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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for Research on Cancer (IARC) international epidemiological study of workers in the pulp and paper industry, previously unpublished exposure measurements were assembled in a database.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.

Samples of artificially contaminated model papers were cleaned by the use of pulsed Nd:YAG laser at 1064 nm and 532 nm and the ArF excimer laser 193 nm. The post-processing effects were analysed basing on comparison of DRIFT spectra and colorimetric data obtained before and after accelerated ageing. In the DRIFT spectra measured after the laser surface cleaning at 1064 nm, the largest long-term changes were observed for the gelatin-sized paper. This paper revealed higher oxidization than the non-sized one after irradiation at 193 nm, too. Presence of gelatin resulted also in yellowing and darkening of the laser treated paper after prolonged ageing.

This paper is a study of the correlation between the humidity, density and matrix suction of non-plastic soil taken from a region located near the city of Rio de Janeiro. The study was conducted through laboratory tests, using minilysimeters and equipment that indirectly measured the humidity through soil suction: in effect, an automated tensiometer, an equivalence tensiometer (EQ2), a TDR and a specially adapted system, which measures the suction in situ, using filter paper. The electronic instruments were connected to a data logger and placed in three mini-lysimeters. Cycles of wetting and drying of the confined material were simulated. The soil was characterised. This characterisation enabled the determination of physical indexes, density, plasticity, grain size, porosity, and the characteristic curve of water retention, using the Richards pressure pan (cooker) test. The results obtained by the instruments, humidity and matrix suction, were compared with the characteristic curve. Overall, the equipment was satisfactory. The low presence of clay in this soil, around 7%, and its associated high porosity, were factors in limiting water retention. The equilibrium time of the soil humidity and the filter paper, obtained at intervals of fifteen days, presented better results than the weekly intervals (seven days). The equivalence tensiometer EQ2 compared to the filter paper presented quite efficient results for high suction values.

The paper has presented a practical application result of large scale linear programming to real-time optimal production scheduling in actual pulp and paper mill. Real-time application brings in several restrictions and requirements. The system based on a 32-bit minicomputer has been in operation since March 1986, providing optimal production schedules every 8 hours. The reduction in production cost is estimated to be more than 1% on the average. We believe that this is one of a few practical and successful real-time application cases of large scale linear programming realized on a mini-computer which also runs several hundreds real-time tasks.

The pulp and paper manufacturing industry generates large quantities of wastewater and has been described as a significant pollutant of the aquatic environment for many decades. The majority of pulp mills are located in the U.S. and Canada, and these countries are therefore subject to the greatest environmental impact. Some form of toxicity following exposure to mill effluent has been documented in numerous species, both aquatic and terrestrial, and the compounds present in effluents can affect multiple physiological processes, including hepatic mechanisms, reproduction and development, and endocrine function. Although the effects of PME on wildlife have been known for some time, the detection of chlorinated organic compounds generated substantial concern to humans because of the potential risk of exposure to these highly toxic compounds through environmental persistence and bioaccumulation. Government regulations were imposed on the pulping industry in an effort to prevent further contamination and reduce the toxic potential of pulp mill effluent to both humans and wildlife.

Infantile haemangioma (IH) is the most frequent childhood tumour. Although it is benign and self-limiting, severe complications can arise due to localisation and fast tumour growth. Management and therapy of IH has changed greatly after 2008 with propranolol. However, the pathogenesis remains elusive. This update provides an overview of all possible mechanisms currently considered. We discuss the possibility that several mechanisms act together, although local hypoxia seems to be important. Clinically, in about half of the cases, an IH is preceded by an anaemic macula (local ischaemia) or a so-called precursor lesion. Laboratory findings indicate stabilisation and an increased transcription activity of hypoxia-inducible factor 1 alpha (HIF1α), leading to up-regulation of its downstream target genes (such as vascular endothelial growth factor (VEGF)), which normally occurs in cases of hypoxia. Conclusion: Three main hypotheses have been proposed, namely (1) the theory of tissue hypoxia, (2) the theory of embolization of placental endothelial cells and (3) the theory of increased angiogenic and vasculogenic activity.

A local workshop series, called Japanese Software Process Workshop (JSPW), has been held annually, the last (4th) in February, 1992. The original motivation behind this workshop series was given by the provocation of Osterweil[5] and the subsequent reinvigorated interest in software process in general, and in software process description in particular. One of the features of the series is that it at tracted participants both from academia and industry, and that in consequence there occurred fruitful interactions between the normally separated communities. The author has attended this workshop series from the outset and gained some insights into the trends of opinions in our locale. This paper presents a personal perspective of the current issues in this field, in view of the discussions held in the workshop series.

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.

century. Throughout the last one hundred and seventeen years, the leadership atGulf States Paper has emphasized ideals and values as the cornerstone of the business.Mildred Warner, the second President of the organization, felt that the company shouldalways strive to possess four virtues: patience, faith, vision, and determination. Eventhough Gulf States Paper has changed its strategic direction several times over the lastcentury, the company has still been able to achieve several of its main organizationalobjectives, namely financial security and family control of the business.Gulf States Paper has experienced slow but steady growth over its one hundredyears plus of operation. However, the company has experienced this growth without agreat deal of external strategic actions, such as mergers and alliances. Instead, thecompany has been very tightly held and managed. The firm’s growth strategy hasconsisted mainly of acquisitions and expansion, strategies such as the building of newmills, the purchasing and development of new equipment, the procurement of forestland,etc. Gulf States Paper has tended to be rather inward-looking as an organization, and inthe words of Jack Warner, “one hundred years after its founding, Gulf States Paper is stilla small, privately held corporation, not bound to Wall Street”(Fletcher, 1984: vii).In this paper, I will trace the historical and strategic development of Gulf StatesPaper Corporation since its founding in 1884. The game metaphor developed by Nasi etal (1998) will be used as the centerpiece for this analysis. An analysis of the company’s

Biodeterioration of organic cultural heritage materials is a common problem. Particularly the removal of discoloration caused by fungal pigments is yet an unsolved problem in paper conservation. In the present study, cellulose (cotton and linters) and 16th century paper (rag), were incubated with several fungi types, such as Cladosporium, Epicoccum, Alternaria, Chaetomium, Aspergillus, Trichophyton, and Penicillium on agar for three weeks. Then they were immersed in 70% Ethanol for removal of hyphae and mycelia and deactivation of the remaining conidia. These specimens were laser-treated in a computer-controlled laser cleaning system with a high pulse energy diode pumped Q-switched Nd:YAG laser operating at 532 nm and a pulse duration of 8 ns. Colour differences were determined spectrophotometrically. Best cleaning results were observed with fungi such as Penicillium and Alternaria. Dry laser cleaning generally turned out to be superb over wet bleaching approaches.

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.

In this paper, the modeling of Fourdrinier paper making machines in basis weight control is discussed under the new approach, where attention is paid to the retention of solid matherials on the wire.

Taking up and expanding on the topic of Michael Cahn’s essay, this paper presents some observations on scientists’ editions of their collected works. These editions span the time from the second half of the eighteenth to the first half of the twentieth century. The main focus is on the practice of claiming literary and scientific authority by editing one’s collected works during one’s own lifetime. The paper begins by briefly describing the collected works of Pierre Louis Moreau de Maupertuis and Charles Bonnet. The central section is devoted to Georges Louis Leclerc de Buffon’s Natural History. Buffon’s work is taken as an example not only of editing, but of writing collected works. Buffon’s edited works had a long history of being expanded after their author’s death. At the end, two examples of early twentieth-century collections of research papers, by Hugo de Vries and Carl Correns, are considered. The paper is a corollary to Michael Cahn’s thoughts on the cultural history of texts and asks for a more general reflection on the historical development of forms and genres of scientific writing.

Firms attempt to adapt themselves through their business strategies to the present and forthcoming (institutional and technical) environments. Whether these strategy choices are planned or implemented is the classic question in business history and strategic management. It is generally agreed that the basic aims of a firm is to be profitable (at least over the long term) and to survive. These basic assumptions seems to fit most of the current, publicly owned companies, but when we are dealing with e.g. governmental owned or cooperatives, this seemingly clear picture becomes fuzzy. This article aims to analyse three major Finnish forestry industry companies, namely Kymmene, United Paper Mills, and Metsaliitto (M-Real). The focus is on the strategies they adapted during the 20 century and the performance they produced. We argue that though the companies were seemingly different (e.g. due to different kinds of ownership structures), neither the strategies nor the performance differed significantly. This, we propose, can be explained by the similar kind of competitive and institutional environment the companies were engaged in. Our aim is besides to give a general overview of the “paths” of these companies, also to analyse specific strategy processes to understand the antecedents of strategic decisions.

The IPPC Directive is concerned more with the diffusion of presently available environmental techniques than with the innovation process, which is a main consideration of this book. The aim of the IPPC Directive is to achieve a high level of protection of the environment as a whole by preventing or reducing the pollution emanating from industrial installations directly at source, through the use of best available techniques as described in BAT reference documents (BREFs). Member States had to bring their national legislation into line with the IPPC Directive by the end of October 1999 and the Directive must be applied to existing plants by October 2007.

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.

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.

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.

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.

Avariety of enzymes are available for the surface modification of cellulosic fibers, both in the area of textile applications and for pulp and paper applications. Enzymatic treatment conditions are milder, less damaging for the fiber, and are environmentally friendly while producing effects comparable to chemical treatments. Surface modifications can be achieved by oxidative and/or hydrolytic enzymes. Some of the enzymatic processes have recently attained commercial importance and more systems are being developed. The following chapter will review current research in the application of oxidoreductases and hydrolases that are valuable for textile and forest products industries.

The use of laboratory toxicity tests to monitor industrial effluent discharges has become a common approach to estimating the potential for environmental effects in North America and Europe. Numerous schemes have been developed to characterize and assess potential toxic effects in aquatic receiving environments. The first regulatory application of Environmental Effects Monitoring (EEM) in Canada was within the 1992 Pulp and Paper Liquid Effluent Regulations, promulgated under the Fisheries Act. A second application of EEM in Canada was within the 2002 Metal

This position paper outlines the rationale for and the approach used at the University of Hawaii at Hilo to further augment the ACM/IEEE computer science curriculum for software engineering considerations.