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Previous studies of serum 25-hydroxyvitamin D (25(OH)D) in relation to melanoma have shown conflicting results. We conducted a nested case–control study of 708 cases and 708 controls, using prediagnostically collected serum, to study 25(OH)D and melanoma risk in the population-based Janus Serum Bank Cohort. Stratified Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for ultraviolet radiation (UVR) indicators and stratified by ambient UVB of residence and body mass index (BMI). Non-linear associations were studied by restricted cubic splines. Missing data were handled with multiple imputation by chained equations. We found an HR of melanoma risk of 1.01 (95% CI: 0.99, 1.04) and an HRimputed of 1.02 (95% CI: 1.00, 1.04) per 5-nmol/L increase. The spline model showed exposure-risk curves with significantly reduced melanoma risk between 60 and 85 nmol/L 25(OH)D (reference 50 nmol/L). Non-significant J-shaped curves were found in sub-analyses of subjects with high ambient UVB of residence and of subjects with BMI 2. Our data did not yield persuasive evidence for an association between 25(OH)D and melanoma risk overall. Serum levels within the medium range might be associated with reduced risk, an association possibly mediated by BMI.

Summary Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation., Graphical abstract, Highlights • A multicohort study identifies 52 previously unknown osteoarthritis genetic risk variants • Similarities and differences in osteoarthritis genetic risk depend on joint sites • Osteoarthritis genetic components are associated with pain-related phenotypes • High-confidence effector genes highlight potential targets for drug intervention, A multicohort genome-wide association meta-analysis of osteoarthritis highlights the impact of joint site types on the features of genetic risk variants and the link between osteoarthritis genetics and pain-related phenotypes, pointing toward potential targets for therapeutic intervention.

Cancer treatment remains a challenge due to a high level of intra- and intertumoral heterogeneity and the rapid development of chemoresistance. In the brain, this is further hampered by the blood-brain barrier that reduces passive diffusion of drugs to a minimum. Tumors grow invasively and form new blood vessels, also in brain tissue where remodeling of pre-existing vasculature is substantial. The cancer-associated vessels in the brain are considered leaky and thus could facilitate the transport of chemotherapeutic agents. Yet, brain tumors are extremely difficult to treat, and, in this review, we will address how different aspects of the vasculature in brain tumors contribute to this.

Background Breslow thickness is the most important prognostic factor of localized cutaneous melanoma (CM), but associations with anthropometric factors have been sparsely and incompletely investigated. Objectives To examine prediagnostic body mass index (BMI), body surface area (BSA), and height, weight and weight change in relation to Breslow thickness, overall and by anatomical site and histological subtype; and to assess possible nonlinear associations between these anthropometric factors and Breslow thickness. Methods CMs in the Janus Cohort were identified between 1972 and 2014. Linear regression was used to estimate geometric mean ratios (GMRs) of Breslow thickness with 95% confidence intervals (CIs) according to anthropometric factors. Restricted cubic splines in generalized linear models predicted adjusted mean Breslow thickness, and were used to assess possible nonlinear relationships. Results Of 2570 cases of CM, obese patients had a GMR of 1·16 (95% CI 1·04–1·30) of Breslow thickness vs. normal‐weight patients. For BSA and weight, quintile 5 showed GMRs of 1·13 (95% CI 1·00–1·27) and 1·17 (95% CI 1·03–1·33) of Breslow thickness vs. quintile 1, respectively. Associations seemed restricted to superficial spreading melanomas and CMs on the trunk and lower limbs. The associations plateaued at an adjusted mean Breslow thickness of about 2·5 mm (BMI 29 kg m−2, BSA 2·05 m2 and weight 90 kg), before declining for the highest values. No associations were found for height and weight change. Conclusions This large case‐series of incident CM demonstrated positive associations between BMI, BSA, weight and Breslow thickness, and suggested that behavioural or other mechanisms apply at high values. This is the peer reviewed version of the article, which has been published in final form at Wiley. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions."

Objectives To explore the frequency of non-starters and stoppers of disease-modifying therapy (DMT) in a cohort of people recently diagnosed with multiple sclerosis (MS) and to identify reasons for non-starting or stopping DMT measured by demographic variables, social support [The Interpersonal Support Evaluation List (ISEL)] and disease-related stress [The Impact of Event Scale (IES)]. Materials and methods A multicentre retrospective cohort study using postal surveys completed by people with MS was performed, comprising all patients diagnosed with MS during 2000–2007 at four university clinics in Norway. Results Of the 424 respondents, 180 (42%) were still using the first prescribed DMT, 83 (20%) were using DMT after switching DMT at least once, 53 (12.5%) had ended DMT, and 108 (25.5%) had never started DMT. The risk of non-starting DMT was associated with increasing age at diagnosis, the region, disease-related stress and avoidant trauma coping. The risk factors for stopping therapy after the first prescribed DMT were adverse events and high education. Conclusions Disease-related stress, avoidant trauma coping, age at diagnosis and education should be considered when motivating people with MS to use DMT. Hence, the challenges to starting and continuing treatment will probably also remain a problem with orally administered DMT.

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

The serotonin transporter (SERT) belongs to a family of sodium-chloride-dependent transporters responsible for uptake of amino acids and biogenic amines from the extracellular space. SERT represents a major pharmacological target in the treatment of several clinical conditions, including depression and anxiety. In the present study we have undertaken a mutational scanning of human SERT in order to identify residues that are responsible for individual differences among related monoamine transporters. One mutant, G100A, was inactive in transport. However, ligand binding affinity was similar to wild-type, suggesting that G100A amongst different possible SERT conformations is restrained to a binding conformation. We suggest that the main role of glycine-100 is to confer structural flexibility during substrate translocation. For the two single mutants, T178A and F263C, uptake rates and K(m) values were both several-fold higher than wild-type while binding affinities and inhibitory potencies decreased considerably for several drugs. Ion dependency increased and only at hyperosmotic concentrations were K(m) values partly restored. For the double mutant, T178A/F263C, shifts in uptake kinetics and ligand affinities, as well as ion dependencies, were drastic. Effects were synergistic compared to the corresponding single mutants. In conclusion, we suggest that mutating threonine-178 to an alanine and phenylalanine-263 to a cysteine mainly alter the overall uptake kinetics of SERT by affecting the conformational equilibrium of different transporter conformations.

A novel heparin-binding protein was purified to homogeneity from bovine prepartum mammary gland secretion using heparin-Sepharose chromatography and reverse-phase high performance liquid chromatography successively. Structural information obtained by N-terminal amino acid sequencing of a series of proteolytically generated peptides permitted the cloning of the corresponding cDNA. The isolated cDNA was 1170 base pairs long and consisted of an 83-base pair 5'-untranslated region followed by a 702-base pair coding region and a 385-base pair 3'-untranslated region. The open reading frame resulted in a protein comprising 234- amino acid residues, including a signal sequence. Instead of Lys(24) as the predicted N terminus, Edman degradation of the native protein revealed N-terminal processing at two sites as follows: a primary site between Arg(31)-Gly(32) and a secondary site between Arg(51)-Ser(52). The amino acid sequence showed a significant similarity with that of human (60%) and mouse (53%) fibroblast growth factor-binding protein (FGF-BP). Accordingly, ligand blotting experiments revealed that bovine FGF-BP bound FGF-2. The theoretical mass of the protein predicted from the cDNA sequence is 22.5 kDa. However, the molecular mass of the purified protein was estimated to 28.6 kDa by mass spectrometry and 36 kDa by electrophoresis. The apparent molecular weight differences are most likely due to post-transcriptional modifications, shown to involve N- and O-glycosylation of Asn(155) and Ser(172), respectively. All 10 cysteine residues in the protein participated in disulfide bonds, and the pattern was identified as Cys(71)-Cys(88), Cys(97)-Cys(130), Cys(106)-Cys(142), Cys(198)-Cys(234), and Cys(214)-Cys(222). As the 10 cysteines of the three known FGF-BPs are positionally conserved, the disulfide bond pattern of bovine FGF-BP may be regarded as representative for the FGF-BP family.

Considerable variation in EMG practice has been described previously. Since 1992, 7 clinical neurophysiologists from 6 European countries prospectively collected electromyographic (EMG) examinations. The aim of this study was to examine whether several years of mutual influence among physicians using medical audit resulted in a more uniform EMG practice. We studied whether there was a change in the number of examinations per patient and the techniques used from the first 12 to the last 12 EMG examinations on patients with polyneuropathy. For F-wave studies and motor nerve studies, there was a clear change towards a more uniform practice. For sensory nerve conduction studies and muscle studies, there were only minor changes. With regard to examination techniques, there was a reduction in the use of more time-consuming examination techniques (near-nerve sensory studies and quantitative muscle studies). It seems possible to change the EMG practice of individual physicians by international collaboration and medical audit. However, until now most changes have been minor and large differences in European EMG practices persist. The diversity of practices suggests a need for studies on the optimal application of existing examination techniques.

This study was undertaken with the aim of evaluating inter- and intraobserver variation on the pathophysiological interpretation of individual electromyographic (EMG) tests on muscles and nerve segments. Seven physicians from 6 European EMG laboratories independently interpreted 81 EMG studies comprising 735 muscle tests and 726 tests on nerve segments. Pathophysiological conclusions were inferred from findings of these tests without considering clinical information. For most combinations of findings, both the inter- and intraobserver variations on the interpretation were low, suggesting that common criteria for pathophysiological interpretations were used and that these were used consistently. For some combinations of findings, however, there was disagreement on whether these indicated specific or unspecific pathophysiological changes. In particular disagreement on whether findings indicated demyelination may be of clinical significance. A large part of the intraobserver variation may be explained by a change towards more cautious interpretations during the study for most of the physicians. It is concluded that there is a need to seek for consensus on the pathophysiological interpretation of individual findings and for incentives to ensure consistency in interpretations. The fact that experienced physicians changed their ways to interpret findings during the study suggests that agreement may be improved globally.

With the purpose of recording responses mediated by the 3 cone systems visual evoked potentials (VEPs) were elicited by the reversal of monochromatic checkerboards superimposed upon strong monochromatic backgrounds (yellow, purple and blue-green). The sensitivity to light of various wave lengths were measured as the reciprocal of the intensity necessary to elicit a VEP amplitude of 3 μV. The spectral sensitivity curves based on this VEP amplitude criterion in the presence of blue-green, purple and yellow adaptation showed peak sensitivities in the red, the green and the blue part of the spectrum, respectively. This indicates that the responses reflect separate modulation of the 3 different cone mechanisms. The potentials obtained with yellow adaptation differed from those obtained with purple and blue-green adaptation. The amplitude versus log intensity function was flatter and the latency of the major positive peak was increased by 20–25 msec. Repeated examinations of 4 subjects suggest that the method yields reliable latency measurements of responses mediated by separate cone mechanisms.

To evaluate the outcomes among patients treated for gastric adenocarcinoma in a referral hospital, and to identify possible trends during the last decade.All patients evaluated for gastric adenocarcinoma during the period 1999-2009 were included.Of 397 patients, 52% were curatively resected. Crude 5-year survival for the first 6 years period was 38.7% (CI 29.5-47.9), for the last 5 years, 49.2% (CI 38.8-59.6). Time period (P = 0.013), age (P0.001) and disease stage (P0.001), were significant predictors of long-term survival rates. Among curatively resected, in-hospital mortality was reduced from 8.5% in the first period to 2.0% in the last one (P = 0.037). There was a significant increase in the use of primary stents from the first to the last period (P = 0.006), paralleled by a significant reduction in the number of explorative laparotomies or bypass procedures (P0.001).During the last decade, long-term survival rates improved among patients curatively resected for gastric adenocarcinoma, and in-hospital mortality was substantially reduced. For patients in a non-curative situation, there was a significant shift from explorative laparotomies or bypass procedures to primary use of stents.

Electrodiagnostic studies comprising electromyography (EMG) and nerve conduction studies (NCS) are well-established objective methods for the diagnosis, quantification and classification of polyneuropathies (PNP). This paper reviews examination techniques, their pathophysiological interpretation, examination strategies and diagnostic criteria for the diagnosis and classification of a PNP. The routine electrodiagnostic evaluation includes sensory NCSs performed with surface or needle electrodes, motor NCSs, F-wave studies and EMG by qualitative or quantitative techniques. Sensory NCSs and F-wave studies have a high sensitivity in PNPs and the different techniques complement each other. The distinction between a PNP with predominantly axonal loss and a PNP with predominantly demyelination is one of the major aims of the electrophysiological examination. There are, however, large variation in suggested criteria for predominantly demyelination. The degree of slowing in conduction taken to indicate demyelination varies between a decrease of 50 to 30% from mean of controls, distal latency prolongation criteria vary from 35% to 70% of mean of controls, F-wave latency prolongation criteria vary from 120% to 150% of upper limit of controls, and criteria for partial motor conduction block vary from 11 to 50% reduction of CMAP amplitude and/or area between proximal and distal stimulation. Needle EMG studies may be valuable in order to detect and quantify denervation activity, to assess chronicity by an evaluation of the extent of reinnervation, and to evaluate the topographical distribution of changes. It is concluded that electrodiagnostic studies are valuable in patients with suspected PNP and the results may have consequences for prognosis and therapy of individual patients. Large variation in examination techniques, strategies, interpretations and diagnostic criteria have been found among electromyographers and it is suggested that the value of electrodiagnostic studies may be further improved by international standardisation.

OBJECTIVES: In order to improve the universal quality of the EMG examination, knowledge about the variation among physicians is needed.METHODS: The variation among physicians in diagnostic strategy or criteria for diagnosing was analysed from a multicentre database with 940 EMG examinations sampled by seven physicians from six laboratories in Europe.RESULTS: For the whole group of patients as well as for the subgroup of patients with polyneuropathy, variation among physicians in examination techniques, number of examined structures per patient and number of abnormal structures per patient required for a diagnosis was found. Some of the variation may be explained by use of different techniques, which showed differences in sensitivity, while some of the variation may be due to differences in diagnostic strategy and criteria for diagnosing.CONCLUSIONS: The study indicates a need for development and revision of international guidelines for EMG practice although implementation of standards requires caution.

Bovine tissue-type plasminogen activator (tPA) was heterologously expressed in the methylotrophic yeast Pichia pastoris and characterized structurally and kinetically. The bovine single-chain tPA-mediated activation of bovine plasminogen was studied in the presence and absence of fibrinogen fragments. We have proposed a refined new method of kinetic analysis which allows examination of both stationary and prestationary phases of this process. The investigation revealed the presence of two interconvertible forms of the recombinant bovine tPA being in equilibrium at a 1 to 50 ratio. Only the minor form was able to bind and activate plasminogen. Saturation of the whole pool of tPA required high plasminogen concentration (Km >/= 5 microM) in order to reverse the equilibrium between the two forms. Fibrinogen fragments activated the single-chain tPA due to preferential binding and stabilization of the minor "active" form of the enzyme until all the molecules of tPA were converted. The same mechanism could be applied to human tPA as well. The Km values, obtained for recombinant bovine and human tPA in the presence of fibrinogen fragments, were found to be similar (Km = 0.1 microM) while kcat of human tPA was 5-10 times higher.

Here we report the molecular cloning and sequencing of three types of human alpha s1-casein transcripts and present evidence indicating that exon skipping is responsible for deleted mRNA transcripts. The largest transcript comprised 981 bp encoding a signal peptide of 15 amino acids followed by the mature alpha s1-casein sequence of 170 amino acids. Human alpha s1-casein has been reported to exist naturally as a multimer in complex with kappa-casein in mature human milk, thereby being unique among alpha s1-caseins [Rasmussen, Due and Petersen (1995) Comp. Biochem. Physiol., in the press]. The present demonstration of three cysteines in the mature protein provides a molecular explanation of the interactions in this complex. Tissue-specific expression of human alpha s1-casein was indicated by Northern-blot analysis. In addition, two cryptic exons were localized in the bovine alpha s1-casein gene.

This study was undertaken to analyse epidemiological and methodological differences in referral pattern, examination techniques and distribution of diagnoses among different European EMG laboratories. Seven European EMG laboratories filled in questionnaires and sampled 700 cases retrospectively. The use of needle or surface electrodes for nerve studies and the selection of quantitative techniques for muscle studies considerable variation. The pattern of referral varied with respect to the type of referral source and the neurological expertise of the referring physician. The proportion of patients without any neurophysiological abnormality ranged from 16 to 33%. The 3 most common diagnostic groups were mononeuropathies, polyneuropathies and radiculopathies although a great inter-laboratory variation was found. The proportion of patients with multiple diagnoses varied from 0 to 23% and most of these diagnoses were from a few known combinations. The presence of an inter-laboratory variation suggests that the quality of the EMG examination may be improved by focussing on the use of techniques, strategies and diagnostic criteria.

A pictorial computerized communication aid for aphasic patients, PicBox, (12) has been developed by a group in Sweden. During the technical and clinical work with the PicBox program we have had the reason and possibility to reflect on the relation between aphasia, language and thinking. From linguistic and neuropsychological research it has been claimed that in aphasia there is often a general cognitive impairment. Preliminary results from three patients' use of PicBox show that aphasic disturbances can, to some extent, be compensated for by pictorial communication, thus indicating an underlying cognitive competence. There are, however, also data indicating a deeper disturbance leading to an inability to fully use alternatives for spoken or written language.

Among predisposed persons the use of home humidifiers may induce febrile conditions named humidifier fever. The disease is considered to be an extrinsic allergic alveolitis. It may also be induced by modern ultrasound humidifiers. A case is described where an ultrasound humidifier was found to be the cause of humidifier fever.

Nine persons in the county of Troms, Norway, were interviewed on their strict vegetarian diet. Improved health was indicated as the main reason for their choice of diet, but religion was a contributing reason for some. Most of the study persons would increase the intake of vitamin B12 if a deficiency state were to occur. One person reported, however, that she would not regard vitamin B12 deficiency as a health problem. The interviews disclosed beliefs regarding human physiology that are very far removed from standard scientific knowledge. The article indicates that communication between patient and the health care system may be difficult in such circumstances. Problems of communication would probably be minimized if the patient had a thorough understanding of human physiology and the health worker a thorough understanding of the reasons for the patient's choice of diet.

A 28 year old woman with a previous history of labile hypertension, migraine and transitory cerebral ischemia was admitted with cerebral infarction. One month later she developed livedo reticularis and amaurosis fugax, which led to the diagnosis of Sneddon's disease (livedo reticularis, labile hypertension and neurological symptoms) and the anticardiolipin antibody (ACA) syndrome. Treatment with prednisone and phenprocoumon resulted in lowering of ACA-titers, but the symptoms did not subside until acetylsalicylic acid was added.

Antiphospholipid antibodies (APA) are acquired, circulating immunoglobulins connected with thrombo-embolic diseases occurring within all organ systems. Whether the antibodies are of pathogenetic relevance for the development of thrombo-embolic states is unresolved. All materials are limited and have yielded contradictory results with regard to important aspects. An increased APTT or PTT does not increase the risk of bleeding in patients with LA, unless abnormalities in the coagulation process are present, e.g. thrombocytopenia or hypoprothrombinaemia. Many questions are unanswered: Should APA be treated in asymptomatic patients? Should patients with APA and relevant symptoms be treated? If so, which treatment should be chosen? And how long should the treatment continue? Are APA of pathogenetic importance or are they markers for another mechanism that causes an immunocoagulopathy? How can it be explained that so many persons produce autoantibodies without becoming seriously ill? In order to clarify the significance of APA it is necessary to standardize tests and to perform extensive, prospective studies, where variations of ACA titres are analysed. Until results from such studies are available, APA should be looked for in patients with recurring arterial or venous thrombosis and in patients with recurring spontaneous abortion with reference to anticoagulant and anti-platelet aggregation therapy if IgG-ACA are elevated over prolonged periods.

Purified phospholipase C from Bacillus cereus caused a significant loss in the procoagulant activity of thromboplastin preparations from man, rabbit, sheep, cow, rat and mouse. However, marked differences were observed with respect to the degree of inactivation. Rat, mouse, bovine and one type of rabbit preparations (prepared from acetone powdered brain) were markedly more sensitive to attack by phospholipase C than were preparations of human, sheep and standard rabbit preparations. The relative amounts of the individual phospholipids in thromboplastin preparations showed only minor variations among the species. The effect of phospholipase C on each of these phospholipids in the various thromboplastin preparations showed some significant differences.

We report here a highly significant positive correlation observed when the factor VII-phospholipid complex (the phospholipase-C sensitive component of factor VII) in plasma was tested in a specific factor VII system and in Normotest (p less than 0.0001). The Normotest system, which is sensitive to variations in coagulation activity within the normal range, was not influenced by phospholipase C when the enzyme was added immediately before the start of the coagulation assay. Normotest is well suited for determination of the factor VII-phospholipid complex in plasma.