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A population-based survey of invasive pneumococcal disease (IPD) was conducted among adults in North-Rhine Westphalia, Germany. The study included 202 of the 386 hospitals in the region, together with the 27 microbiological laboratories that submitted reports of IPD in these hospitals to the National Reference Centre for Streptococci. The reports of 16 laboratories were comprehensively reviewed. Most (95.8%) IPD isolates were susceptible to penicillin G, but 14.5% were resistant to clarithromycin. Serotypes 14 (15.6%), 3 (9.3%), 4 (7.1%) and 7F (7.9%) were the most common. The serotype coverage of the 23-valent pneumococcal polysaccharide vaccine was 80.8%. During 2001–2003, the annual incidence of IPD, after correcting for laboratory and hospital under-reporting, was 16.2/100 000 in individuals aged >65 years. In three university hospitals, blood cultures were obtained for only 37% of patients with community-acquired pneumonia, and fewer than one-third of such cultures were obtained in one hospital before antibiotics were prescribed, suggesting that the true incidence of IPD was closer to 50/100 000.

The SPIRIT complex onboard the CORONAS-F satellite has routinely imaged the Sun in the 171, 175, 195, 284, and 304 A spectral bands since August 2001. The complex incorporates two telescopes. The Ritchey-Chretien telescope operates in the 171, 195, 284, and 304 A bands and has an objective similar to that of the SOHO/EIT instrument. The Herschel telescope obtains solar images synchronously in the 175 and 304 A bands with two multilayer-coated parabolic mirrors. The SPIRIT program includes synoptic observations, studies of the dynamics of various structures on the solar disk and in the corona up to 5 solar radii, and coordinated observations with other spaceborne and ground-based telescopes. In particular, in the period 2002–2003, synoptic observations with the SPIRIT Ritchey-Chretien telescope were coordinated with regular 6-hour SOHO/EIT observations. Since June 2003, when EIT data were temporarily absent (SOHO keyholes), the SPIRIT telescope has performed synoptic observations at a wavelength of 175 A. These data were used by the Solar Influence Data Analysis Center (SIDC) at the Royal Observatory of Belgium for an early space weather forecast. We analyze the photometric and spectral parameters of the SPIRIT and EIT instruments and compare the integrated (over the solar disk) EUV fluxes using solar images obtained with these instruments during the CORONAS-F flight from August 2001 through December 2003.

Since January 1981, the Royal Observatory of Belgium (ROB) has operated the Sunspot Index Data Center (SIDC), the World Data Center for the Sunspot Index. From 2000, the SIDC obtained the status of Regional Warning Center (RWC) of the International Space Environment Service (ISES) and became the “Solar Influences Data analysis Center”. As a data analysis service of the Federation of Astronomical and Geophysical data analysis Services (FAGS), the SIDC collects monthly observations from worldwide stations in order to calculate the International Sunspot Number, R i . The center broadcasts the daily, monthly, yearly sunspot numbers, with middle-range predictions (up to 12 months). Since August 1992, hemispheric sunspot numbers are also provided.

Recent studies have made a distinction between short-term storage capacities for phonological information and short-term storage capacities for lexico-semantic information (R. Martin, Lesch,Bartha, 1999). In this multiple case study, we tried to provide further evidence for the dissociability of phonological and lexico-semantic short-term memory (STM) components, by studying verbal STM in three patients who had recovered from Landau-Kleffner syndrome. Furthermore, we explored to what extent apparent dissociations between phonological and lexico-semantic STM could be related to underlying phonological and lexico-semantic processing impairments. We found clear dissociations between phonological and lexico-semantic STM measures in patients TG, JPH, and DC, whose performance was impaired in nonword immediate serial recall and in a rhyme probe task, while performance was normal for a category probe task. These patients also presented reduced phonological effects (word length, phonological similarity, phonotactic frequency) but normal lexico-semantic effects (lexicality, word imageability, word frequency) in STM. Moreover, there were no systematic correspondencies between phonological and lexico-semantic STM and phonological and lexico-semantic processing impairments. Implications for current models of STM and language processing are discussed.

Resume II a ete fortement suggere qu'une des fonctions importantes des lobes frontaux serait la capacite d'inhibition. Cependant, une revue de la litterature concernant les tests classiques d'inhibition (test de Stroop, WCST, apprentissage AB-AC) suggere que cette proposition n'est pas encore clairement etablie. Nous avons re-examine cette hypothese au moyen de tâches d'oubli dirige a court et a long terme ( Reed, 1970 , Zacks et al., 1996 ), du test de Stroop et du test de Hayling ( Burgess et Shallice, 1996 ) chez 13 patients avec lesions frontales focalisees. Les resultats ont montre des deficits de memoire a court et a long terme et un ralentissement chez les patients frontaux, mais pas de deficit d'inhibition. Ces resultats mettent en question la pertinence de l'hypothese des lobes frontaux comme etant l'unique substrat des mecanismes d'inhibition. Plus globalement, ils soulevent le probleme des fonctions executives : sont-elles soutenues par le cortex frontal ou plutot par un reseau cortico-sous-cortical diffus ?

Resume Un nombre croissant d’etudes ont demontre l’efficacite de differentes interventions neuropsychologiques chez les patients presentant une maladie d’Alzheimer a un stade precoce. Il existe egalement des donnees encourageantes suggerant que ces interventions peuvent etre incorporees dans l’environnement quotidien du patient, disseminees dans une variete de contextes cliniques, et utilisees par differents types de professionnels. La revalidation neuropsychologique devrait etre directement centree sur les situations de la vie quotidienne et elle devrait considerer les patients Alzheimer comme des participants responsables capables de mettre eux-memes en place les moyens d’optimisation, d’exprimer leurs besoins et preferences, et de prendre des decisions relatives aux interventions.

ResumenLos años recientes han visto un interés creciente en la experiencia alucinatoria, incluidas investigaciones de su prevalencia fenomenológica y carácter tanto en poblaciones patológicas como normales (predispuestas). Investigamos la multidimensionalidad de las experiencias alucinatorias en 265 sujetos de la población normal que rellenaron una versión modificada de la Escala de Alucinaciones de Launay-Slade. Se realizó análisis de componentes principales sobre los datos. Se obtuvieron cuatro factores que saturaban en elementos que reflejaban (1) experiencias alucinatorias relacionadas con el sueño, (2) ensoñaciones diurnas vividas, (3) pensamientos intrusos o carácter real del pensamiento y (4) alucinaciones auditivas. Los resultados ofrecen nuevos datos de la multidimensionalidad de la disposición alucinatoria en la población normal. Se analizan direcciones para investigaciones futuras en la predisposición alucinatoria.

OBJECTIVE: To determine whether the use of prophylactic antibiotics is effective in the prevention of postoperative wound infection after Lichtenstein open mesh inguinal hernia repair.SUMMARY BACKGROUND DATA: A recent Cochrane meta-analysis (2003) concluded that "antibiotic prophylaxis for elective inguinal hernia repair cannot be firmly recommended or discarded."METHODS: Patients with a primary inguinal hernia scheduled for Lichtenstein repair were randomized to a preoperative single dose of 1.5 g intravenous cephalosporin or a placebo. Patients with recurrent hernias, immunosuppressive diseases, or allergies for the given antibiotic were excluded. Infection was defined using the Centers for Disease Control and Prevention criteria.RESULTS: We included 1040 patients in the study between November 1998 and May 2003. According to the intention-to-treat principle, 1008 patients were analyzed. There were 8 infections (1.6%) in the antibiotic prophylaxis group and 9 (1.8%) in the placebo group (P = 0.82). There was 1 deep infection in the antibiotic prophylaxis group and 2 in the placebo group (P = 0.57). Statistical analysis showed an absolute risk reduction of 0.19% (95% confidence interval, -1.78%-1.40%) and a number needed to treat of 520 for the total number of infections. For deep infection, the absolute risk reduction is 0.20% (95% confidence interval, -0.87%-0.48%) with a number needed to treat of 508.CONCLUSIONS: A low percentage (1.7%) of wound infection after Lichtenstein open mesh inguinal (primary) hernia repair was found, and there was no difference between the antibiotic prophylaxis or placebo group. The results show that, in Lichtenstein inguinal primary hernia repair, antibiotic prophylaxis is not indicated in low-risk patients.

The G(12) type of heterotrimeric G-proteins play an important role in development and behave as potent oncogenes in cultured cells. However, little is known about the molecular nature of the components that act in the G(12)-signaling pathway in an organism. We characterized a C. elegans Galpha subunit gene, gpa-12, which is a homolog of mammalian G(12)/G(13)alpha, and found that animals defective in gpa-12 are viable. Expression of activated GPA-12 (G(12)QL) results in a developmental growth arrest caused by a feeding behavior defect that is due to a dramatic reduction in pharyngeal pumping. To elucidate the molecular nature of the signaling pathways in which G(12) participates, we screened for suppressors of the G(12)QL phenotype. We isolated 50 suppressors that contain mutations in tpa-1, which encodes two protein kinase C isoforms, TPA-1A and TPA-1B, most similar to PKCtheta/delta. TPA-1 mediates the action of the tumor promoter PMA. Expression of G(12)QL and treatment of wild-type animals with PMA induce an identical growth arrest caused by inhibition of larval feeding, which is dependent on TPA-1A and TPA-1B function. These results suggest that TPA-1 is a downstream target of both G(12) signaling and PMA in modulating feeding and growth in C. elegans. Taken together, our findings provide a potential molecular mechanism for the transforming capability of G(12) proteins.

A coronal heating model is proposed which predicts heating by a series of discrete events of various energies, analogous to the observed range of events from large scale flares through various transient brightening phenomena down to the often discussed "nanoflares". We suggest that an energy release event occurs when a field becomes linearly unstable to ideal MHD modes, with dissipation during the nonlinear phase of such an instability due to reconnection in fine-scale structures such as current sheets. The energy release during this complex dynamic period can be evaluated by assuming the field relaxes to a minimum energy state subject to the constraint of helicity conservation. A model problem is studied: a cylindrical coronal loop, with a current profile generated by slow twisting of the photospheric footpoints parameterised by two values of α (the ratio of current density to field strength). Different initial α profiles, corresponding to different footpoint twisting profiles, lead to energy release events of a wide range of magnitudes, but our model predicts an observationally realistic minimum size for these events.

Whole-Body vibration (WBV) may lead to muscle contractions via reflex activation of the primary muscle spindle (Ia) fibres. WBV has been reported to increase muscle power in the short term by improved muscle activation. The present study set out to investi- gate the acute effects of a standard WBV training session on voluntary activation during maximal isometric force production (MVC) and maximal rate of force rise (MRFR) of the knee extensors. Twelve students under- went a single standard WBV training session: 5·1 min vibration (frequency 30 Hz, amplitude 8 mm) with 2 min rest in between. During vibration, subjects stood barefoot on the vibration platform with their knees at an angle of 110� . At 90 s following vibration, maximal voluntary knee extensor force was reduced to 93 (5)% (mean (SD), P

This paper reviews the growing amount of evidence supporting the hypothesis that Alzheimer's disease includes a disconnection syndrome. This evidence came mainly from neuropathological, electrophysiological, and neuroimaging studies. Moreover, a few recent neuropsychological studies have also explored the effects of a disconnection between cerebral areas on cognitive functioning. Finally, and more generally, the contribution of this interpretation to the understanding of Alzheimer's disease cognitive deficits is considered.

The aim of this study was to develop an image processing and analysis program for peri-implant bone density measurements of the mandible using extraoral radiographs, which includes a correction for the variable projection of the soft tissues of the face. The measurement procedure is based on pairs of reference and follow-up extraoral oblique lateral cephalometric radiographs (OLCRs) of patients with endosseous implants in the anterior part of the atrophic edentulous mandible. The procedure consists of image acquisition, correction for radiographic variation using an aluminium wedge (i.e. film exposure and development) and transformation of the grey values into aluminium-equivalent values. After correction for variation in the projection of the soft tissues of the face using internal calibration fields, the actual peri-implant bone density measurements are performed. The soft tissue projection correction significantly reduces the variation between radiographs owing to the position of the soft tissues. It is concluded that the described image processing and analysis program, in combination with extraorally made OLCRs, is a valuable technique for measurement of peri-implant bone density changes of the mandible. With minor adaptations, the program can be used for other semi-edentulous patients

To identify novel components in heterotrimeric G-protein signalling, we performed an extensive screen for proteins interacting withCaenorhabditis elegansGα subunits. The genome ofC. eleganscontains homologues of each of the four mammalian classes of Gα subunits (Gs, Gi/o, Gq and G12), and 17 other Gα subunits. We tested 19 of the GGα subunits and four constitutively activated Gα subunits in a largescale yeast two-hybrid experiment. This resulted in the identification of 24 clones, representing 11 different proteins that interact with four different Gα subunits. This set includesC. elegansorthologues of known interactors of Gα subunits, such as AGS3 (LGN/PINS), CalNuc and Rap1Gap, but also novel proteins, including two members of the nuclear receptor super family and a homologue of human haspin (germ cell-specific kinase). All interactions were found to be unique for a specific Gα subunit but variable for the activation status of the Gα subunit. We used expression pattern and RNA interference analysis of the G-protein interactors in an attempt to substantiate the biological relevance of the observed interactions. Furthermore, by means of a membrane recruitment assay, we found evidence that GPA-7 and the nuclear receptor NHR-22 can interact in the animal.

Animals dramatically modify their chemosensory behaviors when starved, which could allow them to alter and optimize their food-search strategies. Dynamic changes in the gene expression of chemoreceptors may be a general mechanism underlying food and state-dependent changes in chemosensory behaviors. In our recent study,(1) we identified chemoreceptors in the ADL sensory neuron type of C. elegans that are modulated by feeding state and food availability. Here, we highllight our recent findings by which sensory inputs into ADL, neuronal outputs from ADL, and circuit inputs from the RMG interneuron, which is electrically connected to ADL, are required to regulate an ADL-expressed chemoreceptor. This sensory and circuit-mediated regulation of chemoreceptor gene expression is dependent on cell-autonomous pathways acting in ADL, e.g. KIN-29, DAF-2, OCR-2 and calcium signaling, and circuit inputs from RMG mediated by NPR-1. Based on these findings, we propose an intriguing but speculative feedback modulatory circuit mechanism by which sensory perception of food and internal state signals may be coupled to regulate ADL-expressed chemoreceptors, which may allow animals to precisely regulate and fine-tune their chemosensory neuron responses as a function of feeding state.

Background Locomotor activity is used extensively as a behavioral output to study the underpinnings of circadian rhythms. Recent studies have required a populational approach for the study of circadian rhythmicity in Caenorhabditis elegans locomotion. New method We describe an imaging system for long-term automated recording and analysis of locomotion data of multiple free-crawling C. elegans animals on the surface of an agar plate. We devised image analysis tools for measuring specific features related to movement and shape to identify circadian patterns. Results We demonstrate the utility of our system by quantifying circadian locomotor rhythms in wild-type and mutant animals induced by temperature cycles. We show that 13 °C:18 °C (12:12 h) cycles are sufficient to entrain locomotor activity of wild-type animals, which persist but are rapidly damped during 13 °C free-running conditions. Animals with mutations in tax-2 , a cyclic nucleotide-gated (CNG) ion channel, significantly reduce locomotor activity during entrainment and free-running. Comparison with existing method(s) Current methods for measuring circadian locomotor activity is generally restricted to recording individual swimming animals of C. elegans , which is a distinct form of locomotion from crawling behavior generally observed in the laboratory. Our system works well with up to 20 crawling adult animals, and allows for a detailed analysis of locomotor activity over long periods of time. Conclusions Our population-based approach provides a powerful tool for quantification of circadian rhythmicity of C. elegans locomotion, and could allow for a screening system of candidate circadian genes in this model organism.

Background/Introduction: Psychological distress occurs frequently in patients with cancer. Psychological distress includes mild and severe forms of both anxious and depressive mood states. Literature indicates that effective management of psychological distress seems to require targeted selection of patients (T), followed by enhanced care (E), and the application of evidence based interventions. Besides, it is hypothesized that delivering care according to the stepped care (S) approach results in an affordable program. The aim of the current study is to evaluate the (cost)-effectiveness of the TES program compared to usual care in reducing psychological distress in patients with metastatic colorectal cancer (mCRC). Methods: This study is designed as a cluster randomized trial with 2 treatment arms: TES program for screening and treatment of psychological distress versus usual care. Sixteen hospitals participate in this study, recruiting patients with mCRC. Outcomes are evaluated at the beginning of chemotherapy and after 3, 10, 24, and 48 weeks. Primary outcome is the difference in treatment effect over time in psychological distress, assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes include quality of life, patient evaluation of care, recognition and management of psychological distress, and societal costs. Discussion: We created optimal conditions for an effective screening and treatment program for psychological distress in patients with mCRC. This involves targeted selection of patients, followed by enhanced and stepped care. Our approach will be thoroughly evaluated in this study. We expect that our results will contribute to the continuing debate on the (cost-) effectiveness of screening for and treatment of psychological distress in patients with cancer. Trial Registration: This trial is registered in the Netherlands Trial Register NTR4034.

This article discusses the emergence of the concept of the working class in Western Europe during the nineteenth century; the classical patterns of interpretation (structural, agency-focused, and combinations of these two approaches); the rise of ‘peripheral’ working classes, their historiography, and their conceptual implications; and the new insights offered by Third World historians for the analysis of advanced countries.

Models of the ideal magnetohydrodynamic (MHD) stability of spheromaks and spherical tokamaks are presented, including the effects of current on the open flux which plays a key role in helicity-injected current drive. The stability of spheromak equilibria with both open and closed flux and realistic current profiles representative of helicity-injected state is investigated, where a kink instability in the open flux is shown to dominate a tilt mode in the closed flux as the open flux current density is increased. A previous one-dimensional model is extended to more realistic two-dimensional equilibria which properly incorporate a region of closed magnetic flux as well as open flux penetrating the boundaries at electrodes. A new stability code SCOTS has been developed and benchmarked which can determine the growth rates of ideal MHD modes in this geometry. The coordinate system for this code has been developed such that it extends smoothly across the separatrix between closed and open flux, thus not imposing...

Lexicality and phonotactic frequency effects are observed in many cognitive studies on language processing, but little is known about their underlying neural substrates, especially with regard to phonotactic frequency effects. Here, we conducted a positron emission tomography (PET) study in which 11 right-handed volunteers had either to repeat or to listen to lists of words, high phonotactic frequency nonwords, and low phonotactic frequency nonwords. The comparison of word versus nonword processing consistently confirmed previous findings of left temporal and prefrontal activations classically ascribed to lexicosemantic processing. Higher activation was found in the right posterior superior temporal gyrus when comparing high phonotactic frequency nonwords to words, but not when comparing low phonotactic frequency nonwords to words. We propose that this region is implicated in the formation of temporary phonological representations for high-probability phonological events, which may support processing of high phonotactic frequency nonwords.

Since 1981, the Royal Observatory of Belgium has operated the Sunspot Index Data Centre, the World Data Centre for the Sunspot Index. Recently, the Space Weather Forecast Centre of Paris–Meudon was transferred and added to the activities of the SIDC. Moreover, a complete archive of all images of the SOHO instrument EIT has become available at the SIDC. Given all these extensions, the new style SIDC has become a ‘Solar Influences Data Centre’ that analyses solar activity and provides services on three different time scales: 1. Fast warnings and real time monitoring . As the Regional Warning Centre (RWC) for Western Europe of the International Space Environment Service (ISES), the SIDC collects and redistributes solar, geomagnetic, and ionospheric data in Western Europe. Short-term predictions (3 days) and alerts are produced on a daily basis. 2. Forecasts and middle term analysis . The SIDC takes care of the calculation of a sunspot index, called the International Sunspot Number. We compute and broadcast the daily, monthly, yearly international sunspot numbers, with middle range predictions (up to 12 months). 3. Post-event analysis and long-term solar cycle analysis . Since the launch of SOHO, EIT offers a global view of the EUV corona over the whole rising phase of the solar activity cycle. Such a long-duration data series is unprecedented and allows the study of the evolution over the solar cycle of objects classes such as active regions, coronal holes, coronal mass ejections or flares.

203 Background: Radiotherapy (RT) is an effective treatment for painful bone metastases, although pain is not always sufficiently controlled. Pain management education may improve patient empowerment and, consequently, reduce pain intensity. The effect of nurse-led education (NLE) in patients undergoing RT for painful bone metastases was investigated as compared to care as usual (CAU). Primary endpoint was pain intensity at 12 weeks, secondary outcome was quality of life (QoL). Methods: In this multicentre, randomised phase 3 study, patients referred for short schedule RT, with uncontrolled pain (a score of ≥5 on a 0-10 numeric rating scale (NRS)), were randomised between NLE or CAU before start of RT. The NLE consisted of a structured interview including assessment of pain knowledge, verbal and written education on all aspects of pain and follow-up phone calls at 1, 4, 8 & 12 weeks to address pain-related questions. Patients in CAU received leaflets on RT, cancer pain and opioid use. Patient characteristics were assessed at baseline. Pain intensity and QoL were evaluated with the Brief Pain Inventory, EORTC QLQ-C15-PAL and EORTC QLQ-BM22 at baseline, and week 1, 4, 8 & 12. Power calculation showed that there were 89 patients per arm needed to detect a 10% difference in number of patients with a NRS < 5 at 12 weeks(1-sided α = 0.05; β 0.8). Results: Between May 2011-April 2016, 354 patients were randomised (176 NLE, 178 CAU), 38 were excluded (30 NRS < 5 at baseline, 7 no short schedule RT, 1 missing informed consent). At twelve weeks, 185 (NLE 95) had completed follow-up (72 stopped filling out questionnaires, 59 died prematurely). Baseline characteristics were similar in both groups; mean age 65 years, 56% men. At week 12, more patients in NLE than in CAU had controlled pain (NRS < 5; respectively 66% and 52%, p = 0.036). Moreover, patients in NLE reached faster a pain score < 5 than patients in CAU (31 versus 54 days respectively, p = 0.026). On all time points, no significant differences in QoL were found between both groups. Conclusions: Controlled pain, i.e. a pain intensity < 5, was reached faster and by more patients with painful bone metastases undergoing RT by the addition of nurse-led pain education. Clinical trial information: NCT01358539.

Using Positron Emission Tomography (PET), we investigated cerebral regions associated with the episodic recognition of words alone and words bound to contextual colours. Two modes of colour encoding were tested: incidental and intentional word-to-colour binding. Word-only recognition was associated with brain activation in a lexico-semantic left middle temporal region and in the cerebellum following an incidental colour encoding, and with brain activation in the left posterior middle frontal gyrus, right anterior cingulate and right inferior frontal gyrus following an intentional encoding. Recognition of bound features was associated with activation in left prefrontal and superior parietal regions following an incidental colour encoding, and with preferential right prefrontal cortex activation following an intentional colour encoding. Our results are in line with the hypothesis of a parietal involvement in context processing, and prefrontal areas in monitoring retrieval processes. Our results also support the hypothesis of a ‘cortical asymmetry for reflective activity’ (CARA).

SummaryAlthough many epidemiological studies have shown an association between hyperfibrinogenemia and atherosclerosis, it is not established whether elevated fibrinogen has an etiological role in the pathogenesis or is only a reflection of the ongoing disease.We have studied the contribution of fibrinogen to the development of atherosclerosis in atherosclerosis-prone ApoE*3-Leiden mice that have been cross-bred with transgenic mice overexpressing fibrinogen. Genetic compound offspring were used to evaluate the progression of atherosclerotic lesions after being fed an atherogenic diet for 7 weeks. It was observed that the lesion area of the plaques as well as the severity of the lesions in the aortic valve was comparable in control single transgenic ApoE*3-Leiden mice and in double transgenic apoE*3-Leiden mice overexpressing fibrinogen. No thrombus or fibrin deposition was observed in atherosclerotic lesions in either group of mice.These results indicate that elevated plasma fibrinogen concentrations in ApoE*3-Leiden transgenic mice do not affect the progression of diet-induced atherosclerotic lesions.

CD73 (5′-nucleotidase) expression has no prognostic value in children with acute lymphoblastic leukemia

Purpose We previously demonstrated that 48% of patients with pain at sites of previously irradiated bone metastases benefit from reirradiation. It is unknown whether alleviating pain also improves patient perception of quality of life (QOL). Patients and Methods We used the database of a randomized trial comparing radiation treatment dose fractionation schedules to evaluate whether response, determined using the International Consensus Endpoint (ICE) and Brief Pain Inventory pain score (BPI-PS), is associated with patient perception of benefit, as measured using the European Organisation for Resesarch and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and functional interference scale of the BPI (BPI-FI). Evaluable patients completed baseline and 2-month follow-up assessments. Results Among 850 randomly assigned patients, 528 were evaluable for response using the ICE and 605 using the BPI-PS. Using the ICE, 253 patients experienced a response and 275 did not. Responding patients had superior scores on all items of the BPI-FI (ie, general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life) and improved QOL, as determined by scores on the EORTC QLQ-C30 scales of physical, role, emotional and social functioning, global QOL, fatigue, pain, and appetite. Similar results were obtained using the BPI-PS; observed improvements were typically of lesser magnitude. Conclusion Patients responding to reirradiation of painful bone metastases experience superior QOL scores and less functional interference associated with pain. Patients should be offered re-treatment for painful bone metastases in the hope of reducing pain severity as well as improving QOL and pain interference.

Background Joint destruction is a hallmark of autoantibody-positive rheumatoid arthritis (RA), though the severity is highly variable between patients. The processes underlying these interindividual differences are incompletely understood. Methods We performed a genome-wide association study on the radiological progression rate in 384 autoantibody-positive patients with RA. In stage-II 1557 X-rays of 301 Dutch autoantibody-positive patients with RA were studied and in stage-III 861 X-rays of 742 North American autoantibody-positive patients with RA. Sperm-Associated Antigen 16 ( SPAG16) expression in RA synovium and fibroblast-like synoviocytes (FLS) was examined using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry. FLS secrete metalloproteinases that degrade cartilage and bone. SPAG16 genotypes were related to matrix metalloproteinase (MMP)-3 and MMP-1 expression by FLS in vitro and MMP-3 production ex vivo. Results A cluster of single nucleotide polymorphisms (SNPs) at 2q34, located at SPAG16 , associated with the radiological progression rate; rs7607479 reached genome-wide significance. A protective role of rs7607479 was replicated in European and North American patients with RA. Per minor allele, patients had a 0.78-fold (95% CI 0.67 to 0.91) progression rate over 7 years. mRNA and protein expression of SPAG16 in RA synovium and FLS was verified. FLS carrying the minor allele secreted less MMP-3 (p=1.60×10 −2 ). Furthermore, patients with RA carrying the minor allele had lower serum levels of MMP-3 (p=4.28×10 −2 ). In a multivariate analysis on rs7607479 and MMP-3, only MMP-3 associated with progression (p=2.77×10 −4 ), suggesting that the association between SPAG16 -rs7607479 and joint damage is mediated via an effect on MMP-3 secretion. Conclusions Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.

Feeding state and food availability can dramatically alter an animals' sensory response to chemicals in its environment. Dynamic changes in the expression of chemoreceptor genes may underlie some of these food and state-dependent changes in chemosensory behavior, but the mechanisms underlying these expression changes are unknown. Here, we identified a KIN-29 (SIK)-dependent chemoreceptor, srh-234, in C. elegans whose expression in the ADL sensory neuron type is regulated by integration of sensory and internal feeding state signals. We show that in addition to KIN-29, signaling is mediated by the DAF-2 insulin-like receptor, OCR-2 TRPV channel, and NPR-1 neuropeptide receptor. Cell-specific rescue experiments suggest that DAF-2 and OCR-2 act in ADL, while NPR-1 acts in the RMG interneurons. NPR-1-mediated regulation of srh-234 is dependent on gap-junctions, implying that circuit inputs regulate the expression of chemoreceptor genes in sensory neurons. Using physical and genetic manipulation of ADL neurons, we show that sensory inputs from food presence and ADL neural output regulate srh-234 expression. While KIN-29 and DAF-2 act primarily via the MEF-2 (MEF2) and DAF-16 (FOXO) transcription factors to regulate srh-234 expression in ADL neurons, OCR-2 and NPR-1 likely act via a calcium-dependent but MEF-2- and DAF-16-independent pathway. Together, our results suggest that sensory- and circuit-mediated regulation of chemoreceptor genes via multiple pathways may allow animals to precisely regulate and fine-tune their chemosensory responses as a function of internal and external conditions., Author Summary Animals dramatically modify their chemosensory behaviors to attractive and noxious chemical stimuli when starved. This could allow them to alter and optimize their food-search strategies to increase their survival and reproduction. Changes in the gene expression of chemoreceptors specialized in detecting environmental stimuli is observed in fish, insects and nematodes, and may be a general mechanism underlying the changes in chemosensory behaviors observed in starved animals. To elucidate this mechanism, we have developed an in vivo reporter assay in C. elegans for monitoring the expression of a candidate chemoreceptor gene in a single sensory neuron type, called ADL, as a function of feeding state. Using this reporter assay, we show that sensory inputs into ADL and neural outputs from ADL, as well as inputs from the RMG interneuron, which is electrically connected to ADL, are required to fine-tune expression of chemoreceptor genes in ADL. Sensory and circuit-mediated regulation of chemoreceptor gene expression is dependent on multiple pathways, including the neuropeptide receptor, NPR-1, and the DAF-2 insulin-like receptor. Our results reveal mechanisms underlying chemoreceptor gene expression, and provide insight into how expression changes in chemoreceptor genes may contribute to changes in chemosensory behavior as a function of feeding state.

The objectives of this study were to assess the current incidence of invasive pneumococcal disease (IPD) in Poland (2011-2013), where mass vaccination has not been implemented, and to characterize the Streptococcus pneumoniae isolates responsible for invasive infections by determining their serotype distribution and antimicrobial resistance patterns. For all isolates identification, serotyping and antimicrobial minimal inhibitory concentrations determination were performed based on routine techniques. The highest incidence rates were observed among adults older than 85 years old (4.62/100,000) and children under 1 year of age (4.28/100,000). The general case fatality ratio (CFR) was 25.4%, with the highest CFR in the age group ≥85 years old (59.7%). The most common serotypes were 3, 14, 19A, 4, 9V, 19F, 1, and 23 F (61.3% of all isolates). The 10- and 13-valent pneumococcal conjugated vaccines (PCV) covered 46.0 and 71.8% of all IPD cases, 61.4 and 79.5% of cases in children under two years, and 60.4 and 78.6% of cases involving children under five years of age, respectively. The PCV13 and 23-valent polysaccharide vaccine covered 68.7 and 86.0% of cases in adults >65 years old, respectively. Decreased susceptibility was noted for penicillin (24.8%), cefotaxime (10.0%), meropenem (5.0%), rifampicin (0.8%), chloramphenicol (4.3%), erythromycin (29.7%) and clindamycin (25.6%). Multi-drug resistance characterized 21.6% of the pneumococci tested. Despite deficiencies in the Polish surveillance system and strong underestimation of IPD cases, results of the study showed good theoretical coverage of PCV, which should encourage inclusion of anti-pneumococcal conjugate vaccine into the national immunization program.

Pneumococci remain a major cause of bacterial pneumonia, sepsis and meningitis globally.The German National Reference Center for Streptococci at the Institute for Medical Microbiology of the University Hospital RWTH Aachen, Germany, has carried out surveillance studies on invasive pneumococcal disease (IPD) since 1992. This report is based on IPD-cases from adults and children, received between July 1992 and June 2013 and July 1997 and June 2013 respectively.From 1997-2006 the proportion of infections among children ≤ 23 months of age with serotypes included in the 7-valent vaccine was about 65%. Since the start of childhood vaccination in 2006 the percentage has continuously decreased, reaching5% in 2012 /2013. Also among adults, for whom conjugate vaccination was not indicated, this percentage decreased from 40-45% in 1992-2006 to about 8% in 2012 /2013. This phenomenon is denoted as herd protection. The resistance rate against Penicillin G remained under 4% among children and under 2.5% among adults over the whole study period. Since 2005 /2006 macrolide resistance levels have decreased to about 5% among children and 8% among adults.The continuous decrease of vaccine serotypes as well as the decreasing IPD incidence since the beginning of childhood vaccination document the success of pneumococcal conjugate vaccination.

Disturbances in eruption and related problems are quite common in permanent dentition but rare in deciduous dentition. For the timely recognition of disturbances in eruption, knowledge of the normal development of dentition is essential. Disturbances in eruption comprise disturbances in which eruption does not occur at all, in which it is delayed or incomplete, or in which the normal direction of eruption is influenced. If identified early enough, many undesirable dental conditions can be avoided or their seriousness can be limited. A possible impacting of permanent cuspids, for example, can be avoided by extracting the deciduous cuspids at the right moment; in cases of a large overjet or the threat of a cover-bite, lip interference can be prevented.

Infections due to pneumococci especially in the elderly are vastly underestimated, e.g., because non-invasive infections such as pneumonia may appear with only few symptoms. Sequential vaccination with the pneumococcal conjugate vaccine PCV13, followed by the 23-valent polysaccharide vaccine, is considered as the best preventive measure for individual protection, even though clinical study data demonstrating the efficacy of this sequence are not yet available. Increase of "awareness" by use of computer-based reminder functions may result in a significant improvement of vaccination compliance.

Background Radiotherapy has a good effect in palliation of painful bone metastases, with a pain response rate of more than 60%. However, shortly after treatment, in approximately 40% of patients a temporary pain flare occurs, which is defined as a two-point increase of the worst pain score on an 11-point rating scale compared to baseline, without a decrease in analgesic intake, or a 25% increase in analgesic intake without a decrease in worst pain score, compared to baseline. A pain flare has a negative impact on daily functioning and mood of patients. It is thought to be caused by periostial edema after radiotherapy. Dexamethasone might diminish this edema and thereby reduce the incidence of pain flare. Two non-randomized studies suggest that dexamethasone reduces the incidence of a pain flare by 50%. The aim of this trial is to study the effectiveness of dexamethasone to prevent a pain flare after palliative radiotherapy for painful bone metastases and to determine the optimal dose schedule. Methods and design This study is a three-armed, double-blind, placebo-controlled multicenter trial. We aim to include 411 patients with uncomplicated painful bone metastases from any type of primary solid tumor who receive short schedule radiotherapy (all conventional treatment schedules from one to six fractions). Arm 1 consists of daily placebo for four days, arm 2 starts with 8 mg dexamethasone before the (first) radiotherapy and three days placebo thereafter. Arm 3 consists of four days 8 mg dexamethasone. The primary endpoint is the occurrence of a pain flare. Secondary endpoints are pain, quality of life and side-effects of dexamethasone versus placebo. Patients complete a questionnaire (Brief Pain Inventory with two added questions about side-effects of medication, the EORTC QLQ-C15-PAL and QLQ-BM22 for quality of life) at baseline, daily for two weeks and lastly at four weeks. Discussion This study will show whether dexamethasone is effective in preventing a pain flare after palliative radiotherapy for painful bone metastases and, if so, to determine the optimal dose. Trial registration This study is registered at ClinicalTrials.gov: NCT01669499

Objective : To investigate the neural and cognitive bases of upper limb apraxia in corticobasal degeneration (CBD). Methods : Eighteen patients with CBD underwent a cognitive neuropsychological assessment of apraxia and resting [ 18 F]-fluorodeoxyglucose PET scanning. Two complementary measures of apraxia were computed for each modality of gesture production. First, a performance score measured error frequency during gesture execution. Second, as a more stringent test of the integrity of the praxis system, the correction score measured the patient’s ability to correct his or her errors on a second attempt. For each measure type, a cut-off score for the presence of apraxia was defined with regard to healthy controls. Using each cut-off score, the regional cerebral glucose metabolism of patients with CBD with apraxia (i.e., performing below cut-off score) was compared with that of patients with CBD without apraxia. Results : Mean performance scores were below normal values in all modalities. Anterior cingulate hypometabolism predominated in patients with CBD who performed below the cut-off performance score. At variance, mean correction scores were below normal values for gesture imitation only. Hypometabolism in superior parietal lobule and supplementary motor area characterized patients with CBD who were unable to correct their errors at the same rate as control subjects did. Conclusions : Distinct neural networks underlie distinct aspects of the upper limb apraxic deficits in CBD. Extending previous findings of gesture production deficits in CBD, the use of complementary measures of apraxic behavior discloses a visuoimitative upper limb apraxia in CBD, underlain by a metabolic decrease in a parietofrontal neural network.

One function of sleep is hypothesized to be the reprocessing and consolidation of memory traces (Smith, 1995; Gais et al., 2000; McGaugh, 2000; Stickgold et al., 2000). At the cellular level, neuronal reactivations during post-training sleep in animals have been observed in hippocampal (Wilson and McNaughton, 1994) and cortical (Amzica et al., 1997) neuronal populations. At the systems level, using positron emission tomography, we have recently shown that some brain areas reactivated during rapid-eye-movement sleep in human subjects previously trained on an implicit learning task (a serial reaction time task) (Maquet et al., 2000). These cortical reactivations, located in the left premotor area and bilateral cuneus, were thought to reflect the reprocessing--possibly the consolidation--of memory traces during post-training rapid-eye-movement sleep. Here, the experience-dependent functional connectivity of these brain regions is examined. It is shown that the left premotor cortex is functionally more correlated with the left posterior parietal cortex and bilateral pre-supplementary motor area during rapid-eye-movement sleep of subjects previously trained to the reaction time task compared to rapid-eye-movement sleep of untrained subjects. The increase in functional connectivity during post-training rapid-eye-movement sleep suggests that the brain areas reactivated during post-training rapid-eye-movement sleep participate in the optimization of the network that subtends subject's visuo-motor response. The optimization of this visuo-motor network during sleep could explain the gain in performance observed during the following day.

The results from numerical simulations carried out using a new shock-capturing, Lagrangian-remap, 3D MHD code, Lare3d are presented. We study the evolution of them = 1 kink mode instability in a photospherically line-tied coronal loop that has no net axial current. During the non-linear evolution of the kink instability, large current concentrations develop in the neighbourhood of the innite length mode rational surface. We investigate whether this strong current saturates at a nite value or whether scaling indicates current sheet formation. In particular, we consider the eect of the shear, dened by r 0 = where = LB=rBz is the eldline twist of the loop, on the current concentration. We also include a non-uniform resistivity in the simulations and observe the amount of free magnetic energy released by magnetic reconnection.

The land use of two districts in western Nepal was classified into forest and non-forest by satellite imagery with different topographical corrections. The accuracy of the forest biomass and timber volume estimates was also tested. The forest areas were interpretated correctly, with an accuracy of 82-88%. The best result was derived when the Minnaert constants of forest were separated from those of other land uses which were combined. The timber volume and biomass estimates were computed using the weighted nearest neighbour method. The coefficients of determination were 0.06 for timber volume and 0.09 for biomass. The use of the existing land use data seems to have potential for improving the results of topographic normalization. Because the reflectance in mountainous areas depends on many vegetative and terrain features, the simple non-Lambertian correction over broad categories did not significantly improve the results.

The present experiment investigates the ability of an amnesic patient (AC) to estimate three durations (5, 14 or 38 s) in two different temporal tasks (reproduction and production). In the reproduction task, AC and control subjects first had to encode one of the three durations and then to reproduce it. In the production task, they were asked to produce one of the three durations given in chronometric units. AC's performance showed a clear dissociation according to the tasks and the durations. His productions of the three durations and his reproductions of 5 s did not differ from those of the controls, whilst his reproductions of longer durations (14 and 38 s) were systematic underestimations. The results suggest that reproduction involves a long-term storage in episodic memory for durations exceeding the short-term memory capacity, whereas production of durations given in chronometric units involves semantic memory, which contains the representation of several durations, and working memory, whic...

The equations for the continuous subspectra of the linear magnetohydrodynamic (MHD) normal modes spectrum of two-dimensional (2D) plasmas are derived in general curvilinear coordinates, taking nonadiabatic effects in the energy equation into account. Previously published derivations of continuous spectra in the 2D ideal MHD case and in 1D nonadiabatic MHD are thus complemented with calculations for 2D nonadiabatic MHD spectra. The nonadiabatic MHD spectrum contains a thermal continuum in addition to the well-known Alfven and slow continua. These thermal continuum modes are exponentially decaying or growing in time. The latter unstable modes are widely accepted as an explanation for the onset of marfes in tokamaks and the most favored hypothesis for prominence formation in the solar corona. A numerical code has been developed to calculate the continuum modes. An investigation of a typical 'pre-MARFE' (multifaceted asymmetric vadiation from the edge) equilibrium is presented. (C) 2000 American Institute of Physics. [S1070-664X(00)03604-1].

A prospective study was performed to assess the predictive value of an ultrasonographic examination directly after a spontaneous birth at 16 to 28 weeks' gestation to exclude the possibility of retained placental tissue. The aim of this procedure is to prevent routine curettage, which can induce Asherman's syndrome, uterine perforation, and anesthetic complications. Over a 2 year period the clinical course in 64 women, who had been delivered of their infants at 16 to 28 weeks' gestation, was followed through 6 weeks post partum. Sonographic examination was performed within 30 min after delivery of the placenta independent of macroscopic judgment of completeness of placenta. The examination was classified into three categories (with subsequent clinical interpretation): sharp lining of echogenic uterine wall with translucent cavity (uterine cavity containing fluid blood), sharp lining of the wall with echogenic area in cavity not continuous with the wall (uterine cavity with blood clot), and irregular lining with echogenic area continuous with the uterine wall and extending into the cavity (uterine cavity containing retained placental tissue). Women with sharp uterine lining without (n = 32) or with (n = 7) echogenicity in the cavity had no direct operative removal of placental tissue; 3 underwent curettage at a later stage (17, 18, and 34 days, respectively). A direct digital removal of placenta or curettage was performed on 25 women who revealed echogenicity continuous with the uterine wall. The 25 of 28 operatively obtained tissues were examined microscopically for trophoblasts. The sensitivity of the sonographic examination to find retained placental tissue was 85% (17 of 20) at 95% confidence intervals of 62 to 97%, the specificity was 88% (36 of 41) at 95% confidence intervals of 74 to 96%, and there were 25% (5 of 20) false positive judgments and 8% (3 of 39) false negative judgments. The positive predictive value of ultrasonography to find retained placenta of 68% (17 of 22) at 95% confidence interval of 55 to 92% combined with the negative predictive value of 92% (36 of 39) is sufficient to strongly suggest that curettage should not be performed routinely in these pregnancies at high risk for retained placental tissue.

Oscillations with toroidal mode number n=1 are ubiquitous in helicity injected spheromaks and spherical tokamaks, and play a crucial role in current drive. It has been proposed that these arise from a current driven instability of the open flux tube. Stability calculations are presented to confirm this, and they are compared with experimental data from the Spheromak Experiment (SPHEX) [M. Rusbridge et al., Plasma Phys. Control. Fusion 39, 683 (1997)]. The equilibria are modelled as piece-wise constant μ profile force-free plasmas with different values for the μ in the open (μc) and closed (μa) flux regions. A stability map in μc,μa space is then calculated. The SPHEX experimental data is also reduced to the same space both as a culmination of direct single point measurements of μ and as a time history of the reconstructed equilibrium from a particular shot. The results show a favorable comparison of the stability map with experiment, both in magnitude and shape. The effect of inserting a central current-c...

The multistep model of leukocyte adhesion reveals that selectins mediate rolling interactions and that integrins mediate firm adhesion processes. In this study, the interaction between eosinophils and TNF-α-activated HUVEC (second or third passage) was studied under flow conditions (0.8 and 3.2 dynes/cm2). Especially the role of α4 integrins on eosinophils and E-selectin on HUVEC was studied. Inhibition of the integrin α4 chain on eosinophils reduced the number of firmly adhered resting eosinophils to TNF-α-stimulated endothelium by 43% whereas the percentage rolling cells increased 2.2-fold compared with untreated control eosinophils. Blocking of E-selectin on the endothelium reduced the number of adherent eosinophils by only 23% and 16%. In this situation, however, hardly any rolling adhesion was observed, and the few rolling cells showed a low rolling velocity. Blocking both α4 integrin on eosinophils and E-selectin on HUVEC reduced the number of adhered eosinophils by 95%. P-selectin did not significantly participate in eosinophil adhesion to TNF-α-activated HUVEC. Inhibition of both α4 integrins and β2 integrins on eosinophils resulted in a reduction of adhered cells by 65% and a 3-fold increase in percentage rolling cells. Taken together, these results clearly show that resting eosinophils preferentially use constitutively active α4 integrins (α4β1, α4β7) for the first attachment to TNF-α-activated HUVEC. In addition, α4 integrins and E-selectin work synergistically in eosinophil adherence to TNF-α-activated HUVEC. Although E-selectin is important for eosinophil rolling under these conditions, P-selectin plays only a minor role.

The phonological loop and central executive functioning were examined in patients with Alzheimer's disease (AD) and in normal elderly subjects. AD patients showed abnormal functioning of the phonological loop and decreased performance on tasks assessing the central executive. However, when AD patients were separated into two groups on the basis of their span level, both groups showed deficits of the central executive but only patients with the lower span level presented a dysfunction of the phonological loop as well as impaired performance in tasks of phonological discrimination, articulation rate and speed of processing. These results are interpreted in terms of progression of the disease, with high-span level patients being less severely demented and displaying deficits only in higher-level cognitive functions (such as manipulation of information stored in working memory) whereas patients with a low span level have impairments encompassing a series of more basic processes.