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In turbulent Taylor-Couette flow, the injection of bubbles reduces the overall drag. On the other hand, rough walls enhance the overall drag. In this work, we inject bubbles into turbulent Taylor-Couette flow with rough walls (with a Reynolds number up to 4 x 10(5), finding an enhancement of the dimensionless drag as compared to the case without bubbles. The dimensional drag is unchanged. As in the rough-wall case no smooth boundary layers can develop, the results demonstrate that bubbly drag reduction is a pure boundary layer effect.

Control of integrin-mediated adhesion and migration by chemokines plays a critical role in B cell development, differentiation, and function; however, the underlying signaling mechanisms are poorly defined. Here we show that the chemokine SDF-1 induced activation of Bruton's tyrosine kinase (Btk) and that integrin-mediated adhesion and migration in response to SDF-1 or CXCL13, as well as in vivo homing to lymphoid organs, was impaired in Btk-deficient (pre-)B cells. Furthermore, SDF-1 induced tyrosine phosphorylation of Phospholipase C gamma 2 (PLC gamma 2), which, unlike activation of the migration regulatory GTPases Rac or Rap1, was mediated by Btk. PLC gamma 2-deficient B cells also exhibited impaired SDF-1-controlled migration. These results reveal that Btk and PLC gamma 2 mediate chemokine-controlled migration, thereby providing insights into the control of B cell homeostasis, trafficking, and function, as well as into the pathogenesis of the immunodeficiency disease X-linked agammaglobulinemia (XLA)

We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition, to examine the associations between prediagnostic serum concentrations of C-peptide, insulin-like growth factor binding protein (IGFBP)-l and IGFBP-2, and endometrial cancer risk. Among pre- and postmenopausal women, who were not currently using exogenous hormones, 286 women developed incident endometrial cancer during an average 5.1 years follow-up. Using risk set sampling, 555 matched control subjects were selected. In conditional logistic regression models adjusted for matching factors only, endometrial cancer risk increased with increasing serum levels of C-peptide (relative risks (RR) for the top vs. bottom quartile = 2.13 [95% confidence interval (CI) 1.33-3.41], p(trend) = 0.001, and decreasing serum levels of IGFBP-2 (RR for the lop vs. bottom quartile = 0.56 [95% CI 0.35-0.90], p(trend) = 0.03, but was not significantly associated with IGFBP-1 levels (RR for the top vs. bottom quartile = 0.76 [95% CI 0.47-1.21], p(trend) = 0.25). In BMI-adjusted models, only the C-peptide association remained marginally statistically significant (RR for the top vs. bottom quartile = 1.56 [95% CI 0.94-2.571, p(trend) = 0.05 for C-peptide; 0.84 [95% CI 0.50-1.40], p(trend) = 0.74 for IGFBP-2; and 1.08 [95% CI 0.65-1.781, p(trend) = 0.86 for IGFBP-1 levels). These associations were stronger among nonfasting women (

Background: Adiponectin, an adipocytokine secreted by adipose tissue, is decreased in obesity, insulin resistance, type 2 diabetes, and polycystic ovary syndrome, all of which are well-established risk factors for endometrial cancer. Methods: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition to examine the relation between prediagnostic plasma adiponectin levels and endometrial cancer risk. Among pre- and postmenopausal women who were not currently using exogenous hormones, 284 women developed incident endometrial cancer during an average of 5.1 yr of follow-up. Using risk set sampling, 548 control subjects were selected, matched on center, age, menopausal status, phase of menstrual cycle, time of blood draw, and fasting status. Conditional logistic regression models were used to estimate relative risks and 95% confidence intervals. Results: Adiponectin levels were inversely associated with endometrial cancer risk [body mass index-adjusted relative risk for the top vs. bottom quartile = 0.56 (95% confidence interval 0.36-0.86), P-trend = 0.006]. There was evidence of a stronger inverse association among obese women than among nonobese women (P-heterogeneity = 0.03). The inverse association also appeared stronger for women who were postmenopausal or perimenopausal than premenopausal at baseline, but this was not statistically significantly heterogeneous (P-heterogeneity = 0.51). The association remained statistically significant after separate adjustment for other obesity-related physiological risk factors such as C-peptide, IGF binding protein-1, IGF binding protein-2, SHBG, estrone, or free testosterone but only marginally statistically significant after simultaneous adjustment for these factors. Conclusions: High circulating adiponectin levels are associated with reduced endometrial cancer risk, largely independent of other obesity-related risk factors.

For the development of state-of-the-art CMOS technologies, the integration and introduction of low-k materials are one of the major bottlenecks due to their bad thermal and mechanical integrity and the inherited week interfacial adhesion. The use of Ultra Low-K (ULK) materials, such as porous dielectrics, will require significant development effort in order to result in reliable interconnect structures that are able to withstand the IC, packaging and assembly related thermo-mechanical and mechanical forces. Especially the forces resulting from packaging related processes such as dicing, wire bonding, bumping and molding are critical and can easily result in cracking, delamination and chipping of the IC back-end structure if no appropriate measures are taken. For the thermo-mechanical design of IC back-end structures, an experience based/trial-and-error approach has been mainly used in the past. This is not only time and money consuming, but also inherently troubles the inclusion of packaging requirements in the earlier stages of back-end process development. Due to the reduced design margins and shorter time-to-market, this trail-and-error approach is not sufficient anymore and novel methodology based on advanced simulation and optimization techniques is required. With this virtual prototyping and qualification methodology thermo-mechanical reliability can be dealt with already in the design phase including the interaction with packaging and qualification processes.

Since moisture sensitivity level (MSL) tests are part of the international reliability qualification standards, all the microelectronics components/products have to pass these specifications. Therefore, it is important to be able to efficiently and accurately characterize and predict the moisture related material and interface behavior in the real manufacturing, processing, testing and application conditions. The success of interfacial fracture mechanics approach to analyze moisture-induced failures in IC packaging strongly depend on accurate characterization of the critical adhesion strength, GC . However, its measurement is complicated by the fact that adhesion depends not only on moisture concentration, C, but also temperature, T, and mode mixity, Psi. This paper described our research to develop a reliable methodology for interface toughness evaluation as function of temperature, humidity and mode mixity. Our methodology includes using the four-point bending test and shaft-loaded-blister method. Dedicated specimens consisting of various types of moulding compounds bonded onto leadframe are manufactured. Besides temperature, moisture content and mode mixity effects, also the influences of surface treatment (leadframe oxidation and contamination) and production process on the interface fracture toughness are evaluated. Multi-physics-based numerical methods are used to transfer the experimental critical loads to an interface strength parameter. These analysis covers mechanical, moisture diffusion, vapor pressure, hygro-swelling and CTE-mismatch modeling. To test and improve the methodology, various effects are evaluated, such as crack-length dependency, material properties, specimen-width, displacement-rate of the upper support/shaft, etc. The results of the proposed methodology indicate, as expected, a change in interface toughness by mode mixity, moisture content and temperature. It is found that GC decreases with increasing moisture content and temperature. The presence of moisture at the given interface is observed as the important factor in the reduction of interfacial strength (Gt 20 - 45%). Furthermore, G C; increases by a factor 3-4 when the mode mixity shifts towards mode II

Currently, prediction of interface strength is typically done using the critical energy release rate. Interface strength, however, is heavily dependent on mode mixity. Accurately predicting delamination therefore requires a material model that includes the mode dependency of interface strength. A novel test setup is designed which allows mixed mode delamination testing. The setup is a stabilized version of the mixed mode bending test previously described by Reeder and Crews (1990; 1991). It allows for the measurement of stable crack growth over the full range of mode mixities, using a single specimen design. The crack length, necessary for calculation of the energy release rate, is obtained from an analytical model. Crack length and displacement data are used in a finite element model containing a crack tip to calculate the mode mixity.

Human monocytes adhere to activated platelets, resulting in the formation of platelet-monocyte complexes (PMC). Complex formation depends on the interaction between platelet-displayed P-selectin and the specific ligand for P-selectin on leukocytes, P-selectin glycoprotein ligand-1 (PSGL-1). We have recently shown that monocytes within PMC have increased adhesive capacity to the activated endothelium. To better understand the effect of platelet binding on the capacity of monocytes to adhere to activated endothelium, the P-selectin-PSGL-1 interaction-induced changes in integrin functionality were studied. The binding of platelets to monocytes via P-selectin-PSGL-1 interactions was shown to increase expression and activity of α4β1 and αMβ2 integrin, with a concomitant decrease in L-selectin expression. Furthermore, the binding of platelets to monocytes resulted in increased monocyte adhesion to intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and fibronectin. Platelet binding was also responsible for an increase in monocyte transendothelial migration. Similar effects were observed after engagement of PSGL-1 with specific antibodies or with P-selectin immunoglobulin protein. Our data suggest that platelets, by binding via P-selectin to PSGL-1 on monocytes, induce up-regulation and activation of β1 and β2 integrins and increased adhesion of monocytes to activated endothelium. Hence, monocytes within PMC are in a higher state of activation and may have, therefore, an increased atherogenic capacity.

Piroplasmosis, a disease endemic to most tropical and subtropical areas, appears to be spreading to more temperate zones. This article gives a review of equine piroplasmosis and describes an acute case of infection with Babesia caballi in a Dutch Standard bred foal after a short stay at a stud in Normandy (France). A 3-month-old stallion foal was presented with lethargy, fever of 41 degrees C, and pale mucosal membranes. Haematology revealed a low packed cell volume (14 l/l) leucytosis (25 G/l) and a high blood urea nitrogen concentration (20.1mmol/l). Infection with B. caballi was diagnosed on the basis of Giemsa staining blood smears and was confirmed by polymerase chain reaction in combination with RLB. Treatment with imidocarb dipropionate and a blood transfusion resolved the haemolytic crisis.

For the development of state-of-the-art Cu/low-k CMOS technologies, the integration and introduction of new low-k materials are one of the major bottlenecks due to the bad thermal and mechanical integrity of these materials and the inherited weak interfacial adhesion. Especially the forces resulting from packaging related processes such as dicing, wire bonding, bumping and molding are critical and can easily result in cracking, delamination and chipping of the IC back-end structure if no appropriate measures are taken. This paper presents a methodology for optimizing the thermo-mechanical reliability of bond pads by using a 3D multi-level Finite Element approach. An important characteristic of this methodology is the use of a novel energy-based damage model, which allows a fast qualitative comparison of different back-end structures. The usability of the methodology will be illustrated by the comparison of three different bond pad structures.

The use of pure copper heat-sinks (also termed flange) is a significant step forward to improve the thermal performance of flange mounted RF devices. One of the major risks however, is the large CTE mismatch between copper and silicon, which may result in die fracture. In order to asses the probability of die fracture during temperature cycling, a FE modeling study, combined with experiments to extract material properties, validate the models and get material strength data, has been performed and will be presented here. In order to take into account nonuniform and changing stress distributions and the probabilistic nature of surface defects that determine the die fracture strength, Weibull statistics and a surface area stress integral have been used to calculate the probability of die fracture. With incorporation of the cyclic hardening of the copper, by a combined kinematic and isotropic constitutive model, the predicted failure probability matched experimentally observed failure probabilities and provides a physical explanation for early failures.

Exposed pad packages were introduced in the late 80-90's because of their excellent thermal and electrical performance. Despite these advantages, the exposed pad packages experience a lot of thermo-hygro-mechanical related reliability problems during qualification and testing. Examples are dielift, predominantly after MSL conditions and die/attach-leadframe delamination leading to downbond stitch breaks during temperature cycling. In this study, we have combined novel interfacial adhesion test techniques with non-linear FE models using fracture mechanics based J-value calculations to assess the reliability problems of the exposed pad package family. Using the parametric FE models any geometrical and material effects can be explored to their impact on the occurrence delamination, dielift, etc. For instance the impact of diepad size is found to be of much less importance as the impact of die thickness is. Using the fracture mechanics approach, the starting location for the delamination from thermo-hygro-mechanical point of view is deducted. The results indicate that when diepad delamination is present, cracks are likely to grow beneath the die and dielift will occur. The interaction between dielift and other failure modes, such as lifted ball bonds, are not found to be very significant. In our future work we will combine the FE modeling with simulation based optimization methods to deduct design guidelines for optimal reliability of the exposed pad family.

Human monocytes adhere to activated platelets, resulting in the formation of platelet-monocyte complexes (PMC). Complex formation depends on the interaction between platelet-displayed P-selectin and the specific ligand for P-selectin on leukocytes, P-selectin glycoprotein ligand-1 (PSGL-1). We have recently shown that monocytes within PMC have increased adhesive capacity to the activated endothelium. To better understand the effect of platelet binding on the capacity of monocytes to adhere to activated endothelium, the P-selectin-PSGL-1 interaction-induced changes in integrin functionality were studied. The binding of platelets to monocytes via P-selectin-PSGL-1 interactions was shown to increase expression and activity of α

Background: Analgesia is a part of balanced anaesthesia, but direct indicators of nociception do not exist. We examined the relationship between motor reactions and physiological variables during skin incision in sevoflurane anaesthesia and hypothesized that nociception could be detected and graded by significant changes in these variables. Methods: Thirty‐one women scheduled for abdominal hysterectomy participated in the study. Anaesthesia was induced with fentanyl (1 µg kg−1), propofol (1 mg kg−1) and sevoflurane. Skin incision was performed 14 min after induction during 1.6% end‐tidal sevoflurane anaesthesia without neuromuscular blockade. Electrocardiography (ECG), photoplethysmography (PPG) and electroencephalography (EEG) were registered, and a range of variables was computed from these signals. The postincision values, normalized with respect to their preincision values, of movers vs. non‐movers were compared. The variables showing significant differences between movers and non‐movers were used to develop a logistic regression equation for the classification of patients into movers or non‐movers. Results: Twenty‐six patients were eligible for analysis, and 12 (46%) displayed a motor reaction to skin incision (movers). Many ECG, PPG and EEG‐related variables showed significant differences between the pre‐ and postincision periods. The best classification performance, assessed by leave‐one‐out cross‐validation, between movers and non‐movers was achieved with the combination of response entropy of EEG, RR‐interval and PPG notch amplitude. The corresponding equation yielded 96% correct classification with 90% sensitivity and 100% specificity. The classification performance of any single variable alone was considerably worse. Conclusion: Combination of information from different sources may be required for monitoring the adequacy of analgesia during anaesthesia.

Thermo-mechanical reliability is one of the concerns for semiconductor developments due to miniaturization, introduction of new materials, and higher application temperatures. FE modeling techniques are developed to predict the effect of IC interconnect metal designs on the thermo-mechanically-induced cracking of passivation layers. Experimental techniques on specially designed IC packages are developed to verify the predicted passivation cracks. With the verified 2D and 3D models, various simulations are performed and it is established that delamination of the IC/compound interface is a key trigger for passivation cracking. When delamination is present, crack occurrence is found to depend on the metal layout and location on the IC. Optimizing the metal layout design can even prevent passivation cracks. By combining efficient and accurate simulations with a limited number of experiments, passivation cracks can be quantitatively predicted prior to physical prototyping.

In this paper, the process migration facility in the Eindhoven multiprocessor system (EMPS) is presented. In the EMPS system, mailboxes are used for interprocess communication. These mailboxes provide transparency of location for communicating processes. The major advantages of mailbox communication in the EMPS system are (1) interprocess communication can proceed without losing messages and (2) the communication paths can be updated very efficiently when a process moves to another processor: By redirecting the mailbox connection of the migrating process, the communication paths of all processes connected to the same mailbox are updated. By measurements and a detailed evaluation of the performance it is demonstrated that intra-node process migration in the EMPS system is significantly more efficient than process migration in other distributed systems. The performance measurements of inter-node process migration yield results that can be favourably compared to other distributed systems.

In this research artificial neural network (ANN) based feature extractors were investigated on their suitability to automate the assessment of the location of characteristic peaks in auditory evoked potentials (AEPs). Two types of feature extractors were tested on their ability to determine the latency of peak V and peak Pa in AEPs. The performance on peak V proved to be satisfactory, for the identification of peak Pa improvement is still desired.

Despite increasing possibilities for the citizen to play a more active role in personal health management, the use of Internet based health applications remains limited. Poor usability, limited personalization, and problems with security and accessibility often frustrate a continued use. The paper presents a possible solution by actively using wireless communications and ad-hoc networking techniques to minimize the user's efforts in using the application. Overweightness is a widespread and increasing problem in western countries. There are indications that self-monitoring combined with guidelines provide a good basis for personal weight management. The wireless wellness monitor implements a self-monitoring and guidance system using Bluetooth- and Jini-based networking. A scale, heart rate monitor, mobile terminal (personal digital assistant or WAP-enabled digital cellular phone), and home server communicate locally via Bluetooth. Internet based communications take care of remote use. The set-up allows us to investigate the behavior and use cases based on equipment and protocols that are expected to be in general use in the coming years. Thus, the system provides a useful test-bed for evaluating new techniques that may bring personal health management to a new level.

As critical care is critical, the demands for patient monitoring are high. The methods need to function properly over a large variety of possible physiological conditions in an environment full of sources for technical artifacts, and they need to support clinical reasoning. Several iterations are usually required in the method development to meet these demands. First, the proposed method is developed and tested with simulated or optimal test data on a proof-of-principle basis. When this level is passed, the method needs to be tested offline with more realistic and nonoptimal data. Only after passing these levels may clinical trials be conducted. Usually, these developments require a significant period of time. Availability of extensive, well-characterized, and well-documented real physiological data during critical care would potentially reduce the amount of time required for the first phases of the method development. Such databases would also enable bench validation of any new methods and objective comparison between different methods. Recently, there have been some attempts to collect large signal databases during critical care. In this article, we aim to discuss the special requirements for collecting signal databases in critical care and to summarize the main features of the existing databases.

With the fast development of information and communications technology, devices with some computing power are becoming increasingly abundant in the average home. The trend for theses devices to also be provided with inter-communication functionality opens up new possibilities for health care. The availability of ubiquitous computing allows the individual to perform health-related measurements review data or consult guidelines independent of place or time, thus providing the individual with a better means to follow certain treatment programs. In this study, we set out to implement as a system based on ubiquitous computing for the application of weight management using behavioral feedback. The goals were a) to gain insights in the technical feasibility and caveats of such a system as a basis for setting up more advanced and generic infrastructures, and b) to study the degree to whether people are actually willing to use such a technology-laden system for their health management. The results lead us to the conclusion that such a system is possible with the current technology, although many issues need to be solved before generic architectures and implementations are a reality, and that many people, especially those who have serious weight problems, are eager to use such a system.

The IBIS Data Library (DL) is an annotated data library that contains practically all the monitored data and other clinical information from critically ill patients during surgery and in intensive care. The data have been collected at three sites: the intensive care unit of the Kuopio University Hospital, Finland; Royal Brompton Hospital, London, UK; and St. Bartholomew's Hospital, London, UK. The purpose of the DL is to form the basis for development of biosignal interpretation methods in the Improved Monitoring for Brain Dysfunction in Intensive Care and Surgery project in the European Union (EU) BIOMED2 programme (BMH4-97-2570). The DL contains continuous electroencephalography signals, multimodal evoked potential recordings and diagnostic electrocardiography recorded during intensive care and surgery. In addition, signal types similar to those recorded during an earlier project, the EU-BIOMED1 project IMPROVE, are stored in the DL. In addition, trend data from patient monitors, laboratory data, annotations, nursing actions, and medications recorded and stored by a Patient Data Management System (PDMS) during routine care are included. The data obtained routinely are complemented by special annotations made by a physician who observes the patient during the data collection session. Annotations include, for example, assessment of the awareness of the patient and specific events during surgery not recorded routinely by the PDMS. Inclusion of information about the care plan and the aims of the care make the contents of the DL complete. The present paper describes the technical set-up used for recording of the DL and the contents of the DL. The paper also includes an appendix defining a new data format, the extended evoked potentials format, used for storage of sweep data in the DL.

Improved monitoring improves outcomes of care. As critical care is "critical", everything that can be done to detect and prevent complications as early as possible benefits the patients. In spite of major efforts by the research community to develop and apply sophisticated biosignal interpretation methods (BSI), the uptake of the results by industry has been poor. Consequently, the BSI methods used in clinical routine are fairly simple. This paper postulates that the main reason for the poor uptake is the insufficient bridging between the actors (i.e., clinicians, industry and research). This makes it difficult for the BSI developers to understand what can be implemented into commercial systems and what will be accepted by clinicians as routine tools. A framework is suggested that enables improved interaction and cooperation between the actors. This framework is based on the emerging commercial patient monitoring and data management platforms which can be shared and utilized by all concerned, from research to development and finally to clinical evaluation.

The rapid accurate diagnosis of critical disorders is an essential component of intensive care. Traditional diagnostic techniques have relied on physician experience, which is based on a data set chosen from his or her personal preferences, rather than from scientific merit. In this article, we show that there are alternative methods of selecting clinical variables on which to base a diagnosis. We suggest that a model-based technique utilizing artificial neural networks (ANNs) can be used to investigate alternative, objectively chosen data input sets. Traditionally, ANNs have been used for diagnosis or prediction tasks; however, this article introduces a novel method of exploring the inner structure of suitably trained ANNs to determine a set of key variables for each clinical state defined. Two different ANN techniques are proposed: self-organizing maps and backpropagation networks. We do not claim that these techniques provide the optimal data set for decision making, but we do show that other combinations of data exist that may be an improvement over the physician methods currently used.

Purpose: A quantitative 3D intramodality ultrasound (US) imaging system was verified for daily in-room prostate localization, and compared to prostate localization based on implanted fiducial markers (FMs). Methods: Thirteen prostate patients underwent multiple US scans during treatment. A total of 376 US-scans and 817 matches were used to determine the intra- and interoperator variability. Additionally, eight other patients underwent daily prostate localization using both US and electronic portal imaging (EPI) with FMs resulting in 244 combined US-EPI scans. Scanning was performed with minimal probe pressure and a correction for the speed of sound aberration was performed. Uncertainties of both US and FM methods were assessed. User variability of the US method was assessed. Results: The overall US user variability is 2.6 mm. The mean differences between US and FM are: 2.5 ± 4.0 mm (LR), 0.6 ± 4.9 mm (SI), and −2.3 ± 3.6 mm (AP). The intramodality character of this US system mitigates potential errors due to transducer pressure and speed of sound aberrations. Conclusions: The overall accuracy of US (3.0 mm) is comparable to our FM workflow (2.2 mm). Since neither US nor FM can be considered a gold standard no conclusions can be drawn on the superiority of either method. Because US imaging captures the prostate itself instead of surrogates no invasive procedure is required. It requires more effort to standardize US imaging than FM detection. Since US imaging does not involve a radiation burden, US prostate imaging offers an alternative for FM EPI positioning.

Besides higher efficiency and sensitivity, another advantage of capillary/nano LC is the volume compatibility with the μ-liter fraction requirements of MALDI targets. One of the challenges is the collection of nanoliter volumes without remixing the separated compounds and losing chromatographic separation. In this work, a high-precision X/Y/Z robotic system, ProbotTM, was used that allows for the collection of tiny nanoliter volumes with zero chromatographic dispersion.

Background Shifts in pneumococcal serotypes following introduction of 7-valent pneumococcal conjugate vaccine (PCV-7) may alter the presence of other bacterial pathogens co-inhabiting the same nasopharyngeal niche. Methodology/Principal Findings Nasopharyngeal prevalence rates of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis were investigated before, 3 and 4.5 years after introduction of PCV-7 in the national immunisation program in children at 11 and 24 months of age, and parents of 24-month-old children (n≈330/group) using conventional culture methods. Despite a virtual disappearance of PCV-7 serotypes over time, similar overall pneumococcal rates were observed in all age groups, except for a significant reduction in the 11-month-old group (adjusted Odds Ratio after 4.5 years 0.48, 95% Confidence Interval 0.34–0.67). Before, 3 and 4.5 years after PCV-7 implementation, prevalence rates of S. aureus were 5%, 9% and 14% at 11 months of age (3.59, 1.90–6.79) and 20%, 32% and 34% in parents (1.96, 1.36–2.83), but remained similar at 24 months of age, respectively. Prevalence rates of H. influenzae were 46%, 65% and 65% at 11 months (2.22, 1.58–3.13), 52%, 73% and 76% at 24 months of age (2.68, 1.88–3.82) and 23%, 30% and 40% in parents (2.26, 1.58–3.33), respectively. No consistent changes in M. catarrhalis carriage rates were observed over time. Conclusions/Significance In addition to large shifts in pneumococcal serotypes, persistently higher nasopharyngeal prevalence rates of S. aureus and H. influenzae were observed among young children and their parents after PCV-7 implementation. These findings may have implications for disease incidence and antibiotic treatment in the post-PCV era.

Cells expressing the V delta 1+ gene segment are a minor gamma delta T cell population in human peripheral blood but predominate in epithelial and (inflamed) tissues. The characteristic dendritic-like morphology of these gamma delta T cells is consistent with their putative immune surveillance role in epithelia. Their function, however, remains unknown. We and others previously reported that a subset of V delta 1+ gamma delta T cells proliferates after stimulation with Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines (LCL), but not with fresh peripheral blood-derived B cells. These responses were independent of the type of T cell receptor (TcR) gamma chain co-expressed with the V delta 1 chain. The in vivo relevance of this LCL-mediated activation as well as the nature of the stimulatory ligand on the LCL is not well established. In this study, we tested the proliferative response of V delta 1+ LCL-responsive T cells against non-EBV-transformed B cells, activated through CD40 by murine EL4 B5 cells, and to a panel of B cell lines differing in the expression of EBV nuclear antigen proteins and adhesion/co-stimulatory molecules. The role of the Epstein-Barr virus-derived antigen in the induction of this response could be excluded as the activated (non-EBV-transformed) peripheral blood B cells were also able to induce a proliferative response in the LCL-responsive V delta 1+ T cells. Therefore, the stimulatory ligand on B cells is of cellular rather than of viral origin, and its expression is up-regulated upon activation of B cells. The expression of B7 and CD39 molecules on the surface of activated B cells appeared to be crucial since antibodies to these structures could block the induction of proliferation of the V delta 1+ T cells. Finally, we investigated the diversity of the responding V delta 1+ gamma delta T cell clones by sequence analysis of the TcR delta junctional regions. No restricted V-D-J sequences were found among the LCL-responsive V delta 1+ T cell clones, arguing strongly against a mono- or oligoclonal V delta 1+ gamma delta T cell response to LCL. These findings may explain the presence of polyclonally activated V delta 1+ T cells in inflamed tissues where activated B cells are often present.

Objective To determine whether nasopharyngeal pneumococcal carriage with serotypes 6B, 19F, or 23F interferes with immunoglobulin G (IgG) antibody responses to vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) at the age 24 months. Study design Blood samples were collected before and after a PCV7 challenge vaccination at age 24 months from subsets of children participating in a randomized controlled trial. Children previously had received two doses of PCV7 at 2 and 4 months, two plus one doses of PCV7 at 2, 4, and 11 months, or no dosage until 24 months. Nasopharyngeal swabs were cultured at for Streptococcus pneumoniae at age 6 weeks and at 6, 12, 18, and 24 months. IgG responses were determined with enzyme immunoassay. Results Lower IgG responses against serotypes 6B, 19F, and 23F were observed on PCV7 challenge vaccination at 24 months in children who had received earlier PCV7 vaccinations and had been found positive for homologous carriage compared with non-carriers of these serotypes. Lower non-homologous IgG responses were observed after the PCV7 challenge at 24 months against serotype 6B after earlier 19F carriage and against serotype 19F after earlier 23F carriage compared with children who had not been positive for carriage of these serotypes. Conclusions Pneumococcal colonization with serotypes 6B, 19F, and 23F is associated with diminished immune responses against these serotypes on PCV7 vaccination at 2 years of age. Underlying mechanisms deserve further investigation.

Purpose: Image Guided Radiotherapy(IGRT) is a necessity for accurate radiotherapy.Ultrasound(US)imaging is a frequently used diagnostic technique for qualitative imaging of soft tissues. Recently, a quantitative 3D US system was introduced (Clarity system, Resonant Medical, Canada) which can assess the position of soft tissue in absolute space. Before introducing the device into daily practice, user variability, during both image acquisition and matching procedures must be determined. In this study we determined the inter‐ and intra‐operator variability of 3D US matching in prostate cancer patients. Moreover, we studied the influence of the scan variability on patient setup corrections, and the influence of probe pressure on the prostate position while using a strict bladder filling protocol. Methods: For 12 prostate patients multiple US scans are acquired by one or two operators during treatment. The repeated scans are matched to the reference US‐scan by a single user (variability for scanning). The remaining scans are matched three times by different users, and for each patient one single scan is matched five times by the same user (variability for matching). Results: In all three directions the mean intra‐operator difference ranges from 1.5 to 2.4 mm, with a standard deviation of approximately 1.7 mm. The mean inter‐operator difference is of the same order, 1.7 to 2.3 ± 1.8 mm. The prostate displacement due to the probe pressure varies from patient to patient and is not limited to one direction. Only the superior/inferior displacement seemed significant for high pressure, which was not needed to obtain good image quality with our bladder filling protocol. The total uncertainty is conservatively estimated to be 4 mm. Conclusions: The uncertainty of the 3D USIGRT system is comparable to the uncertainty of the current standard IGRT for prostate: electronic portal imager in combination with fiducial markers.

The electrical response of the central nervous system to an auditory stimulus is called an Auditory Evoked Potential (AEP), it can be extracted from the electroencephalogram (EEG) by averaging a large number of epochs of the EEG that are time-locked to the auditory stimuli. There are strong indications that information on anesthetic depth is reflected in certain features of AEPs; the location as well as the amplitude of characteristic peaks in AEPs tend to change when the level of anesthetic depth changes [1][2]. Therefore, it is to be expected that AEPs can be used to serve in a monitor for anesthetic depth. The interpretation of AEPs and the extraction of these features is a task that is performed off-line by human experts who inspect the signals visually. If AEPs are to be used in an on-line monitor for anesthetic depth it is necessary that these features can be extracted automatically. Current research assesses the value of artificial neural networks for performing this task. The work described here concentrates on the recognition of one important peak, peak Pa, in AEPs.

CONTEXT: The rapid increase in multiresistant serotype 19A as a cause of invasive and respiratory pneumococcal disease has been associated in time with the widespread implementation of 7-valent pneumococcal conjugate vaccination (PCV-7) in several countries. Because spontaneous fluctuations in time and antibiotic selective pressure may have induced this serotype 19A increase, controlled studies are needed to assess the role of PCV-7. OBJECTIVE: To examine the association of PCV-7 vaccination and nasopharyngeal acquisition of serotype 19A pneumococci, their clonal distribution, and antibiotic susceptibility. Design, Setting, and PATIENTS: Post hoc per-protocol completer's analysis as part of a randomized controlled trial of nasopharyngeal Streptococcus pneumoniae carriage enrolling 1003 healthy newborns with follow-up to the age of 24 months in the Netherlands, which has low antibiotic resistance rates. The study was conducted before widespread PCV-7 implementation in infants, between July 7, 2005, and February 14, 2008. Nasopharyngeal swabs were obtained at the age of 6 weeks and at 6, 12, 18, and 24 months. INTERVENTION: Infants were randomly assigned to receive 2 doses of PCV-7 at 2 and 4 months; 2 + 1 doses of PCV-7 at 2, 4, and 11 months; or no dosage (unvaccinated control group). MAIN OUTCOME MEASURE: Cumulative proportion of children with nasopharyngeal acquisition of a new serotype 19A strain from 6 through 24 months of age. RESULTS: Nine hundred forty-eight children completed the study. Fifty-four nasopharyngeal serotype 19A carriage isolates from 318 in the 2-dose group, 66 isolates from 327 in the 2 + 1-dose group, and 33 isolates from 303 in the unvaccinated were collected from 6 weeks through 24 months. The cumulative proportion who tested positive for new nasopharyngeal serotype 19A acquisition from 6 through 24 months of age was significantly higher in those having received the 2 + 1-dose PCV-7 schedule (16.2%; 95% confidence interval [CI], 12.6%-20.6%) vs those who were unvaccinated (9.2%; 95% CI, 6.5%-13.0%; relative risk [RR], 1.75; 95% CI, 1.14-2.70) but not after a 2-dose schedule (13.2%; 95% CI, 9.9%-17.4%; RR, 1.43; 95% CI, 0.91-2.25). There were 28 different sequence types identified, including 6 new types. The proportion of children with new 19A acquisition who had used antibiotics in the last 6 months (18.7%) did not differ among groups. Five isolates were penicillin-intermediate susceptible and another 3 were nonsusceptible to erythromycin and azithromycin, all in the vaccine groups. CONCLUSION: A 2 + 1-dose PCV-7 schedule was associated with an increase in serotype 19A nasopharyngeal acquisition compared with unvaccinated controls. Trial Registration clinicaltrials.gov Identifier: NCT00189020

AIM: To investigate the therapeutic effect of Schistosoma mansoni (S. mansoni) soluble worm proteins on gastrointestinal motility disturbances during experimental colitis in mice. METHODS: Colitis was induced by intrarectal injection of trinitrobenzene sulphate (TNBS) and 6 h later, mice were treated ip with S. mansoni proteins. Experiments were performed 5 d after TNBS injection. Inflammation was quantified using validated inflammation parameters. Gastric emptying and geometric center were measured to assess in vivo gastrointestinal motility. Peristaltic activity of distal colonic segments was studied in vitro using a modified Trendelenburg set-up. Cytokine profiles of T-lymphocytes isolated from the colon were determined by real time reverse transcriptase-polymerase chain reaction. RESULTS: Intracolonic injection of TNBS caused severe colitis. Treatment with S. mansoni proteins significantly ameliorated colonic inflammation after 5 d. TNBS did not affect gastric emptying but significantly decreased the geometric center and impaired colonic peristaltic activity 5 d after the induction of colitis. Treatment with S. mansoni proteins ameliorated these in vivo and in vitro motility disturbances. In addition, TNBS injection caused a downregulation of effector T cell cytokines after 5 d, whereas a S. mansoni protein effect was no longer observed at this time point. CONCLUSION: Treatment with S. mansoni proteins attenuated intestinal inflammation and ameliorated motility disturbances during murine experimental colitis.

Fall accidents among elderly are costly for the society. Gait and balance are reported to reflect best the risk of falling. We recorded gait and balance properties of 15 patients with neurological disease, 20 elderly and 19 young adults. During the Berg Balance Scale test and walk test we collected kinetic data with wearable 3D accelerometers. Results showed significant differences between different subject groups in features calculated from the accelerometer signals. We found that accelerometer signals collected during the walk test could be used to discriminate between subject groups divided according to their Berg Balance Scale score.

Zusammenfassung Der Einflus von Kationen-Anionen (Im)Balancen beim Mastkalb 96 rotweise mannliche Mastkalber erhielten nach 2-wochiger Futterung mit einem Starterfutter 5 verschiedene Rationen. Dabei wurden zu einer Kontrolldiat NaHCO3 (1,15%), KHCO3 (1,36%), (NH4)2SO4 (0,86%) oder NH4Cl (0,73%) zugesetzt. Die [Na + K] - [Cl-SO4]-Bilanz betrug in den Rationen –10, –11, +20, +19 meq/100 g im Vergleich zur Kontrolldiat mit +5 meq/100 g. Der Zusatz von NaHCO3 oder KHCO3 fuhrte in beiden Fallen zu ahnlich geringeren taglichen Zunahmen und schlechterer Futterverwertung (P < 0,05) im Vergleich zu den Tieren, die die Kontrollrationen erhielten. Beim Zusatz von NH4Cl traten geringere Gewichtszunahmen auf (P < 0,05) und bei (NH.4)2SO4 mittlere Ergebnisse. Dies war etwa 8 Wochen nach Versuchsbeginn zu beobachten. Die Supplementation mit NH4Cl fuhrte nach 17 Versuchswochen zu einem niedrigeren pH-Wert, Basen-Uberschus und HCO-Gehalt (P < 0,05) im Blut im Vergleich mit den Kontrolltieren. Der Zusatz von NaHCO3 oder KHCO3 fuhrte zu keiner Veranderung des Sauren-Basen-Verhaltnisses (P < 0,05) im Blut, so das zwischen NaHCO3 und KHCO3 keine Unterschiede beobachtet wurden. Dagegen scheinen Cl-Ionen die Homeostase starker zu beeinflussen als SO4-Ionen.

Purpose: To improve the specificity in prostate cancer diagnosis and to prevent unnecessary prostate biopsies, especially in the serum prostate-specific antigen (PSA) ''gray zone'' between 3 and 15 ng/mL, the implementation of prostate cancer ^ specific markers is urgently needed. The recently discovered prostate cancer antigen 3 (PCA3) is such a promising prostate cancer marker. In a previous single institution study, the PCA3 urine test clearly proved to be of diagnostic value.Therefore, the diagnostic performance of the PCA3 urine test was validated in a multicenter study. Experimental Design:The first voided urine after digital rectal examination was collected from a total of 583 men with serum PSA levels between 3 and 15 ng/mL who were to undergo prostate biopsies. We determined the PCA3 score in these samples and correlated the results with the results of the prostate biopsies. Results: A total of 534 men (92%) had an informative sample. The area under the receiver- operating characteristic curve, a measure of the diagnostic accuracy of a test, was 0.66 for the PCA3 urine test and 0.57 for serum PSA. The sensitivity for the PCA3 urine test was 65%, the specificity was 66% (versus 47% for serum PSA), and the negative predictive value was 80%. Conclusions: In this multicenter study, we validated the diagnostic performance of the PCA3 urine test in the largest group studied thus far using a PCA3 gene-based test. This study shows that the PCA3 urine test, when used as a reflex test, can improve the specificity in prostate cancer diagnosis and could prevent many unnecessary prostate biopsies.

Monocyte adhesion to and transmigration across the endothelium are essential steps in atherogenesis. We have shown that the adhesive interactions between monocytes and the activated endothelium are increased when platelets bind to the monocyte surface and form platelet-monocyte complexes (PMC). PMC formation is dependent on interactions between platelet-displayed P-selectin and PSGL-1 on the monocyte surface. To better understand the effect of platelet binding on the capacity of monocytes to adhere to activated endothelium the P-selectin-PSGL-1 interaction - induced changes in integrin functionality were studied. The binding of platelets to monocytes via P-selectin-PSGL-1 interactions was shown to increase expression and activity of α4 beta;1 - and αM β2 - integrins which, resulted in increased monocyte adhesion to ICAM-1, VCAM-1, fibronectin and subsequently to stimulated endothelial cells. Platelet binding also induced monocyte migration (up to a 3-fold increase), compared to monocytes without platelets on their surface. To investigate the role of platelets in this process we determined the fate of platelets (within the PMC) during monocyte transendothelial migration. After forming PMC by mixing freshly isolated and fluorescently labeled platelets and monocytes, PMC were seeded on endothelial cells cultured on top of a fibrin gel. The cells were allowed to migrate across the endothelial layer into the gel where afterwards the position of platelets and monocytes was analyzed by confocal laser scanning microscopy. We found that the platelets were retained at the endothelium, suggesting that they detach from the PMC and are left behind on the endothelial layer upon monocyte transendothelial migration. In line with this we observed that the monocytes that were in the fibrin gel, underneath the endothelial layer, did not carry any platelets. This was confirmed by PMC migration over endothelial layered transwell filters since almost only monocytes were found in the lower compartment after migration. After testing different migration barriers, platelets seem to be shed from the monocyte surface upon monocyte migration by mechanical stress rather than only endothelial interaction. Our data suggest that monocytes bound to platelets are in a higher state of activation and have an increased atherogenic capacity. Furthermore, platelets seem to mainly play a role in the monocyte recruitment to the endothelium because once the monocytes cross the endothelial layer, platelets detach from their surface. Altogether, our findings, by showing that PMC have a strong atherogenic capacity, might be helpful in finding new therapeutic ways to prevent atherosclerosis and inflammation.