Precision of the PET activity range during irradiation with10C,11C, and12C beams.

Objective. Beams of stable ions have been a well-established tool for radiotherapy for many decades. In the case of ion beam therapy with stable12C ions, the positron emitters10,11C are produced via projectile and target fragmentation, and their decays enable visualization of the beam via positron emission tomography (PET). However, the PET activity peak matches the Bragg peak only roughly and PET counting statistics is low. These issues can be mitigated by using a short-lived positron emitter as a therapeutic beam.Approach.An experiment studying the precision of the measurement of ranges of positron-emitting carbon isotopes by means of PET has been performed at the FRS fragment-separator facility of GSI Helmholtzzentrum für Schwerionenforschung GmbH, Germany. The PET scanner used in the experiment is a dual-panel version of a Siemens Biograph mCT PET scanner.Main results.High-quality in-beam PET images and activity distributions have been measured from the in-flight produced positron emitting isotopes11C and10C implanted into homogeneous PMMA phantoms. Taking advantage of the high statistics obtained in this experiment, we investigated the time evolution of the uncertainty of the range determined by means of PET during the course of irradiation, and show that the uncertainty improves with the inverse square root of the number of PET counts. The uncertainty is thus fully determined by the PET counting statistics. During the delivery of 1.6 × 107ions in 4 spills for a total duration of 19.2 s, the PET activity range uncertainty for10C,11C and12C is 0.04 mm, 0.7 mm and 1.3 mm, respectively. The gain in precision related to the PET counting statistics is thus much larger when going from11C to10C than when going from12C to11C. The much better precision for10C is due to its much shorter half-life, which, contrary to the case of11C, also enables to include the in-spill data in the image formation.Significance. Our results can be used to estimate the contribution from PET counting statistics to the precision of range determination in a particular carbon therapy situation, taking into account the irradiation scenario, the required dose and the PET scanner characteristics.

The intergenerational impact of trauma and family violence on parents and their children.

BACKGROUND: Children who experience Child Abuse and Neglect (CAN) are at an increased risk of becoming a victim of Intimate Partner Violence (IPV) or a perpetrator of IPV or CAN. Moreover, maltreated children are at risk for developing long-lasting trauma symptoms, which can subsequently affect their own children's lives. Understanding the mechanisms of the intergenerational transmission of violence and trauma is a prerequisite for the development of interventions. OBJECTIVE: We examine whether the relation between historical CAN and current trauma symptoms of mothers is mediated by current IPV. Furthermore, we investigate whether current CAN mediates the relation between current maternal trauma symptoms and child Post-Traumatic Stress Disorder (PTSD) symptoms. These mechanisms are compared for mothers and fathers. PARTICIPANTS: We have recruited 101 fathers and 360 mothers (426 children, 50% boys, mean age 7 years) through child protection services. METHODS: Respondents completed questionnaires about IPV, (historical) CAN and trauma symptoms. RESULTS: Structural equation models revealed that historical CAN of father and mothers was related to trauma symptoms. Only for mothers, this association was mediated by IPV. Trauma symptoms of both fathers and mothers were related to child PTSD symptoms. This effect was not mediated by current CAN. CONCLUSION: In violent families, maternal and paternal trauma can be transmitted over generations. However, intergenerational transmission of violence is found for mothers only. When family violence is reported, professionals should take the violence into account, as well as the history of parents and trauma symptoms of all family members.

Energy enhancement of the target surface electron by using a 200 TW sub-picosecond laser.

One order of magnitude energy enhancement of the target surface electron beams with central energy at 11.5 MeV is achieved by using a 200 TW, 500 fs laser at an incident angle of 72° with a prepulse intensity ratio of 5×10-6. The experimental results demonstrate the scalability of the acceleration process to high electron energy with a longer (sub-picosecond) laser pulse duration and a higher laser energy (120 J). The total charge of the beam is 400±20 pC(E>2.7 MeV). Such a high orientation and mono-energetic electron jet would be a good method to solve the problem of the large beam divergence in fast ignition schemes and to increase the laser energy deposition on the target core.

Dose build-up effects induced by delta electrons and target fragments in proton Bragg curves-measurements and simulations.

Dose build-up effects in the entrance channel of proton Bragg curves were investigated in detail by means of simulations and experiments. There are two relevant dose build-up effects. Firstly, the δ-electron build-up effect which takes place in the first few millimeters of the tissue until an equilibrium state of the forward-scattered δ-electrons is reached. Secondly, the target fragment build-up effect that covers the first centimeters in the entrance channel of the proton Bragg curve. These target fragments are created in inelastic interactions of the beam protons with the target nuclei and partially have low kinetic energies and/or high atomic numbers compared to the incident beam protons. Consequently, the target fragments possess high LET values and thus an increased RBE. However, the production cross sections relevant for target fragmentation in ion beam therapy still have large uncertainties. Therefore, in this work target fragmentation was investigated indirectly by measuring low-noise proton Bragg curves with the focus placed on their build-up regions. The measurements clearly show the magnitude and shape of the two different build-up effects. Additionally, with the application of a magnetic filter, it was possible to separate the measurement of the target fragment build-up effect from the δ-electron build-up effect. Corresponding FLUKA Monte Carlo simulations were carried out for the experimental setup. A comparison of the experimental results with the FLUKA predictions enabled the assessment of the precision of FLUKA models, e.g. the δ-electron production models and the nuclear event generators which are responsible for target fragmentation reactions. It could be shown that the relevant models worked well to reproduce both build-up effects.

One-year persistence of individual gait patterns identified in a follow-up study - A call for individualised diagnose and therapy.

Although a hunch about the individuality of human movements generally exists, differences in gait patterns between individuals are often neglected. To date, only a few studies distinguished individual gait patterns in terms of uniqueness and emphasised the relevance of individualised diagnoses and therapy. However, small sample sizes have been a limitation on identifying subjects based on gait patterns, and little is known about the permanence of subject-specific characteristics over time. The purpose of this study was (1) to prove the uniqueness of individual gait patterns within a larger sample and (2) to prove the long-term permanence of individual gait patterns. A sample of 128 healthy participants each walked a distance of 10m barefoot 10 times. Two force plates recorded the ground reaction forces during a double step at a self-selected walking speed. A subsample of 46 participants repeated this procedure after a period of 7-16 months. The application of support vector machines resulted in classification rates of 99.8% (1278 out of 1280) and 99.4% (914 out of 920) for the initial subject-classification and the subsample follow-up-classification, respectively. The results showed that gait patterns based on time-continuous ground reaction forces were unique to an individual and could be differentiated from those of other individuals. Support vector machines classified gait patterns to the corresponding individual almost error-free. Hence, human gait is not only different between individuals but also exhibits unique individual characteristics that are persistent over years. Our findings provide evidence for the individual nature of human walking and emphasise the need to evaluate individualised clinical approaches for diagnoses and therapy.

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression.

BACKGROUND: Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation. METHOD: To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase. RESULTS: TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially. CONCLUSIONS: vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory.

Daily changes of individual gait patterns identified by means of support vector machines.

Despite the common knowledge about the individual character of human gait patterns and about their non-repeatability, little is known about their stability, their interactions and their changes over time. Variations of gait patterns are typically described as random deviations around a stable mean curve derived from groups, which appear due to noise or experimental insufficiencies. The purpose of this study is to examine the nature of intrinsic inter-session variability in more detail by proving separable characteristics of gait patterns between individuals as well as within individuals in repeated measurement sessions. Eight healthy subjects performed 15 gait trials at a self-selected speed on eight days within two weeks. For each trial, the time-continuous ground reaction forces and lower body kinematics were quantified. A total of 960 gait patterns were analysed by means of support vector machines and the coefficient of multiple correlation. The results emphasise the remarkable amount of individual characteristics in human gait. Support vector machines results showed an error-free assignment of gait patterns to the corresponding individual. Thus, differences in gait patterns between individuals seem to be persistent over two weeks. Within the range of individual gait patterns, day specific characteristics could be distinguished by classification rates of 97.3% and 59.5% for the eight-day classification of lower body joint angles and ground reaction forces, respectively. Hence, gait patterns can be assumed not to be constant over time and rather exhibit discernible daily changes within previously stated good repeatability. Advantages for more individual and situational diagnoses or therapy are identified.

Vitamin K1 in oral solution or tablets: a crossover trial and two randomized controlled trials to compare effects.

BACKGROUND: Vitamin K1 (VK1) reverses the effects of vitamin K antagonists (VKAs). The literature shows that the bioavailability from solutions might be higher than that from tablets, possibly resulting in different effects. OBJECTIVES: To compare the bioavailability and effect on the International Normalized Ratio (INR) of 5-mg VK1 tablets and solution in three randomized clinical trials. METHODS AND RESULTS: The bioavailability was determined in a crossover trial with 25 healthy volunteers. VK1 plasma concentrations were assessed at 0, 2, 4, 5, 6, 8, 10 and 24 h, and the area under the curve was higher in the solution group than in the tablet group (mean difference 365 µg L(-1) h, 95% confidence interval [CI] 230-501, P < 0.0001). In the other two trials, the effects of both formulations on the INR were measured at 0, 24 and 48 h. In the second trial, on 72 patients on phenprocoumon with planned invasive procedures, both formulations were similarly effective, because all patients reached an INR of < 2.0, which was the primary endpoint. In the last trial, on 72 patients on phenprocoumon with an INR of 7.0-11.0, the INR decreased slightly more in the solution group (4.7, 95% CI 4.3-5.1) than in the tablet group (4.2, 95% CI 3.8-4.6). The solution group had a 3.3-fold increased likelihood (95% CI 0.7-15.1) of reaching an INR of < 2.0 at 48 h. Additionally, the increases in VK1 concentrations were similar (tablets, 3.2 µg L(-1) ; solution, 3.4 µg L(-1) ; P = 0.99) after 24 h. CONCLUSIONS: VK1 tablets are at least as clinically effective as the solution in countering VKAs.

[Avoidable visual impairment among residents in care institutions: lessons from an intervention project in the Den Bosch region]. / Onnodige slechtziendheid onder ouderen in zorginstellingen: lessen uit een interventieproject in de regio Den Bosch.

INTRODUCTION: Many elderly in care institutions in The Netherlands are visually impaired (visual acuity < 0.3). They fall more frequently, are more depressed and require more care. In this project visually impaired residents were identified and referred for adequate eye care. The aim of this study is to evaluate the intervention, including validation of the screening, assessment of the prevalence and causes of visual impairment as well as the outcome of the treatment. The effectiveness of the care chain is also evaluated. MATERIALS AND METHODS: 640 residents were offered a basic eye examination and 210 of them were referred, via their general practitioner, to an optometrist (10), ophthalmologist (98), or centre for visually impaired persons (1). RESULTS: Compliance in this study was poor. The prevalence of visual impairment (24%) was lower than in comparable studies. Cataract was the main cause in 51%. Overall 17 (8.1%) residents were treated by ophthalmologists and nine (4.3%) were referred to optical shops. Constraints in the care chain are identified. DISCUSSION: Vision screening in care institutions for elderly is feasible and useful. The care chain should be shorter and simpler. That will increase the effectiveness of this intervention, and thereby the quality of life for many residents.

Bioinformatics tools allow targeted selection of chromosome enumeration probes and aneuploidy detection.

Accurate determination of cellular chromosome complements is a highly relevant issue beyond prenatal/pre-implantation genetic analyses or stem cell research, because aneusomy may be an important mechanism by which organisms control the rate of fetal cellular proliferation and the fate of regenerating tissues. Typically, small amounts of individual cells or nuclei are assayed by in situ hybridization using chromosome-specific DNA probes. Careful probe selection is fundamental to successful hybridization experiments. Numerous DNA probes for chromosome enumeration studies are commercially available, but their use in multiplexed hybridization assays is hampered due to differing probe-specific hybridization conditions or a lack of a sufficiently large number of different reporter molecules. Progress in the International Human Genome Project has equipped the scientific community with a wealth of unique resources, among them recombinant DNA libraries, physical maps, and data-mining tools. Here, we demonstrate how bioinformatics tools can become an integral part of simple, yet powerful approaches to devise diagnostic strategies for detection of aneuploidy in interphase cells. Our strategy involving initial in silico optimization steps offers remarkable savings in time and costs during probe generation, while at the same time significantly increasing the assay's specificity, sensitivity, and reproducibility.

BAC-FISH assays delineate complex chromosomal rearrangements in a case of post-Chernobyl childhood thyroid cancer.

Structural chromosome aberrations are known hallmarks of many solid tumors. In the papillary form of thyroid cancer (PTC), for example, activation of the receptor tyrosine kinase (RTK) genes, RET and neurotrophic tyrosine kinase receptor type I (NTRK1) by intra- and interchromosomal rearrangements has been suggested as a cause of the disease. However, many phenotypically similar tumors do not carry an activated RET or NTRK-1 gene or express abnormal ret or NTRK-1 transcripts. Thus, we hypothesize that other cellular RTK-type genes are aberrantly expressed in these tumors. Using fluorescence in situ hybridization-based methods, we are studying karyotype changes in a relatively rare subgroup of PTCs, i.e., tumors that arose in children following the 1986 nuclear accident in Chernobyl, Ukraine. Here, we report our technical developments and progress in deciphering complex chromosome aberrations in case S48TK, an aggressively growing PTC cell line, which shows an unusual high number of unbalanced translocations.

Heterophilic antibodies may be a cause of falsely low total IGF1 levels.

BACKGROUND: A low serum total IGF1 is considered as a diagnostic indicator of GH deficiency (GHD) in the presence of hypopituitarism. Introduction of IRMA and chemiluminescent immunometric assay (CLIA) IGF1 immunoassays has introduced endogenous antibodies as a new source of interference. In general, this goes unnoticed and might lead to unnecessary diagnostic and therapeutic interventions. CASE: A 56-year-old man was referred with a decline in physical performance, unexplained osteopenia, and weight loss of 3 kg over the past 8 months. Although clinical signs and symptoms were unremarkable, laboratory results pointed to secondary hypothyroidism and secondary hypogonadism. In addition, the serum total IGF1 level (CLIA; Siemens Medical Solutions Diagnostics) was in the low normal range. Two GH stimulation tests were performed, but these tests did not support the diagnosis GHD. Moreover, IGF1 bioactivity measured by the kinase receptor activation assay was normal. Interference of heterophilic antibodies was considered. After pretreatment with specific heterophilic blocking tubes that contain blocking reagents to eliminate heterophilic antibodies, serum-free thyroxine, testosterone, and IGF1 levels turned out to be normal. CONCLUSION: To the best of our knowledge, we here describe the first case in the literature of a patient with low serum total IGF1 levels due to interference from heterophilic antibodies in the used IGF1 immunoassay. When confronted with low-IGF1 levels that do not fit the clinical picture, interference of heterophilic antibodies should be considered in the differential diagnosis.

Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1.

BACKGROUND: Psoriasis is a genetically complex, chronic inflammatory skin disease. The authors have previously identified a susceptibility locus on chromosome 19p13 (PSORS6). METHODS AND RESULTS: In a follow-up linkage disequilibrium (LD) study in an independent family based cohort, the authors found evidence for association to a newly discovered microsatellite at this locus (D19SPS21, p<5.3x10(-5)). An LD based association scan in 300 trios revealed association to several single, single nucleotide polymorphisms (SNPs) in one LD block. When the authors stratified this cohort for carrying the PSORS1 risk allele at the HLA-C locus, evidence for association became much stronger at single SNP and haplotype levels (p values between 1.0x10(-4) and 8.0x10(-4)). In a replication study of 1114 patients and 937 control individuals, evidence for association was also observed after stratification to the PSORS1 risk allele. In both study groups, logistic regression showed evidence for interaction between the risk alleles at PSORS1 and PSORS6. Best p values for rs12459358 in both study groups remained significant after correction for multiple testing. The associated LD block did not comprise any known genes. Interestingly, an adjacent gene, MUC16, coding for a large glycosylated protein expressed in epithelia and of unknown function, could be shown to be also expressed in tissues relevant for pathogenesis of psoriasis such as skin and thymus. Immunohistochemical analyses of skin revealed focal staining for MUC16 in suprabasal epidermal cells. Further functional studies are required to clarify its potential role in psoriasis and identify the causal variant(s) at this locus. CONCLUSION: The data establish PSORS6 as a confirmed psoriasis susceptibility locus showing interaction with PSORS1.

DNA probe pooling for rapid delineation of chromosomal breakpoints.

Structural chromosome aberrations are hallmarks of many human genetic diseases. The precise mapping of translocation breakpoints in tumors is important for identification of genes with altered levels of expression, prediction of tumor progression, therapy response, or length of disease-free survival, as well as the preparation of probes for detection of tumor cells in peripheral blood. Similarly, in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for carriers of balanced, reciprocal translocations benefit from accurate breakpoint maps in the preparation of patient-specific DNA probes followed by a selection of normal or balanced oocytes or embryos. We expedited the process of breakpoint mapping and preparation of case-specific probes by utilizing physically mapped bacterial artificial chromosome clones. Historically, breakpoint mapping is based on the definition of the smallest interval between proximal and distal probes. Thus, many of the DNA probes prepared for multiclone and multicolor mapping experiments do not generate additional information. Our pooling protocol, described here with examples from thyroid cancer research and PGD, accelerates the delineation of translocation breakpoints without sacrificing resolution. The turnaround time from clone selection to mapping results using tumor or IVF patient samples can be as short as 3 to 4 days.

Chromosomal changes characterize head and neck cancer with poor prognosis.

It is well established that genetic alterations may be associated to prognosis in tumor patients. This study investigates chromosomal changes that predict the clinical outcome of head and neck squamous cell carcinoma (HNSCC) and correlate to characteristic clinicopathological parameters. We applied comparative genomic hybridization (CGH) to tissue samples from 117 HNSCC patients scheduled for radiotherapy. Genomic aberrations occurring in more than five patients were studied for impact on locoregional progression (LRP)-free survival. p values were adjusted by the Hochberg-Benjamini procedure and significant aberrations and clinical variables subjected to a stepwise backwards Cox proportional model. Significant alterations were further analyzed by array-CGH and fluorescence in situ hybridization (FISH). In multivariate survival analysis gains on 1q and 16q predict reduced LRP-free survival independently from known prognostic factors. Cluster analysis separated the HNSCC cases into two groups (cluster 1 and 2) that are characterized by significant differences for imbalances in 13 chromosomal regions. Moreover, it became apparent that cluster 1 correlates to nonanemic patients, while cluster 2 represents predominantly anemic cases. Array-CGH pinpoints 16q24.3 to be the region of interest on chromosome 16 which was further verified by FISH analysis where an increased copy number of FANCA, a member of the Fanconi anemia/breast cancer pathway, could be identified. This study demonstrates that chromosomal gains on 1q and 16q as well as chromosomal loss on 18q represent prognostic markers in HNSCC and that these alterations may explain to some extent the dismal course of a subgroup of patients.

Novel insight in the association between salmonellosis or campylobacteriosis and chronic illness, and the role of host genetics in susceptibility to these diseases.

We studied the role of host genetics in the susceptibility to severe Salmonella and Campylobacter infections and chronic sequelae of these infections. Participants of a previous case-control study were sent a buccal swab kit and a questionnaire about occurrence of chronic sequelae. Single nucleotide polymorphisms (SNPs) in the TLR4 (rs4986790), IFNG (rs2430561 and rs1861493), STAT1 (rs1914408), IL1B (rs16944), NRAMP (SLC11A1 rs2276631), JUN (rs11688) and VDR (rs10735810) genes were determined. In total, 687 controls, 457 Campylobacter cases and 193 Salmonella cases participated. None of the SNPs were associated with Campylobacter or Salmonella infections. None of the participants developed Guillain-Barré, Miller-Fisher or Reiter's syndrome. Reactive arthritis occurred in 5% and 2% of cases and controls, respectively. Campylobacter cases more frequently experienced gastroenteritis episodes than controls. Campylobacter or Salmonella infection in women, use of proton pump inhibitors and an SNP in the IFNG gene were independent risk factors for reactive arthritis. Another SNP in the IFNG gene and use of proton pump inhibitors were risk factors for recurrent episodes of gastroenteritis. In conclusion, reactive arthritis and recurrent gastroenteritis episodes are common after infection and host genetic factors play a role in susceptibility to these long-term health effects.

Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition.

INTRODUCTION: The beneficial effects of ACE inhibitors are generally ascribed to blockade of neurohormonal activation. However, especially in chronic heart failure (CHF) patients plasma angiotensin II and aldosterone levels can be elevated despite ACE inhibition, the so-called ACE escape. In the present study, we aimed to identify the frequency and determinants of ACE escape in CHF patients. METHODS: We studied 99 stable chronic heart failure patients (NYHA class III and IV, 66% ischemic etiology) receiving long-term therapy with ACE inhibitors. In all patients, cardiac, renal, and neurohormonal parameters were measured. ACE escape was defined as plasma angiotensin level > or = 16 pmol/L. RESULTS: Mean (+/- SD) left ventricular ejection fraction of our 99 patients (79 men and 20 women, age 69 +/- 12 years) was 28 +/- 10%. In addition to an ACE inhibitor, 93% of patients received diuretics, 71% a beta-blocker, and 49% spironolactone. None of the patients used an angiotensin receptor blocker. In our population, 45% of the patients had an angiotensin II plasma concentration higher than 16 pmol/L (median concentration was 14.1 pmol/L). Spironolactone use was an independent predictor of elevated plasma angiotensin II levels. Furthermore, spironolactone users had significantly higher plasma active renin protein and aldosterone levels. Plasma angiotensin II concentration was positively correlated to active renin, plasma angiotensin I and plasma aldosterone. No correlation was found between plasma angiotensin II levels and serum ACE activity, dose of ACE inhibitor, or duration of use. CONCLUSION: In a group of severe chronic heart failure patients, 45% had elevated plasma angiotensin II levels independent of serum ACE activity despite long-term ACE inhibitor use. Although a causal link could not be proven, an association was found between spironolactone use and active renin protein, angiotensin II and aldosterone levels, suggesting that escape from ACE is mainly caused by a feedback mechanism.

Evidence for susceptibility determinant(s) to psoriasis vulgaris in or near PTPN22 in German patients.

INTRODUCTION: Variant R620W of protein tyrosine phosphatase non-receptor type 22 (PTPN22) has consistently been reported as a susceptibility factor for several autoimmune diseases. We investigated its role in susceptibility to psoriasis, the relevance of possibly other disease-causing variants, and interdependency of the major risk factor for psoriasis at PSORS1. METHODS: R620W was tested in a case-control study initially with 375 German patients and then with an enlarged sample of an additional 418 patients. Analyses were extended to linkage disequilibrium (LD) based haplotypes. Potential interaction between risk haplotypes of PTPN22 and the PSORS1 associated risk allele was tested by regression analysis. PTPN22 coding sequence was determined in 20 patients carrying the risk haplotype. Association and regression analysis were also performed in the extended case-control study. RESULTS: R620W was not associated in either case-control study, while significant association (corrected for multiple testing) with one haplotype (C-4) of the LD block encompassing PTPN22 as well with another haplotype (B-3) within an adjacent telomeric LD block was detected. No evidence for interaction between risk haplotype C-4 and the PSORS1 associated risk allele was found. Sequencing excluded other coding variants within PTPN22 as a basis for association findings. Analysis of the extended study group confirmed association for haplotypes B-3 and C-4 and independence of risk haplotypes C-4 and PSORS1. DISCUSSION: We exclude a major role of *620W in German psoriasis patients but suggest that other susceptibility determinant(s) within non-coding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor.