 72) from the University of Limoges were involved in a hybrid teaching using the Moodle platform (2.9 version). After the theoretical lectures, an online activity was proposed to students. Each student submitted a report addressing a clinical case for peer evaluation. Students evaluated the pedagogical approach using an online survey. Quantitative benefits were assessed from students randomly assigned into two groups: PE in pharmacodynamics items (PE-PD) or PE in pharmacokinetics items (PE-PK). During this activity, three marks were given: one from peers for their evaluation work and two from teachers for oral group presentation of the clinical cases and for the final written examination. Statistics were performed using two-tailed unpaired t-test and significance was set for p < 0.05. RESULTS: Only a few students (n = 14, 20.6%) were aware of the peer evaluation principle and even less, only one student (n = 1, 1.5%), had already encountered it. Students considered that they benefited from this evaluation (n = 65, 95.6%); from their work being reviewed (n = 62, 91.2%) and that they participated in improving their classmates understanding (n = 59, 86.8%). Peers' allocated marks were similar in the two PE groups (PE-PD = 17.4 ± 1.4; PE-PK = 17.3 ± 1.4). Teachers' marks for oral presentation were significantly lower for pharmacodynamics than for pharmacokinetics items (PE-PD = 15.2 ± 1.2; PE-PK = 16.1 ± 2.1; p < 0.05). The final examination marks were equivalent in both groups (PE-PD = 11.0 ± 2.1; PE-PK = 11.2 ± 1.9). CONCLUSIONS: Besides the fact that a major short-term quantitative improvement was not detected, our teaching approach was qualified as being a positive and stimulating learning tool by students.

Epidermal growth factor receptor expression and KRAS and BRAF mutations: study of 39 sinonasal intestinal-type adenocarcinomas.

Sinonasal intestinal-type adenocarcinomas (ITACs) are uncommon tumors of poor prognosis defined by their similarities to colorectal adenocarcinomas. The involvement of the epidermal growth factor receptor (EGFR) pathway in colorectal adenocarcinoma oncogenesis is well established, and the same is expected to apply to ITACs. In a series of 39 ITACs, we investigated EGFR amplification and chromosome 7 polysomy by fluorescence in situ hybridization; EGFR, KRAS, and BRAF mutational status by polymerase chain reaction sequencing; EGFR variant messenger RNA expression by quantitative reverse transcriptase polymerase chain reaction; and EGFR protein expression by immunohistochemistry with antibodies targeting the extracellular domain, the intracellular domain, and the phosphorylated isoform. The findings were analyzed with respect to clinical data, histologic typing, and patient outcome. EGFR amplification was observed in 3 cases with a focal distribution. EGFR proteins were overexpressed in all these foci with both extracellular domain and intracellular domain antibodies, suggesting involvement of the whole receptor. Chromosome 7 polysomy was observed in 15 cases and was not associated with EGFR protein expression. EGFR, KRAS, or BRAF mutations were observed in 5 different cases. The EGFRvIII mutant was not detected. In all cases, EGFR variants were expressed. There was no association between these molecular features and patient survival. In conclusion, (1) our study revealed various EGFR expression patterns in ITACs, indicating tumor heterogeneity; (2) EGFR amplification should be distinguished from chromosome 7 polysomy; (3) fluorescence in situ hybridization analysis could be guided by immunohistochemistry; and (4) ITACs share common alterations of the EGFR pathway with colorectal adenocarcinomas, except for a lower frequency of KRAS and BRAF mutations.

A new custom made bioceramic implant for the repair of large and complex craniofacial bone defects.

INTRODUCTION: Neurosurgery and Maxillofacial Surgery Departments of Limoges University Hospital Centre have developed a new concept of a custom made ceramic implant in hydroxyapatite (HA) for the reconstruction of large and complex craniofacial bone defects (more than 25 cm(2)). MATERIALS AND METHODS: The manufacturing process of the implants used a stereolithography technique that produces implants with three-dimensional shapes derived directly from the scan file of the patient's skull without moulding or machining. Eight patients received 8 implants between 2005 and 2008. RESULTS: The surgical procedure is simple and fast. The post-operative follow-up was 12 months. No major complications (infection or fracture of the implant) were observed. The cosmetic result was considered satisfactory by both patients and surgeons. CONCLUSIONS: These new implants are well suited for reconstruction of large craniofacial bone defects (greater than 25 cm(2)) in adults and children over 8 years.

Adult diffuse gliomas produce mRNA transcripts encoding EGFR isoforms lacking a tyrosine kinase domain.

The epidermal growth factor receptor (EGFR) gene encodes four alternatively spliced mRNA, variants 1, 2, 3 and 4, respectively, encoding the whole isoform a (EGFR) and truncated isoforms b, c and d, all of which lack the receptor's intracellular domain. In addition, a mutant EGFRvIII differs from isoform a in a truncated extracellular domain. The expression pattern of these isoforms is unknown in adult diffuse gliomas. Thus, we investigated in 47 cases: i) EGFR protein expression by immunohistochemistry using an extracellular domain-recognizing antibody (Ext-Ab) and an intracellular domain specific one (Int-Ab), ii) mRNA expression of EGFRv1, -v2, -v3, -v4 and -vIII by RT-PCR and iii) EGFR amplification by fluorescent in situ hybridization. The relation of these data with histological criteria and patient outcome was studied. The immunostaining was stronger with the Ext-Ab than with the Int-Ab. EGFRv1, -v2, -v3 and -v4 mRNA expression were highly correlated. They were expressed in all tumors, with highest levels in glioblastomas. EGFRv1 strong levels and the presence of vIII mRNAs were more closely associated with Int-Ab staining. EGFR gene amplification concerned only glioblastomas and was associated with the presence of EGFRvIII and high levels of EGFRv2, -v3 and -v4 transcripts. A pejorative outcome was associated with: histology (glioblastomas), EGFR amplification, strong Int-Ab labeling and high levels of variant mRNAs. Our results indicated that the full-length EGFR and mutant EGFRvIII are not the sole EGFR isoform expressed in diffuse gliomas. This could explain discordant immunohistochemical results reported in the literature and may have therapeutic implications.

The mamillothalamic tract is a good landmark for the anterior border of the subthalamic nucleus on axial MR images.

BACKGROUND: Identification of the subthalamic nucleus (STN) on MR images is difficult, and the use of external landmarks could be of interest for STN targeting in deep brain stimulation (DBS). OBJECTIVES: Our aim was to explore the relationship between the anteroposterior coordinates of (1) the center of the mamillothalamic tract and (2) the anterior border of the STN on axial MR images. PATIENTS AND METHODS: The brains of 16 healthy volunteers were imaged on a 3T MR system. Four millimeters under the anterior-posterior commissure plane, we noted the y coordinates of (1) the center of the mamillothalamic tract and (2) the anterior border of the STN. RESULTS: The coordinates were y(STN) = 14.7 ± 1.23 mm and y(Tmth) = 14.3 ± 1.13 mm from the posterior commissure for the STN and the mamillothalamic tract, respectively. The mean difference was 0.4 mm (range 0-1 mm). Pearson's coefficient was 0.97 (p < 0.01). CONCLUSION: We observed a strong correlation between the anteroposterior coordinates of the mamillothalamic tract and the anterior border of the STN (which is located between 0 and 1 mm in front of the mamillothalamic tract). The mamillothalamic tract could be a good anterior landmark for STN targeting. It could also be tested for target determination in DBS for severe obsessive-compulsive disorder.

Alpha-internexin expression in gliomas: relationship with histological type and 1p, 19q, 10p and 10q status.

BACKGROUND: The alpha-internexin (INA) gene encodes an intermediate filament involved in neurogenesis and maps in 10q24.33. A strong INA protein expression has been reported in oligodendroglial tumours and was associated with 1p19q deletion. To assess the relevance of INA immunohistochemistry in glioma typing, this paper studied the relationship between INA expression, histological type, genomic status and patient outcome. METHODS: The study analysed INA, nestin, Olig2 and p53 expression, loss of heterozygosity of microsatellite markers from telomere to centromere of 10p, 10q, 1p and 19q chromosomes and epidermal growth factor receptor gene (EGFR) amplification in 40 gliomas (five astrocytomas, 12 oligodendrogliomas, 11 oligoastrocytomas, 12 glioblastomas). INA expression was scored as absent, weak (<10% of labelled tumour cells) or strong (>10%). RESULTS: Oligodendrogliomas showed strong INA and Olig2 expression, and 1p19q whole loss of heterozygosity (wLOH). Astrocytomas and glioblastomas were characterised by no or weak INA expression, high p53 and nestin expression, 10p10q wLOH, and epidermal growth factor receptor amplification. Most oligoastrocytomas had characteristics of astrocytic tumours. All tumours with strong INA expression retained the 10q chromosome arm and, except for one, had a 1p19q wLOH status. However, despite a strong link between INA expression, 1p19q wLOH and 10q retention, discrepancies were observed in 10% of cases. The presence of INA expression, whether weak or strong, was related to a better prognosis. CONCLUSION: INA expression study can be helpful for glioma typing and prognosis determination in combination with other markers. Nevertheless, INA immunohistochemistry cannot replace the genomic analysis to determine 1p19q and 10p10q status.

mRNA levels of enzymes and receptors implicated in arachidonic acid metabolism in gliomas.

BACKGROUND: Gliomas are tumors of the central nervous system derived from glial cells. They show cellular heterogeneity and lack specific diagnostic markers. Although a possible role for the eicosanoid cascade has been suggested in glioma tumorigenesis, the relationship between enzymes and receptors implicated in arachidonic acid metabolism, with histological tumor type has not yet been determined. DESIGN AND METHODS: Quantitative real-time reverse transcription-polymerase chain reaction was performed to measure and compare transcript levels of enzymes and receptors implicated in both lipoxygenase and cyclooxygenase pathways between oligodendrogliomas, astrocytomas, glioblastomas and mixed oligoastrocytomas. RESULTS: Arachidonic acid metabolism-related enzymes and receptor transcripts (i) were underexpressed in classical oligodendrogliomas compared to astrocytomas and/or glioblastomas, (ii) differed between astrocytomas and glioblastomas and (iii) had an intermediate expression in mixed oligoastrocytomas. CONCLUSIONS: mRNA levels of enzymes and receptors implicated both in lipoxygenase and cyclooxygenase pathways differed significantly in gliomas according to the histological type.

[Changing the teaching of neurosurgery with information technology]. / Campus numérique de neurochirurgie: mobiliser une discipline des sciences médicales autour d'un projet pédagogique fédérateur.

A digital campus is a distance learning site that uses the potential of information and communication technologies to disseminate and improve educational services. This website, with open and free access, is built from free software with Web 2.0 technology. It is hosted at the University of Limoges. It functions as a digital library, containing scanned books, slide shows, more than 200 hours of recorded courses and round tables accessible by streaming video. The site is indexed according to the users' needs, by level of knowledge, specialty, keywords, and supplementary MeSH terms. The campus is organized as the College of Neurosurgery (http://college.neurochirurgie.fr). The durability of this type of training (in existence for 9 years now) is made possible by a powerful and committed consortium: the French Society of Neurosurgery, which has created high-quality intellectual and scientific resources, the University of Limoges, the Dupuytren University Hospital Center in Limoges, the region of Limousin, and the French-language Virtual Medical University, which have provided logistic and financial support. To target appropriate levels at various users, we distinguished four groups: medical students, neurosurgery students, neurosurgeons (continuing medical education), and students in allied health fields. All areas of neurosurgery are concerned. All the courses, including tests for self-evaluation and scientific meetings (organized with information and communication technologies) are digitally recorded for the site. The principles that make it possible for a medical discipline to organize around an online project are: a pedagogical conception of projects built in the form of models reusable by other health specialties; a stronghold within professional societies of the relevant specialties able to create high-quality intellectual and scientific resources; an organization by educational levels that can be extended transversally to other health disciplines; and free access to the digital campus, the durability of which depends on the dissemination and dynamism of its consortium.

WHO grade II and III meningiomas: a study of prognostic factors.

Meningiomas represent one of the largest subgroups of intracranial tumors. They are generally benign, but may show a histological progression to malignancy. Grades II and III meningiomas have been less well studied and are not well controlled because of their aggressive behaviour and recurrences. There is no consensus on therapeutic strategies and no prognostic factors are known. In order to determine these parameters, a multi-institutional retrospective analysis was performed in France with the support of the Neuro-Oncology Club of the French Neurosurgical Society. This study was performed on 199 adults treated for WHO grade II (166 patients) or grade III (33 patients) meningiomas between 1990 and 2004 in the Neurosurgery Departments of five French University Hospitals. Data on epidemiology, clinical behaviour and therapy were collected. Overall survival and progression-free survival were analysed as a function of each possible prognostic factor. For patients with grade II meningiomas, the 5- and 10-year OS rates were 78.4 and 53.3%, respectively, while, for patients with grade III meningiomas, the corresponding values were 44.0 and 14.2%. For patients with grade II meningiomas, the 5- and 10-year PFS rates were 48.4 and 22.6%, respectively, the corresponding values for patients with grade III meningiomas being 8.4 and 0%. For the grade II meningiomas, univariate analysis showed that age < 60 years (P < 0.0001) and Simpson 1 resection (P = 0.055) were associated with a longer OS. For the grade III meningiomas, univariate analysis showed that age < 60 years (P < 0.0001) and RT (P = 0.036) were associated with a longer OS. Histological grade II was found to be associated with a longer PFS (P = 0.0032) and RT reduced the PFS in grade II meningiomas (P = 0.0006) There were no other prognostic factors in terms of PFS for grades II and III meningiomas in univariate analysis. Multivariate analysis confirmed that age (< 60 years), Simpson 1 and histological grade II were independent prognostic factors for survival. This retrospective study might improve the management of grades II and III meningiomas. Prospective trials should delineate strong therapeutic guidelines for high-grade meningiomas.

Determination of EGFR status in gliomas: usefulness of immunohistochemistry and fluorescent in situ hybridization.

Epidermal growth factor receptor (EGFR) is produced during the molecular pathogenesis of glioma, and new anti-EGFR molecules are available for therapeutics. Consequently, analyses of the EGFR gene and protein are frequently used for glioma characterization. We compare the accuracy and the usefulness of 2 currently used techniques for histologic classification of gliomas. Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) techniques were used to assess EGFR gene amplification and protein abundance in a series of 35 gliomas, including World Health Organization (WHO) grade I, II, and III astrocytomas (AI, AII, AIII), grade II and III tumors with oligodendroglial component (OII, OIII) and grade IV glioblastomas (GBs). EGFR gene amplification was found in one-third of the tumors studied. It was frequent in GB and OIII but was never found in AI, AII, AIII, and OII tumors. IHC and FISH provided similar findings for grade of tumor, despite the fact that, in contrast to the FISH gene amplification, EGFR protein was overexpressed in AIII and in GB. EGFR gene amplification was never observed in tumors not containing EGFR protein: therefore FISH is unnecessary when IHC shows no EGFR protein expression. EGFR gene amplification seems to be restricted to high-grade tumors, WHO grade IV astrocytomas, and grade III oligodendroglial tumors.

Analysis of several PLA2 mRNA in human meningiomas.

In view of the important oncogenic action of phospholipase A(2)(PLA(2)) we investigated PLA(2) transcripts in human meningiomas. Real-time PCR was used to investigate PLA(2) transcripts in 26 human meningioma tumors. Results indicated that three Ca(2+)-dependent high molecular weight PLA(2) (PLA(2)-IVA, PLA(2)-IVB, PLA(2)-IVC), one Ca(2+)-independent high molecular weight PLA(2) (PLA(2)-VI) and five low molecular weight secreted forms of PLA(2) (PLA(2)-IB, PLA(2)-IIA, PLA(2)-III, PLA(2)-V, and PLA(2)-XII) are expressed with PLA(2)-IVA, PLA(2)-IVB, PLA(2)-VI, and PLA(2)-XIIA as the major expressed forms. PLA(2)-IIE, PLA(2)-IIF, PLA(2)-IVD, and PLA(2)-XIIB are not detected. Plasma (PLA(2)-VIIA) and intracellular (PLA(2)-VIIB) platelet-activating factor acetylhydrolase transcripts are expressed in human meningiomas. However no difference was found for PLA(2) transcript amounts in relation to the tumor grade, the subtype of meningiomas, the presence of inflammatory infiltrated cells, of an associated edema, mitosis, brain invasion, vascularisation or necrosis. In conclusion numerous genes encoding multiples forms of PLA(2) are expressed in meningiomas where they might act on the phospholipid remodeling and on the local eicosanoid and/or cytokine networks.

Transcranial puncture through the parietal and mastoid foramina for the treatment of dural fistulas. Report of four cases.

In this report the authors describe the endovascular treatment of dural arteriovenous fistulas (DAVFs) through transcranial puncture of the feeding arteries. Four patients had DAVFs that were fed by occipital arteries (OAs) that supplied blood to the intracranial meningeal arteries via the transcranial branches and coursed through the parietal and mastoid foramina. Due to the excessive tortuosity of the OA, conventional endovascular navigation had failed in all cases. Transcranial puncture of the meningeal feeding arteries was performed through the parietal or mastoid foramen, allowing navigation with a microcatheter until the level of the shunts. Complete cure of the DAVF was attained in all patients after injection of acrylic glue.

The Quantitative analysis of bFGF and VEGF by ELISA in human meningiomas.

The quantitative analysis of VEGF using ELISA in various subtypes of grade I meningiomas reported higher VEGF contents in meningothelial (2.38 +/- 0.62 pg/microg protein, n = 7), transitional (1.08 +/- 0.21 pg/microg protein, n = 13), and microcystic meningiomas (1.98 +/- 0.87 pg/microg protein, n = 5) as compared with fibrous ones (0.36 +/- 0.09 pg/microg protein, n = 5). In contrast to VEGF, no difference in the concentrations of bFGF was detected. VEGF levels did not correlate with meningioma grade (1.47 +/- 0.23 pg/microg versus 2.29 +/- 0.58 pg/microg for 32 and 16 grade I and II, resp), vascularisation (1.53 +/- 0.41 pg/microg versus 1.96 +/- 0.28 pg/microg for 24 low and 24 high vascularisated tumours, resp), and brain invasion (2.32 +/- 0.59 pg/microg versus 1.46 +/- 0.27 pg/microg for 7 and 41 patients with and without invasion, resp). The ELISA procedure is, thus, an interesting tool to ensure VEGF and bFGF levels in meningiomas and to test putative correlations with clinical parameters. It is, thus, tempting to speculate that ELISA would also be valuable for the quantitative analysis of other angiogenic growth factors and cytokines in intracranial tumours.

Contact forces in a granular packing.

We present the results of a systematic numerical investigation of force distributions in granular packings. We find that all the main features of force transmission previously established for two-dimensional systems of hard particles hold in three-dimensional systems and for soft particles, too. In particular, the probability distribution of normal forces falls off exponentially for forces above the mean force. For forces below the mean, this distribution is either a decreasing power law when the system is far from static equilibrium, or nearly uniform at static equilibrium, in agreement with recent experiments. Moreover, we show that the forces below the mean do not contribute to the shear stress. The subnetwork of the contacts carrying a force below the mean thus plays a role similar to a fluid surrounding the solid backbone composed of the contacts carrying a force above the mean. We address the issue of the computation of contact forces in a packing at static equilibrium. We introduce a model with no local simplifying force rules, that allows for an exact computation of contact forces for given granular texture and boundary conditions. (c) 1999 American Institute of Physics.