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As part of an International Agency for Research on Cancer (IARC) international epidemiological study of workers in the pulp and paper industry, previously unpublished exposure measurements were assembled in a database. This article summarizes the results of 3,873 measurements carried out in the production departments of paper and paperboard mills and recycling plants in 12 countries. In the paper and paperboard mills, most of the agents were measured in the pulping and refining departments and in on-machine coating and winding of paper/paperboard. Exposures to asbestos, carbon monoxide, formaldehyde, fungal spores, bacteria, nitrogen dioxide, minerals dusts, paper dust, sulphuric acid and different solvents sometimes exceeded exposure limit values. In the re-pulping and de-inking departments of recycling plants high exposures to formaldehyde, fungal spores, bacteria and paper dust were observed. High exposures to asbestos, bioaerosols, carbon monoxide and paper dust were found in many departments; ammonia, formaldehyde, mineral and paper dust and solvents were found in coating machines; and diphenyl and polychlorobiphenyls (PCBs) were found in some special circumstances. Measurements in the newsprint and uncoated paper machine departments revealed only a few elevated exposures. In nearly all departments, measurements of epichlorohydrin, PCBs, sulphur dioxide, hydrogen sulphide and mercaptans tended to be low, often even below their detection limits. In spite of some uncertainties in the measurement data, the study provides new insights into the level and variation of occupational exposures of production workers in the paper and paperboard industry. © Springer-Verlag 2004.

The syndromic primary immunodeficiencies are disorders in which not only the immune system but also other organ systems are affected. Other features most commonly involve the ectodermal, skeletal, nervous, and gastrointestinal systems. Key in identifying syndromic immunodeficiencies is the awareness that increased susceptibility to infections or immune dysregulation in a patient known to have other symptoms or special features may hint at an underlying genetic syndrome. Because the extraimmune clinical features can be highly variable, it is more difficult establishing the correct diagnosis. Nevertheless, correct diagnosis at an early age is important because of the possible treatment options. Therefore, diagnostic work-up is best performed in a center with extensive expertise in this field, having immunologists and clinical geneticists, as well as adequate support from a specialized laboratory at hand. This paper provides the general pediatrician with the main clinical features that are crucial for the recognition of these syndromes.

Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency characterized by absence of functional T lymphocytes. It is a paediatric emergency, which is life-threatening when recognized too late. The clinical presentation varies from the classical form of SCID through atypical SCID to Omenn syndrome. In addition, there is a considerable immunological variation, which can hamper the diagnosis. In this educational review, we describe the immunopathological background, clinical presentations and diagnostic process of SCID, as well as the therapeutic possibilities.

Despite the increasing availability of various forms of digital maps and guides, paper still prevails as the main information medium used by tourists during city visits. The authors describe how recent technologies for digitally augmented paper maps can be used to develop interactive paper maps that provide value-added services for tourists through digital overlays. An initial investigation into the use of these maps to support visitors to the Edinburgh festivals is also presented.

Background Multiparametric MRI (mpMRI) became recognised in investigating those with suspected prostate cancer between 2010 and 2012; in the USA, the preventative task force moratorium on PSA screening was a strong catalyst. In a few short years, it has been adopted into daily urological and oncological practice. The pace of clinical uptake, born along by countless papers proclaiming high accuracy in detecting clinically significant prostate cancer, has sparked much debate about the timing of mpMRI within the traditional biopsy-driven clinical pathways. There are strongly held opposing views on using mpMRI as a triage test regarding the need for biopsy and/or guiding the biopsy pattern. Objective To review the evidence base and present a position paper on the role of mpMRI in the diagnosis and management of prostate cancer. Methods A subgroup of experts from the ESUR Prostate MRI Working Group conducted literature review and face to face and electronic exchanges to draw up a position statement. Results This paper considers diagnostic strategies for clinically significant prostate cancer; current national and international guidance; the impact of pre-biopsy mpMRI in detection of clinically significant and clinically insignificant neoplasms; the impact of pre-biopsy mpMRI on biopsy strategies and targeting; the notion of mpMRI within a wider risk evaluation on a patient by patient basis; the problems that beset mpMRI including inter-observer variability. Conclusions The paper concludes with a set of suggestions for using mpMRI to influence who to biopsy and who not to biopsy at diagnosis. Key Points • Adopt mpMRI as the first, and primary, investigation in the workup of men with suspected prostate cancer. • PI-RADS assessment categories 1 and 2 have a high negative predictive value in excluding significant disease, and systematic biopsy may be postponed, especially in men with low-risk of disease following additional risk stratification. • PI-RADS assessment category lesions 4 and 5 should be targeted; PI-RADS assessment category lesion 3 may be biopsied as a target, as part of systematic biopsies or may be observed depending on risk stratification. Electronic supplementary material The online version of this article (10.1007/s00330-019-06166-z) contains supplementary material, which is available to authorized users.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation OnBehalf Swiss-AF Investigators Background Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients. Methods Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they presented in AF ("AF group") or in sinus rhythm ("SR group") on a baseline 5-minute ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), the root mean square of successive differences (RMSSD) and the standard deviation of the normal-to-normal intervals (SDNN)) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function. Results 1,685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. The MoCA score was 24.5 ± 3.2 in the AF group (n = 710 patients) and 25.4 ± 3.2 in the SR group (n = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group (β=0.049; 95% confidence interval (CI): 0.016 to 0.081; p = 0.003) and in the AF group (β=0.068; 95% CI: 0.020 to 0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β=-0.008; 95% CI: -0.014 to -0.002; p = 0.014 ). Other parameters of CAF were not associated with cognition. Conclusion Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Elderly AF patients with impaired HRVI might undergo cognitive testing in order to screen for cognitive impairment.

This study analyzes the relation between attention-deficit hyperactivity disorder (ADHD) and later-life labor market outcomes in the United States and whether these relationships are mediated by educational attainment. To overcome endogeneity concerns in the estimation of these relationships, we exploit the polygenic risk score (PRS) for ADHD in a cohort where the diagnosis of and treatment for ADHD were generally not available. We find that an increase in the PRS for ADHD reduces the likelihood of employment, individual income, and household wealth. Moreover, it increases the likelihood of receiving social security disability benefits, unemployment or worker compensation, and other governmental transfers. We provide evidence that educational attainment mediates these relationships to a considerable extent (14-58%).

Background We aimed to investigate the burden of informal care in Hungary (HU), Poland (PL) and Slovenia (SI). Methods A cross-sectional online survey was performed involving representative samples of 1000 respondents per country. Caregiving situations were explored; health status of informal caregivers/care recipients and care-related quality of life were assessed using the EQ-5D-5L and CarerQol-7D. Results The proportion of caregivers was (HU/PL/SI) 14.9, 15.0 and 9.6%, respectively. Their mean age was 56.1, 45.6 and 48.0, and the average time spent on informal care was 27.6, 35.5 and 28.8 h/week. Chronic care was dominant (> 1 year: 78.5%, 72.0%, 74.0%) and care recipients were mainly (own/in-law) parents. Average EQ-5D-5L scores of care recipients were 0.53, 0.49 and 0.52. For Poland and Slovenia, EQ-5D-5L scores of informal care providers were signifcantly lower than of other respondents. Average CarerQol-7D scores were (HU/PL/SI) 76.0, 69.6 and 70.9, and CarerQol-VAS was 6.8, 6.4 and 6.6, respectively. Overall, 89, 87, and 84% of caregivers felt some or a lot fulflment related to caring. Problems with combining tasks with daily activities were most important in Hungary and Slovenia. Women had a higher probability of being a caregiver in Hungary. CarerQol-7D scores were signifcantly associated with caregivers’ EQ-5D-5L scores. In Hungary and Poland, living in a larger household was positively, while caring for patients with mental health problems was negatively associated with CarerQol-7D scores. Conclusions These frst results from the Central and Eastern European region using preference-based measures for the evaluation of informal care can serve as a valuable input for health economic analyses.

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1744-4) contains supplementary material, which is available to authorized users.

Background Hypermobility of the first carpometacarpal joint is mostly surgically treated with a volar approached stabilization by Eaton, but recent studies indicate the importance of the dorsoradial and intermetacarpal ligaments (DRL and IML) for carpometacarpal joint stability. The aim of this study was to compare a dorsal and volar technique for primary carpometacarpal hypermobility regarding pain and functional outcome. Methods Patients with non-degenerative, painful carpometacarpal hypermobility were included and were randomly assigned to either the volar technique using the FCR, or a dorsal technique using the ECRL. After premature termination of the trial, we followed all patients treated with the volar approach. Pain, strength, and ADL function using DASH and Michigan Hand Questionnaires (MHQ) were measured at baseline and 3 and 12 months after surgery. Results After including 16 patients, the randomized trial comparing the volar and dorsal technique was terminated because of significant increased pain in the dorsal group. Although none of the other outcome measures were significant in the underpowered comparison, in line with the pain scores, all variables showed a trend towards a worse outcome in the dorsal group. Between 2009 and 2012, 57 thumbs were surgically stabilized. We found significant better pain and MHQ scores, and after 1 year improved grip and key pinch strength. Patients returned to work within 8 (±7) weeks, of which 85 % in their original job. Conclusions Surgical stabilization of the thumb is an effective method for patients suffering from hypermobility regarding pain, daily function, and strength. We recommend a volar approach. Level of Evidence: Level I, therapeutic study

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins. Interactomes of WT and mutant ALS proteins were very similar except for OPTN and UBQLN2, in which mutations caused loss or gain of protein interactions. Several of the identified interactomes showed a high degree of overlap: shared binding partners of ATXN2, FUS and TDP-43 had roles in RNA metabolism; OPTN- and UBQLN2-interacting proteins were related to protein degradation and protein transport, and C9orf72 interactors function in mitochondria. To confirm that this overlap is important for ALS pathogenesis, we studied fragile X mental retardation protein (FMRP), one of the common interactors of ATXN2, FUS and TDP-43, in more detail in in vitro and in vivo model systems for FUS ALS. FMRP localized to mutant FUS-containing aggregates in spinal motor neurons and bound endogenous FUS in a direct and RNA-sensitive manner. Furthermore, defects in synaptic FMRP mRNA target expression, neuromuscular junction integrity, and motor behavior caused by mutant FUS in zebrafish embryos, could be rescued by exogenous FMRP expression. Together, these results show that interactomics analysis can provide crucial insight into ALS disease mechanisms and they link FMRP to motor neuron dysfunction caused by FUS mutations. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1575-8) contains supplementary material, which is available to authorized users.

Objects Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective. Methods First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’. Conclusion ‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.

Purpose We conducted this study to gauge the health-related problems, quality of life and the performance of the Health Utility Index Mark 3 (HUI-3) in patients with syndromic and complex craniosynostosis. Patients with syndromic and complex craniosynostosis have various physical and mental problems. More insight on these problems, per syndrome, could provide guidance to improve patient treatment and follow-up. Methods A cross-sectional, comparative study on 131 patients and their parents was performed. Health-related quality of life was measured with the HUI-3 and the Visual Analogue Scale (VAS). All data were compared to a normative Dutch population. Vision, hearing and intelligence were objectively measured. Results The HUI-3 and the VAS were significant lower compared to the normative Dutch population. All syndromes have a high prevalence of vision and speech problems. Cognitive problems were mainly reported in patients with Apert, Crouzon and Muenke syndrome. Ambulation and dexterity problems were seen in Apert, Crouzon, Saethre–Chotzen and complex craniosynostosis. Only patients with Apert syndrome scored significantly worse on pain. The HUI-3 had a medium to strong correlation with the objectively measured outcomes. Conclusions The overall quality of life is lower in patients with syndromic and complex craniosynostosis. To improve quality of life, more attention is needed for problems with vision and speech.

Background/aims Chronic hepatitis B (CHB) infection is a serious public health problem due to its potential liver disease sequelae and highly expensive medical costs such as the need for liver transplantation. The aim of this study was to quantify the burden of active CHB in terms of mortality and morbidity, the eligibility of antiviral treatment and to assess various treatment scenarios and possible salvage combinations for cost-effectiveness. Methods A population cohort from a large data base of chronic hepatitis B patients was constructed and stratified according to 10-year age groups, the prevalence of HBsAg, HBV DNA level, ALT level, HBeAg status and the presence of cirrhosis. An age-specific Markov model for disease progression and cost-effectiveness analysis was constructed and calibrated for the specific population setting. Results Of about 3.2 million estimated HBsAg carriers, 25 % are eligible for treatment. If the active cohort remains untreated, 31 % will die due to liver related complications. Within a 20-year period, 11 % will have developed decompensated cirrhosis, 12 % liver cancer and 6 % will need liver transplantation. Quality adjusted life years (QALYs) for the no treatment scenario ranged from 9.3 to 14.0. For scenarios with antiviral treatment, QALYs ranged from 9.9 to 14.5 for lamivudine, 13.0–17.5 for salvage therapy, and 16.6–19.0 for the third generation drugs entecavir and tenofovir. Conclusion In a country with considerable amount of active CHB patients, monotherapy with a highly potent third generation drug has the most health-gain, and is cost-effective in both HBeAg-positive and negative in all stages of liver disease. Electronic supplementary material The online version of this article (doi:10.1007/s10198-012-0413-8) contains supplementary material, which is available to authorized users.

Autoantibodies are increasingly used as biomarkers in the detection of autoimmune disorders and cancer. Disease specific antibodies are generally detected by their binding to specific antigens. As an alternative approach, we propose to identify specific complementarity determining regions (CDR) of IgG that relate to an autoimmune disorder or cancer instead of the specific antigen(s). In this manuscript, we tested the technical feasibility to detect and identify CDRs of specific antibodies by mass spectrometry. We used a commercial pooled IgG preparation as well as purified serum IgG fractions that were spiked with different amounts of a fully human monoclonal antibody (adalimumab). These samples were enzymatically digested and analyzed by nanoLC Orbitrap mass spectrometry. In these samples, we were able to identify peptides derived from the CDRs of adalimumab. These peptides could be detected at an amount of 110 attomole, 5 orders of magnitude lower than the total IgG concentration in these samples. Using higher energy collision induced dissociation (HCD) fragmentation and subsequent de novo sequencing, we could successfully identify 50% of the detectable CDR peptides of adalimumab. In addition, we demonstrated that an affinity purification with anti-dinitrophenol (DNP) monoclonal antibody enhanced anti-DNP derived CDR detection in a serum IgG background. In conclusion, specific CDR peptides could be detected and sequenced at relatively low levels (attomole-femtomole range) which should allow the detection of clinically relevant CDR peptides in patient samples. Electronic supplementary material The online version of this article (doi:10.1007/s00216-010-4361-9) contains supplementary material, which is available to authorized users.

Contains fulltext : 87601.pdf (Publisher’s version ) (Closed access) Kaletra (Abott Laboratories) is a co-formulated medication used in the treatment of HIV-1-infected children, and it contains the two antiretroviral protease inhibitor drugs lopinavir and ritonavir. We validated two new ultrafast and high-throughput mass spectrometric assays to be used for therapeutic drug monitoring of lopinavir and ritonavir concentrations in whole blood and in plasma from HIV-1-infected children. Whole blood was blotted onto dried blood spot (DBS) collecting cards, and plasma was collected simultaneously. DBS collecting cards were extracted by an acetonitrile/water mixture while plasma samples were deproteinized with acetone. Drug concentrations were determined by matrix-assisted laser desorption/ionization-triple quadrupole tandem mass spectrometry (MALDI-QqQ-MS/MS). The application of DBS made it possible to measure lopinavir and ritonavir in whole blood in therapeutically relevant concentrations. The MALDI-QqQ-MS/MS plasma assay was successfully cross-validated with a commonly used high-performance liquid chromatography (HPLC)-ultraviolet (UV) assay for the therapeutic drug monitoring (TDM) of HIV-1-infected patients, and it showed comparable performance characteristics. Observed DBS concentrations showed as well, a good correlation between plasma concentrations obtained by MALDI-QqQ-MS/MS and those obtained by the HPLC-UV assay. Application of DBS for TDM proved to be a good alternative to the normally used plasma screening. Moreover, collection of DBS requires small amounts of whole blood which can be easily performed especially in (very) young children where collection of large whole blood amounts is often not possible. DBS is perfectly suited for TDM of HIV-1-infected children; but nevertheless, DBS can also easily be applied for TDM of patients in areas with limited or no laboratory facilities. 01 september 2010

The objective of this study was to evaluate clinical symptoms and findings on cranial ultrasound (CUS) in preterm infants with cerebellar haemorrhage through retrospective analysis of all preterm infants with a postnatal CUS or MRI diagnosis of cerebellar haemorrhage admitted in a tertiary care centre between January 2002 and June 2009. Fifteen infants were identified; median gestational age was 25 2/7 weeks and median birth weight 730 g. We discerned six types of haemorrhage: subarachnoid (n = 3), folial (n = 1), lobar (n = 9, of which 4 bilateral), giant lobar (n = 1, including vermis) and contusional (n = 1). Especially in infants with lobar cerebellar haemorrhage, CUS showed preceding or concurrent lateral ventricle dilatation, mostly without intraventricular haemorrhage (IVH). Thirteen infants suffered from notable, otherwise unexplained motor agitation in the days preceding the diagnosis. In conclusion, motor agitation may be a presenting symptom of cerebellar haemorrhage in preterm infants. Unexplained ventriculomegaly can be a first sign of cerebellar haemorrhage and should instigate sonographic exploration of the cerebellum.

The preceding chapters describe the various efforts, initiatives and policy attempts to realise transformation in the South African higher education system from 1994 up to 2000. Chapter 12 (New South African Realities) is to some extent a summary assessment of the findings and discussions of chapters 4 to 11. As these chapters show, and as we will argue here, transformation in higher education was seen by politicians and laymen, policy specialists and ordinary people as an indissoluble part of moving away from apartheid as a state form to a more open, inclusive, equitable and democratic society. This book describes how the transformation project was launched, with great acclaim, consensus and fanfare – through a series of founding documents such as the National Education Policy Initiative (NEPI, 1993), the ANC Policy Document (Centre for Education Policy Development, 1994), the report of the National Commission on Higher Education (NCHE, 1996), and even the first Higher Education White Paper of 1997 – only to seem to veer off track. A loss of course was detected in at least three areas. First, it seemed as if, after 1997, the policy process gradually became less participatory and democratic, and it even seemed to some that we were returning to something of a top-down style of policy imposition reminiscent of an earlier era. Secondly, it seemed as if the state was forsaking the values of equity and social justice in favour of the values of efficiency, effectiveness and responsiveness. Thirdly, even where policy had been implemented as intended (in the National Student Financial Aid Scheme [NSFAS], for example), it was producing effects different from the ones expected and desired. What was producing these contrary effects? Why had the transformation project in higher education come to be so widely seen as an unpleasant surprise and distasteful disappointment?

Caching, one of the oldest ideas in computer science, often improves performance and sometimes improves availability [1, 3]. Previous uses of caching have focused on data content. It is the presence of a local copy of data that reduces access latency and masks server or network failures. This position paper puts forth the idea that it can sometimes be useful to merely cache knowledge sufficient to recognize valid data. In other words, we do not have a local copy of a data item, but possess a substitute that allows us to verify the content of that item if it is offered to us by an untrusted source. We refer to this concept as caching trust.Mobile computing is a champion application domain for this concept. Wearable and handheld computers are constantly under pressure to be smaller and lighter. However, the potential volume of data that is accessible to such devices over a wireless network keeps growing. Something has to give. In this case, it is the assumption that all data of potential interest can be hoarded on the mobile client [1, 2, 6]. In other words, such clients have to be prepared to cope with cache misses during normal use. If they are able to cache trust, then any untrusted site in the fixed infrastructure can be used to stage data for servicing cache misses --- one does not have to go back to a distant server, nor does one have to compromise security. The following scenario explores this in more detail.

Aims The diagnostic value of natriuretic peptides in asymptomatic patients at risk for diastolic or systolic HF is controversial. We tested (1) the prevalence of preclinical LV dysfunction in an at-risk cohort; (2) the diagnostic accuracy of natriuretic peptides alone or in combination with clinical parameters for predicting asymptomatic left ventricular systolic or diastolic dysfunction. Methods 542 primary care patients (mean age 63 ± 11 years, 42% female) without prediagnosed HF, but with risk factors for left ventricular dysfunction, underwent thorough cardiological workup, including echocardiography and analysis of natriuretic peptides. Results 23 patients (4%) showed reduced systolic function (EF

In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Aβ in Alzheimer’s disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Aβ accumulation in human brain often used antibodies targeting the C-terminus of Aβ and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Aβ antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Aβ detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the β-cleaved APP C-terminal fragment (β-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Aβ in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Aβ peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Aβ aggregation in AD. Electronic supplementary material The online version of this article (doi:10.1007/s00401-010-0666-1) contains supplementary material, which is available to authorized users.

Off-label drug use in paediatrics is associated with an increased risk of adverse drug reactions. Any risk–benefit analysis has to be based on value judgments that should include parents' views. However, nothing is known so far about the parents' perspective on this critical issue. Therefore, a quantitative survey with parents of healthy and chronically ill children was carried out (n = 94). Knowledge about the practise of off-label use is generally poor in both groups. Surprisingly, this is also true for the parents of children with chronic disease. Nine percent of the parents of chronically ill children and 20% of the parents of healthy children would refuse treatment with an off-label drug. Parents who have poor knowledge about the practise of off-label use tend to refuse to volunteer their child for study participation. Therefore, the information of parents on the off-label use of drugs is important to meet ethical standards and to increase the parents' acceptance of medical studies with children. peerReviewed

Linkage disequilibrium was investigated in canola quality winter rapeseed to analyze (1) the prospects for whole-genome association analyses and (2) the impact of the recent breeding history of rapeseed on linkage disequilibrium. A total of 845 mapped AFLP markers with allele frequencies ≥0.1 were used for the analysis of linkage disequilibrium in a population of 85 canola quality winter rapeseed genotypes. A low overall level of linkage disequilibrium was found with a mean r2 of only 0.027 over all 356,590 possible marker pairs. At a significance threshold of P = 2.8 × 10−7, which was derived by a Bonferroni correction from a global α-level of 0.1, only 0.78% of the marker pairs were in significant linkage disequilibrium. Among physically linked marker pairs, the level of linkage disequilibrium was about five times higher with more than 10% of marker pairs in significant linkage disequilibrium. Linkage disequilibrium decayed rapidly with distance between linked markers with high levels of linkage disequilibrium extending only for about 2 cM. Owing to the rapid decay of linkage disequilibrium with distance association analyses in canola quality rapeseed will have a significantly higher resolution than QTL analyses in segregating populations by interval mapping, but much larger number of markers will be necessary to cover the whole genome. A major impact of the recent breeding history of rapeseed on linkage disequilibrium could not be observed. Electronic supplementary material The online version of this article (doi:10.1007/s00122-009-1221-0) contains supplementary material, which is available to authorized users.

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia. peerReviewed

Purpose To evaluate toxicity of radiochemotherapy schedule using daily-low-dose-cisplatin in radiochemotherapy of locally-advanced head-and-neck-cancer (HNSCC). Methods and patients From October 2003 to October 2006, 50 patients with HNSCC (stage III/IVA/IVB) were treated. In 32 patients, surgery and adjuvant radiotherapy(64 Gy), in 18 patients definitive radiotherapy(70 Gy) was performed. Low-dose-cisplatin was applied concomitantly (6 mg/m2/every radiotherapy-day). Results Acute toxicity ≥grade 3 was observed in 22 patients (11 patients mucositis/dysphagia, 7 hematologic toxicity, 4 mucositis/dysphagia/hematologic toxicity). 90% of our patients received >80% of the planned cumulative chemotherapy dose, 94% the intended dose of radiotherapy. After median follow-up of 24.2 months, 3-year overall survival and loco-regional control rates were 67.1 and 78%. During follow-up, chronic toxicity ≥grade 3 (xerostomia, subcutaneous fibrosis, or lymphedema) was observed in nine patients. Conclusion We found chemoradiation with daily-low-dose-cisplatin to be feasible with advantage of low acute and chronic toxicity. Therefore, use of low-dose-cisplatin should be evaluated in future clinical trials. peerReviewed

The preceding chapters of this book discuss scientific research results on natural and managed oak forests growing in the highlands of the American Tropics. Chapter authors highlight evolutionary, ecological and socioeconomic aspects of specific oak forests and identify existing gaps in our understanding. Their work and studies published elsewhere forms the basis for this chapter’s overview of the current state of knowledge on ecological patterns and processes which determine the structure and functioning of these magnificent forests. The increasingly important human use and much needed conservation of these biodiverse and threatened habitats are dealt with as well. Cross-cutting trends and issues are discussed and conclusions drawn. Neotropical montane oak forests are a special type of tropical montane forests (Kappelle 2004), in which tall oak trees (Quercus) dominate a 30to 60-m-high forest canopy, often in pure stands or mixed with pines (Pinus) or other predominant trees. Though Neotropical oak forest history, structure, species diversity, species interactions, ecosystem functioning, post-disturbance recovery, and human use may vary considerably over short geographical ranges, regional trends are now becoming evident. Research presented in this book clearly illustrates these large-scale trends. The following sections in this chapter synthesize our knowledge for each of these trends and themes.

Due to the frequent use of domestic sewage sludges as organic additives to soils with low humus content, the chemical characteristics of the extractable polymers from composted and uncomposted sludges were described.

The operative cycle in a pasta production plant is divided in four phases: a) receipt and storing of the raw material (floor), b) control and mixing of the raw material (floor), c) hvdratation and kneading of dough, extrusion and drying of the pasta, d) packing, palletization and final storing.

Reference GR-CEL-ARTICLE-2004-003doi:10.1007/s00128-004-0497-7View record in Web of Science Record created on 2005-07-15, modified on 2016-08-08

Access to research papers has changed in the last decades: from printed to digital sources, from close to open access. Despite these changes and broader access to research results, there are still accessibility barriers. A very few number of conferences and journals state an accessibility policy of their publications in their websites. The production of accessible documents is not a common practice in conferences devoted to accessibility. Purpose: The purpose of this paper is to present the case study of DSAI 2016 (Software Development and Technologies for Enhancing Accessibility and Fighting Infoexclusion) conference, wherein we were in charge of making accessible its proceedings. Methods: We discuss the methods and technical procedures we carried out to turn the original articles in MS Word and Latex formats into accessible PDFs and the steps necessary in authoring, conversion and validation. Results: the papers of DSAI 2016 were published in accessible format after much effort, best tools and procedure were using MS Word plus PDF Axes plus PDF Accessibility checker. Conclusion: We state the need to include a new role in the organizing committee of conferences for dealing with accessible publishing.

Independent living technologies are fast gaining interest within both academia and industry, amid the realization that the world's population is ageing. Technology can increase the quality of life of older people, allowing them to age-in-place and helping them to remain physically, cognitively and socially engaged with their environment. However, little research in this area is applied. The paper argues for the necessity of moving such technology out of the research laboratory and into the home, where its real impact on the lives of older adults can be assessed. Moreover, a series of recommendations are outlined, encompassing the life cycle of independent living technologies, from ethnographic assessment, through to design, deployment and evaluation. This work is based on lessons learned in deploying such technologies to older people in over 200 homes. This paper can act as a guide for other researchers interested in developing technologies with older people.

The exchange of design models in the design and construction industry is evolving away from 2-dimensional computer-aided design (CAD) and paper towards semantically-rich 3-dimensional digital models. This approach, known as Building Information Modelling (BIM), is anticipated to become the primary means of information exchange between the various parties involved in construction projects. From a technical perspective, the domain represents an interesting study in model-based interoperability, since the models are large and complex, and the industry is one in which collaboration is a vital part of business. In this paper, we present our experiences with issues of model-based interoperability in exchanging building information models between various tools, and in implementing tools which consume BIM models, particularly using the industry standard IFC data modelling format. We report on the successes and challenges in these endeavours, as the industry endeavours to move further towards fully digitised information exchange.

This paper deals with the problem of estimating the following road sign parameters: height, dimensions, visibility distance and partial occlusions. This work belongs to a framework whose main applications involve road sign maintenance, driver assistance, and inventory systems. From this paper we suggest a multisensory system composed from two cameras, a GPS receiver, and a distance measurement device,all of them installed in a car. The process consists of several steps which include road sign detection, recognition and tracking , and road signs parameters estimation. From some trigonometric properties, and a camera model, the information provided by the tracking subsystem and the distance measurement sensors, we estimate the road signs parameters.Results show that the described calculation methodology offers a correct estimation for all types of traffic signs.

Random variables may be compared with respect to their location by comparing certain functionals ad hoc, such as the mean or median, or by means of stochastic ordering based directly on the properties of the corresponding distribution functions. These alternative approaches are brought together in this paper. We focus on the class of L-functionals discussed by Bickel and Lehmann (1975) and characterize the comparison of random variables in terms of these measures by means of several stochastic orders based on iterated integrals, including the increasing convex order.

Combining expressiveness and plainness in the design of web documents is a difficult task. Validation languages are very powerful and designers are tempted to over-design specifications. This paper discusses an offbeat approach: describing any structured content of any document by only using a very small set of patterns, regardless of the format and layout of that document. The paper sketches out a formal analysis of some patterns, based on grammars and language theory. The study has been performed on XML languages and DTDs and has a twofold goal: coding empirical patterns in a formal representation, and discussing their completeness.

The curse of dimensionality is a well known but not entirely well-understood phenomena. Too much data, in terms of the number of input variables, is not always a good thing. This is especially true when the problem involves unsupervised learning or supervised learning with unbalanced data (many negative observations but minimal positive observations). This paper addresses two issues involving high dimensional data: The first issue explores the behavior of kernels in high dimensional data. It is shown that variance, especially when contributed by meaningless noisy variables, confounds learning methods. The second part of this paper illustrates methods to overcome dimensionality problems with unsupervised learning utilizing subspace models. The modeling approach involves novelty detection with the one-class SVM.

This paper highlights how artefacts can be used as an effective tool to understand users and encourage dialogue. The paper will reflect on how the role of the designer is evolving, some limitations of user-centred design and how a more holistic ‘human-centred’ design approach may be more productive. The nature and applications of artefacts in understanding users will be considered. Finally three case studies will illustrate how artefacts have been used to enable human-centred design.

Internet accessibility for the visually impaired community is still an open issue. Guidelines have been issued by the W3C consortium to help web designers to improve web site accessibility. However several studies show that a significant percentage of web page creators are still ignoring the proposed guidelines. Several tools are now available, general purpose, or web specific, to help visually impaired readers. But is reading a web page enough? Regular sighted users are able to scan a web page for a particular piece of information at high speeds. Shouldn't visually impaired readers have the same chance? This paper discusses some features already implemented to improve accessibility and presents a user feedback report regarding the AudioBrowser, a talking browser. Based on the user feedback the paper also suggests some avenues for future work in order to make talking browsers and screen readers compatible., The research reported in here was supported by SNRIP (The Portuguese National Secretariat of Rehabilitation and Integration for the Disabled) under program CITE 2001, and also FCT (Portuguese Foundation for Science and Technology) and POSI/2001 (Operational Program for the Information Society) with funds partly awarded by FEDER.

Ramsey’s posthumously published Theories has become one of the classics of the twentieth century philosophy of science. The paper was written in 1929 and was first published in 1931, in a collection of Ramsey’s papers edited by Richard Braithwaite. Theories was mostly ignored until the 1950s, though Ramsey’s reputation was growing fast, especially in relation to his work in the foundations of mathematics. Braithwaite made some use of it in his Scientific Explanation, which appeared in 1953. It was Hempel’s The Theoretician’s Dilemma, published in 1958, which paid Ramsey’s paper its philosophical dues. Hempel coined the now famous expression ‘Ramsey-sentence’.

The Business Process Execution Language (BPEL) is an XML based language; the BPEL standard defines the structure, tags and attributes of an XML document that corresponds to a valid BPEL specification. In addition, the standard defines a number of natural language constraints of which some can be ambiguous and are complex. This paper uses the Unified Modelling Language (UML) and Object Constraint Language to provide a model of the XML based BPEL language. Based on this model the paper shows how OCL can be used to give a precise version of the natural language constraints defined in the BPEL standard. We then use this precise specification to generate a Validation tool automatically that can check that a BPEL document is well-formed.

The lack of interoperability between ICT systems is becoming more and more a bottleneck in the collaboration and co-operation of enterprises. Co-operating parties have to exchange business information and have to have the same understanding of the meaning of the exchanged information and to trust both the communication itself and the validity of its contents. The paper reviews two ISO standards, which are aiming on the interoperability issue comparing the different aspects of these standards and introduces a new work item in standardisation, which expects support from two current European initiatives on interoperability and others. The paper is intended to guide further standard developments by identifying current solutions and their relation with one another.

The intramolecular model (Ehrenfeucht et al, 2001) for gene assembly in ciliates considers three operations, ld, hi, and dlad that can assemble any micronuclear gene pattern through folding and recombination: the molecule is folded so that two occurrences of a pointer (short nucleotide sequence) get aligned and then the sequence is rearranged through recombination of pointers. In general, the sequence rearranged by one operation can be arbitrarily long and may consist of many coding and non-coding blocks. We consider in this paper some restricted variants of the three operations, where only one coding block is rearranged at a time. We present in this paper the molecular model of these simple operations. We also introduce a mathematical model for the simple operations, on three levels of abstractions: MDS descriptors, signed permutations, and signed double occurrence strings. Interestingly, we show that simple assemblies possess rather involved properties: a gene pattern may have both successful and unsuccessful assemblies and also more than one successful strategy. TUCS Laboratory Computational Biomodelling Discrete Mathematics for Information Technology

The paper presents an attempt at the construction of a wide scale parser for English based on Inductive Learning and limited resources. The parser loosely preserves the shift-reduce scheme, enriched with powerful actions, and a compound Decision Tree instead of the decision table. The attempt originates directly from Hermjakob’s ideas [3], but an important goal was to analyse possible extensions to a wide scale solution. Several supporting heuristics, as well as the overview of the development process and experiments, are described in the paper.

In the paper an approach to the construction of rule-based morphosyntactic tagger for Polish is proposed. The core of the tagger are modules of rules (classification systems), acquired from the IPI PAN corpus by application of Genetic Algorithms. Each module is specialised in making decisions concerning different parts of a tag (a structure of attributes). The acquired rules are combined with linguistic rules made by hand and memory-based rules acquired also from the corpus. The construction of the tagger and experiments concerning its properties are also presented in the paper.

Fuzzy control has shown to be a very useful tool in the field of autonomous mobile robotics, characterized by a high uncertainty in the knowledge about the environment where robot evolves. The design of a fuzzy controller is generally made using expert knowledge about the task to be controlled. Expert knowledge is applied in order to decide the number of linguistic labels for each variable, to tune the membership functions, to select the most adequate linguistic values for the consequents, and to define the rules in the fuzzy knowledge base. This process is tedious and highly time-consuming. For this reason, automated learning techniques, such as evolutionary algorithms, have been employed for helping in some, or in all, of the tasks involved in the design process. A knowledge base is formed of a data base (number and definition of the linguistic values, and universe of discourse of each of the variables) and the rule base. Some authors have utilized evolutionary algorithms for learning or tuning fuzzy controllers in robotics [1, 2, 3]. In some of the approaches evolutionary algorithms are used just for tuning the membership functions. In others, the complete rule base is learned, starting from a hand designed data base. But only in a few of them both the data base and the rule base are learned. In this paper we describe the learning of a fuzzy controller for the wall-following behaviour in a mobile robot. No restrictions are placed neither in the number of linguistic labels, nor in the values of the membership functions. The methodology is based on the Iterative Rule Learning (IRL) approach [4]. The paper is organized as follows: in Sect. 2 some general comments about the evolutionary learning of knowledge bases are made, whilst in Sect. 3 the genetic learning methodology employed is explained. Section 4 describes the application of the proposed algorithm to the wall-following behaviour, and Sect. 5 presents the results we obtained. Finally, conclusions and future work are pointed out in Sect. 6.

About the book: An invited collection of peer-reviewed papers surveying key areas of Roger Needham's distinguished research career at Cambridge University and Microsoft Research. From operating systems to distributed computing, many of the world's leading researchers provide insight into the latest concepts and theoretical insights--many of which are based upon Needham's pioneering research work. A critical collection of edited-survey research papers spanning the entire range of Roger Needham's distinguished scientific career, from operating systems to distributed computing and security. Many of the world's leading researchers survey their topics' latest developments and acknowledge the theoretical foundations of Needham's work. Introduction to book written by Rick Rashid, Director of Microsoft Research Worldwide.

This paper provides an extension of general equilibrium theory that incorporates the actions of individuals both as demanders and suppliers of goods and as members of firms, schools, social groups, and contractual relationships. The central notion of the paper is a group: a collection of individuals associated with one another for some purpose. The model takes as primitive an exogenous set of group types, interpretable as (potential) firms, schools, social groups, contracts etc. The types of schools and firms that materialize in equilibrium, as well as the way that agents acquire skills, are determined endogenously in a competitive market, as are the contracts they enter into, and the production and consumption of private commodities. Equilibrium exists and the core coincides with the set of equilibrium states. Examples and Applications illustrate the flexibility and power of the framework.4

This paper considers an exchange economy with a measure space of agents and consumption externalities, which take into account two possible external effects on consumers’ preferences: dependence upon prices and dependence upon other agents’ consumption. We first consider a model with a general externality mapping and we then treat the particular case of reference coalition externalities, in which the preferences of each agent a are influenced by prices and by the global or the mean consumption of the agents in finitely many (exogenously given) reference coalitions associated with agent a. Our paper provides existence results of equilibria in both models when consumers have transitive preferences. It extends in exchange economies the standard results by Aumann [2], Schmeidler [16], Hildenbrand [12], and previous results by Greenberg et al. [11] for price dependent preferences, Schmeidler [17] for fixed reference coalitions and Noguchi [15] for a more particular concept of reference coalitions. We also mention related results obtained independently by Balder [4].

When analyzing business cycle data, one observes that the relevant predictor variables are often highly correlated. This paper presents a method to obtain measures of importance for the classification of data in which such multicollinearity is present. In systems with highly correlated variables it is interesting to know what changes are inflicted when a certain predictor is changed by one unit and all other predictors according to their correlation to the first instead of a ceteris paribus analysis. The approach described in this paper uses directional derivatives to obtain such importance measures. It is shown how the interesting directions can be estimated and different evaluation strategies for characteristics of classification models are presented. The method is then applied to linear discriminant analysis and multinomial logit for the classification of west German business cycle phases.