Multi-faceted functions of secretory IgA at mucosal surfaces.

Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer's patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.

Controlled nerve growth factor release from multi-ply alginate/chitosan-based nerve conduits.

The delivery kinetics of growth factors has been suggested to play an important role in the regeneration of peripheral nerves following axotomy. In this context, we designed a nerve conduit (NC) with adjustable release kinetics of nerve growth factor (NGF). A multi-ply system was designed where NC consisting of a polyelectrolyte alginate/chitosan complex was coated with layers of poly(lactide-co-glycolide) (PLGA) to control the release of embedded NGF. Prior to assessing the in vitro NGF release from NC, various release test media, with and without stabilizers for NGF, were evaluated to ensure adequate quantification of NGF by ELISA. Citrate (pH 5.0) and acetate (pH 5.5) buffered saline solutions containing 0.05% Tween 20 yielded the most reliable results for ELISA active NGF. The in vitro release experiments revealed that the best results in terms of reproducibility and release control were achieved when the NGF was embedded between two PLGA layers and the ends of the NC tightly sealed by the PLGA coatings. The release kinetics could be efficiently adjusted by accommodating NGF at different radial locations within the NC. A sustained release of bioactive NGF in the low nanogram per day range was obtained for at least 15days. In conclusion, the developed multi-ply NGF loaded NC is considered a suitable candidate for future implantation studies to gain insight into the relationship between local growth factor availability and nerve regeneration.

A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 - 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8-37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8-8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL.

Need of reduced and harmonized bureaucracy in multi-centre clinical research - a case-report from a Swiss trial

Introduction: We launched an investigator-initiated study (ISRCTN31181395) to evaluate the potential benefit of pharmacokinetic-guided dosage individualization of imatinib for leukaemiapatients followed in public and private sectors. Following approval by the research ethics committee (REC) of the coordinating centre, recruitment throughout Switzerland necessitatedto submit the protocol to 11 cantonal RECs.Materials and Methods: We analysed requirements and evaluation procedures of the 12 RECs with associated costs.Results: 1-18 copies of the dossier, in total 4300 printed pages, were required (printing/posting costs: ~300 CHF) to meet initial requirements. Meeting frequencies of RECs ranged between 2 weeks and 2 months, time from submission to fi rst feedback took 2-75 days. Study approval was obtained from a chairman, a subor the full committee, the evaluation work being invoiced by0-1000 CHF (median: 750 CHF, total: 9200 CHF). While 5 RECs gave immediate approval, the other 6 rose in total 38 queries before study release, mainly related to wording in the patient information, leading to 7 different fi nal versions approved. Submission tasks employed an investigator half-time over about 6 months.Conclusion: While the necessity of clinical research evaluation by independent RECs is undisputed, there is a need of further harmonization and cooperation in evaluation procedures. Current administrative burden is indeed complex, time-consuming and costly. A harmonized electronic application form, preferably compatible with other regulatory bodies and European countries, could increase transparency, improve communication, and encourage academic multi-centre clinical research in Switzerland.

Multi-scale integration and predictability in resting state brain activity.

The human brain displays heterogeneous organization in both structure and function. Here we develop a method to characterize brain regions and networks in terms of information-theoretic measures. We look at how these measures scale when larger spatial regions as well as larger connectome sub-networks are considered. This framework is applied to human brain fMRI recordings of resting-state activity and DSI-inferred structural connectivity. We find that strong functional coupling across large spatial distances distinguishes functional hubs from unimodal low-level areas, and that this long-range functional coupling correlates with structural long-range efficiency on the connectome. We also find a set of connectome regions that are both internally integrated and coupled to the rest of the brain, and which resemble previously reported resting-state networks. Finally, we argue that information-theoretic measures are useful for characterizing the functional organization of the brain at multiple scales.

Remote control of pulmonary blood flow: a dream comes true.

The indication for pulmonary artery banding is currently limited by several factors. Previous attempts have failed to produce adjustable pulmonary artery banding with reliable external regulation. An implantable, telemetrically controlled, battery-free device (FloWatch) developed by EndoArt SA, a medical company established in Lausanne, Switzerland, for externally adjustable pulmonary artery banding was evaluated on minipigs and proved to be effective for up to 6 months. The first human implant was performed on a girl with complete atrioventricular septal defect with unbalanced ventricles, large patent ductus arteriosus and pulmonary hypertension. At one month of age she underwent closure of the patent ductus arteriosus and FloWatch implantation around the pulmonary artery through conventional left thoracotomy. The surgical procedure was rapid and uneventful. During the entire postoperative period bedside adjustments (narrowing or release of pulmonary artery banding with echocardiographic assessment) were repeatedly required to maintain an adequate pressure gradient. The early clinical results demonstrated the clinical benefits of unlimited external telemetric adjustments. The next step will be a multi-centre clinical trial to confirm the early results and adapt therapeutic strategies to this promising technology.

HACEK infective endocarditis: characteristics and outcomes from a large, multi-national cohort.

The HACEK organisms (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) are rare causes of infective endocarditis (IE). The objective of this study is to describe the clinical characteristics and outcomes of patients with HACEK endocarditis (HE) in a large multi-national cohort. Patients hospitalized with definite or possible infective endocarditis by the International Collaboration on Endocarditis Prospective Cohort Study in 64 hospitals from 28 countries were included and characteristics of HE patients compared with IE due to other pathogens. Of 5591 patients enrolled, 77 (1.4%) had HE. HE was associated with a younger age (47 vs. 61 years; p<0.001), a higher prevalence of immunologic/vascular manifestations (32% vs. 20%; p<0.008) and stroke (25% vs. 17% p = 0.05) but a lower prevalence of congestive heart failure (15% vs. 30%; p = 0.004), death in-hospital (4% vs. 18%; p = 0.001) or after 1 year follow-up (6% vs. 20%; p = 0.01) than IE due to other pathogens (n = 5514). On multivariable analysis, stroke was associated with mitral valve vegetations (OR 3.60; CI 1.34-9.65; p<0.01) and younger age (OR 0.62; CI 0.49-0.90; p<0.01). The overall outcome of HE was excellent with the in-hospital mortality (4%) significantly better than for non-HE (18%; p<0.001). Prosthetic valve endocarditis was more common in HE (35%) than non-HE (24%). The outcome of prosthetic valve and native valve HE was excellent whether treated medically or with surgery. Current treatment is very successful for the management of both native valve prosthetic valve HE but further studies are needed to determine why HE has a predilection for younger people and to cause stroke. The small number of patients and observational design limit inferences on treatment strategies. Self selection of study sites limits epidemiological inferences.

Multi-phase postmortem CT angiography: recognizing technique-related artefacts and pitfalls.

BACKGROUND AND PURPOSE: Multi-phase postmortem CT angiography (MPMCTA) is increasingly being recognized as a valuable adjunct medicolegal tool to explore the vascular system. Adequate interpretation, however, requires knowledge about the most common technique-related artefacts. The purpose of this study was to identify and index the possible artefacts related to MPMCTA. MATERIAL AND METHODS: An experienced radiologist blinded to all clinical and forensic data retrospectively reviewed 49 MPMCTAs. Each angiographic phase, i.e. arterial, venous and dynamic, was analysed separately to identify phase-specific artefacts based on location and aspect. RESULTS: Incomplete contrast filling of the cerebral venous system was the most commonly encountered artefact, followed by contrast agent layering in the lumen of the thoracic aorta. Enhancement or so-called oedematization of the digestive system mucosa was also frequently observed. CONCLUSION: All MPMCTA artefacts observed and described here are reproducible and easily identifiable. Knowledge about these artefacts is important to avoid misinterpreting them as pathological findings.

Calceology : an introduction to North Western European archaeological leather footwear (Neolithic period to c. AD 1600)

Calceology is the study of recovered archaeological leather footwear and is comprised of conservation, documentation and identification of leather shoe components and shoe styles. Recovered leather shoes are complex artefacts that present technical, stylistic and personal information about the culture and people that used them. The current method in calceological research for typology and chronology is by comparison with parallel examples, though its use poses problems by an absence of basic definitions and the lack of a taxonomic hierarchy. The research findings of the primary cutting patterns, used for making all leather footwear, are integrated with the named style method and the Goubitz notation, resulting in a combined methodology as a basis for typological organisation for recovered footwear and a chronology for named shoe styles. The history of calceological research is examined in chapter two and is accompanied by a review of methodological problems as seen in the literature. Through the examination of various documentation and research techniques used during the history of calceological studies, the reasons why a standard typology and methodology failed to develop are investigated. The variety and continual invention of a new research method for each publication of a recovered leather assemblage hindered the development of a single standard methodology. Chapter three covers the initial research with the database through which the primary cutting patterns were identified and the named styles were defined. The chronological span of each named style was established through iterative cross-site sedation and named style comparisons. The technical interpretation of the primary cutting patterns' consistent use is due to constraints imposed by the leather and the forms needed to cover the foot. Basic parts of the shoe patterns and the foot are defined, plus terms provided for identifying the key points for pattern making. Chapter four presents the seventeen primary cutting patterns and their sub-types, these are divided into three main groups: six integral soled patterns, four hybrid soled patterns and seven separately soled patterns. Descriptions of the letter codes, pattern layout, construction principle, closing seam placement and list of sub-types are included in the descriptions of each primary cutting pattern. The named shoe styles and their relative chronology are presented in chapter five. Nomenclature for the named styles is based on the find location of the first published example plus the primary cutting pattern code letter. The named styles are presented in chronological order from Prehistory through to the late 16th century. Short descriptions of the named styles are given and illustrated with examples of recovered archaeological leather footwear, reconstructions of archaeological shoes and iconographical sources. Chapter six presents documentation of recovered archaeological leather using the Goubitz notation, an inventory and description of style elements and fastening methods used for defining named shoe styles, technical information about sole/upper constructions and the consequences created by the use of lasts and sewing forms for style identification and fastening placement in relation to the instep point. The chapter concludes with further technical information about the implications for researchers about shoemaking, pattern making and reconstructive archaeology. The conclusion restates the original research question of why a group of primary cutting patterns appear to have been used consistently throughout the European archaeological record. The quantitative and qualitative results from the database show the use of these patterns but it is the properties of the leather that imposes the use of the primary cutting patterns. The combined methodology of primary pattern identification, named style and artefact registration provides a framework for calceological research.

Non-monophyly of the woody bamboos (Bambuseae; Poaceae): a multi-gene region phylogenetic analysis of Bambusoideae s.s.

The taxonomy of Bambusoideae is in a state of flux and phylogenetic studies are required to help resolve systematic issues. Over 60 taxa, representing all subtribes of Bambuseae and related non-bambusoid grasses were sampled. A combined analysis of five plastid DNA regions, trnL intron, trnL-F intergenic spacer, atpB-rbcL intergenic spacer, rps16 intron, and matK, was used to study the phylogenetic relationships among the bamboos in general and the woody bamboos in particular. Within the BEP clade (Bambusoideae s.s., Ehrhartoideae, Pooideae), Pooideae were resolved as sister to Bambusoideae s.s. Tribe Bambuseae, the woody bamboos, as currently recognized were not monophyletic because Olyreae, the herbaceous bamboos, were sister to tropical Bambuseae. Temperate Bambuseae were sister to the group consisting of tropical Bambuseae and Olyreae. Thus, the temperate Bambuseae would be better treated as their own tribe Arundinarieae than as a subgroup of Bambuseae. Within the tropical Bambuseae, neotropical Bambuseae were sister to the palaeotropical and Austral Bambuseae. In addition, Melocanninae were found to be sister to the remaining palaeotropical and Austral Bambuseae. We discuss phylogenetic and morphological patterns of diversification and interpret them in a biogeographic context.

Multi-stage garnet in the internal Brianconnais basement (Ambin massif, Savoy): New petrological constraints on the blueschist-facies metamorphism in the Western Alps and tectonic implications

Three types of garnet have been distinguished in pelitic schists from an epidote-blueschist-facies unit of the Ambin and South Vanoise Brianconnais massifs on the basis of texture, chemical zoning and mineral inclusion characterization. Type-1 garnet cores with high Mn/Ca ratios are interpreted as pre-Alpine relicts, whereas Type-1 garnet rims, Type-2 inclusion-rich porphyroblasts and smaller Type-3 garnets are Alpine. The latter are all characterized by low Mn/Ca ratios and a coexisting mineral assemblage of blue amphibole, high-Si phengite, epidote and quartz. Prograde growth conditions during Alpine D-1 high-pressure (HP) metamorphism are recorded by a decrease in Mn and increase in Fe (+/-Ca) in the Type-2 garnets, culminating in peak P-T conditions of 14-16 kbar and 500degreesC in the deepest parts of the Ambin dome. The multistage growth history of Type-1 garnets indicates a polymetamorphic history for the Ambin and South Vanoise massifs; unfortunately, no age constraints are available. The new metamorphic constraints on the Alpine event in the massifs define a metamorphic T `gap' between them and their surrounding cover (Brianconnais and upper Schistes Lustres units), which experienced metamorphism only in the stability field of carpholite-lawsonite (T < 400degreesC). These data and supporting structural studies confirm that the Ambin and South Vanoise massifs are slices of `eclogitized' continental crust tectonically extruded within the Schistes Lustres units and Brianconnais covers. The corresponding tectonic contacts with top-to-east movement are responsible for the juxtaposition of lower-grade metamorphic units on the Ambin and South Vanoise massifs.