Development of a body dysmorphic disorder screener for DSM-5 (BDDS-5).

Early identification of individuals with Body dysmorphic disorder (BDD) is essential to direct them to appropriate care and to reduce the chance of developing or maintaining comorbid psychiatric disorders (like an eating disorder (ED)). The present study aimed to develop a simple screener, the Body Dysmorphic Disorder Screener for DSM-5 (BDDS-5), to overcome existing screeners' limitations and test its psychometric properties. The BDDS-5 consists of 12 statements with dichotomous answer options. Specific attention is paid to the readability of the screener for those with lower reading skills. Additional eating disorder screening questions (S section) were added to investigate whether these questions are necessary for detecting potential BDD cases. Finally, the factor structure, internal consistency, and validity of the BDDS-5 were examined within populations with a high risk of screening positive for BDD or ED. Principal axis factor analysis showed that two factors accounted for 63.5% of the variance. The factor analysis was based on polychoric correlation. Based on the BDDS-5, 33 persons (14% of N = 235) were screened as likely BDD cases. Nineteen persons were excluded as potential BDD cases based on the eating disorder related question (question D). Based on the S-section, this turned out to be largely correct for the majority, however, in 8% (n = 4) of the cases BDD was probably missed. The convergent validity appeared to be high (r > 0.80) with three other BDD measures. The BDDS-5 is a valid and widely applicable screener for BDD that may help in the early detection of BDD. The BDDS-5 uses simple wording and is thus suitable for people 8 years and older.

The association of the lipid profile with knee and hand osteoarthritis severity: the IMI-APPROACH cohort.

OBJECTIVE: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. DESIGN: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. RESULTS: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. CONCLUSIONS: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity.

Identification of pharmacogenetic biomarkers for efficacy of cytoreductive surgery plus hyperthermic intraperitoneal mitomycin C in patients with colorectal peritoneal metastases.

INTRODUCTION: Mitomycin C (MMC) is commonly used in patients with colorectal peritoneal metastases (CPM) treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). MMC requires metabolic activation prior to exert its cytotoxic effect of which the main activating enzymes are NQO1 and POR. However, not all patients are able to activate MMC for example due to polymorphisms in the genes encoding these enzymes. The aim of this study was to investigate the association of NQO1∗2, NQO1∗3, and POR∗28 with the efficacy of CRS + HIPEC with MMC in patients with CPM. METHOD: A retrospective follow-up design was used to study genetic association in patients with histologically proven CPM treated with CRS + HIPEC with MMC with respect to peritoneal recurrence rate after 3 months (primary endpoint), after 6 months, disease-free survival and overall survival. Genetic polymorphisms NQO1∗2, NQO1∗3, and POR∗28 were tested for association. RESULTS: A total of 253 patients were included. In NQO1∗3 carriers the peritoneal recurrence rate 3 and 6 months after HIPEC was significantly higher than in wild type patients, respectively 30.0% vs 3.8% (p = 0.009) and 40.0% vs 12.1% (p = 0.031). In line with these results, NQO1∗3 was associated with a shorter disease-free survival (HR 2.04, 95% CI [1.03-4.03]). There was no significant association with overall survival (HR 1.42, 95% CI [0.66-3.07]). CONCLUSION: Carriership of the NQO1∗3 allele is associated with worse peritoneal recurrence rate and disease-free survival. These results suggest that individualization of patients treated with CRS + HIPEC based upon pharmacogenetics may be beneficial.

Percentile curves for the knee injury and osteoarthritis outcome score in the middle-aged Dutch population.

OBJECTIVE: To improve the interpretation of the Knee injury and Osteoarthritis Outcome Score (KOOS) in individual patients, we explored associations with age, sex, BMI, history of knee injury and presence of clinical knee osteoarthritis, and developed percentile curves. METHODS: We used cross-sectional data of middle-aged individuals from the population-based Netherlands Epidemiology of Obesity (NEO) study. Clinical knee osteoarthritis was defined using the ACR classification criteria. KOOS scores were handled according to the manual (zero = extreme problems, 100 = no problems). Patient characteristics associated with KOOS were explored using ordered logistic regression, and sex and body mass index (BMI)-specific percentile curves were developed using quantile regression with fractional polynomials. The curves were applied as a benchmark for comparison of KOOS scores of participants with knee osteoarthritis and comorbidities. RESULTS: The population consisted of 6,643 participants (56% women, mean (SD) age 56(6) years). Population-based KOOS subscale scores (median; interquartile range) near optimum: pain (100;94-100), symptoms (96;86-100), ADL function (100;96-100), sport/recreation function (100;80-100), quality of life (100;75-100). Worse KOOS scores were observed in women and in participants with higher BMI. Clinical knee osteoarthritis was defined in 15% of participants, and was, in comparison to other patient characteristics, associated with the highest odds of worse KOOS scores. Furthermore, presence of any comorbidity and cardiovascular disease specifically, was associated with worse KOOS scores, particularly in women. CONCLUSIONS: In the middle-aged Dutch population KOOS scores were generally good, but worse in women and with higher BMI. These percentile curves may be used as benchmarks in research and clinical practice.

[Work sampling in ophthalmological clinical studies. A multicenter field study]. / Zeiterfassung in ophthalmologischen klinischen Studien. Eine multizentrische Feldstudie.

BACKGROUND: Work in clinical studies is generally more elaborate and therefore more time-consuming in comparison to the clinical routine. The purpose of this study was to systematically investigate the time consumption in the German ophthalmological clinical trial centers. METHODS: The members of the working group of the German Ophthalmology Society clinical study centers (Arbeitsgemeinschaft DOG Klinische Studienzentren) were asked to fill in three questionnaires about best estimations for the time spent on study-related procedures and administration. Additionally, work sampling was performed for each employee at each study center over a period of 3 weeks. RESULTS: The questionnaires were completed by 9 of the 11 centers. Overall, 5504 working hours were recorded. On an average working day, the time spent for both documentation and administration averaged 4 h each. Operative interventions consumed a significant amount of time (2.8 h), as did ophthalmological examinations (2.5 h) and obtaining informed consent (1.5 h). The recorded time consumption for visual acuity testing, informed consent and documentation was well aligned with the best estimates of the three questionnaires. By contrast, interventions, ophthalmological examinations and biomaterial sample handling were underrated in the best estimations. DISCUSSION: A considerable amount of time in clinical studies is spent on documentation and administration. From work sampling, ophthalmological examinations and biomaterial sampling turned out to be surprisingly time consuming. This is probably due to preparation and postprocessing tasks. It is important to consider this when calculating the overall costs of a clinical study. In addition, many administrative activities cannot be attributed to specific patients and can therefore not be compensated on the basis of case payments alone. Additional remuneration is required to fully cover the costs in an ophthalmological study center.

Three-dimensional soft tissue effects of mandibular midline distraction and surgically assisted rapid maxillary expansion: an automatic stereophotogrammetry landmarking analysis.

Studies on mandibular midline distraction (MMD) are mostly performed using conventional research methods. Concerning surgically assisted rapid maxillary expansion (SARME), more research is conducted using three-dimensional (3D) techniques. Research on bimaxillary expansion, the combination of MMD and SARME, is reported sparsely. The main objective of this study was to provide a 3D evaluation of soft tissue effects following SARME and/or MMD. Patients who underwent SARME and/or MMD between 2008 and 2013 were included. Stereophotogrammetry was undertaken at the following time points: preoperative (T1), immediately post-distraction (T2), 1year postoperative (T3). An automatic 3D facial landmarking algorithm using two-dimensional Gabor wavelets was applied for the analysis. Twenty patients who had undergone SARME were included, 12 of whom had undergone bimaxillary expansion. Age at the time of surgery ranged from 16 to 47 years. There was a significant downward displacement of soft tissue pogonion. Furthermore, there was a significant mean increase of 2.20mm in inter-alar width and a non-significant mean increase of 1.77mm in inter-alar curvature point width. In conclusion, automatic stereophotogrammetry landmarking analysis of soft tissue effects showed downward displacement of soft tissue pogonion following bimaxillary expansion and transverse widening of the inter-alar width and a tendency towards an increase in inter-alar curvature point width after SARME.

[Religious beliefs and spirituality in medical residency : A survey among physicians in charge of training psychiatry and psychotherapy]. / Religiosität und Spiritualität in der Facharztweiterbildung : Eine Umfrage bei den Weiterbildungsermächtigten für Psychiatrie und Psychotherapie.

Religion and spirituality (R/S) as empirically measurable and treatment-relevant variables are growing in significance in psychiatry and psychotherapy worldwide. In a survey conducted among physicians in charge of psychiatric residency training in Germany respondents were asked about the integration of R/S in their curricula. Data suggest that subjects (n = 285) attach considerable importance to R/S and especially to existential issues. The importance of R/S in psychiatric training is essentially linked to the trainers' personal views of the world and the corporate culture of the training centers. A possible selection bias and the need to integrate R/S in psychiatric training on the basis of scientific evidence and ethical considerations are discussed.

Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies.

Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers.

Genetic variants in the region of the C1q genes are associated with rheumatoid arthritis.

Rodent models for arthritis implicate a role for complement in disease development and progression. In humans, complement deposition has been observed in inflamed synovia of rheumatoid arthritis (RA) patients. In this study we analysed whether genetic variants of complement component C1q predispose to RA. We genotyped single nucleotide polymorphisms (SNPs) in and around the C1q genes, C1qA, C1qB and C1qC, in a Dutch set of 845 RA cases and 1046 controls. Replication was sought in a sample set from North America (868 cases/1193 controls), and a meta-analysis was performed in a combined samples set of 8000 cases and 23 262 controls of European descent. We determined C1q serum levels in relation to C1q genotypes. In the discovery phase, five of the 13 SNPs tested in the C1q genes showed a significant association with RA. Additional analysis of the genomic area around the C1q genes revealed that the strongest associating SNPs were confined to the C1q locus. Within the C1q locus we observed no additional signal independent of the strongest associating SNP, rs292001 [odds ratio (OR) = 0·72 (0·58-0·88), P = 0·0006]. The variants of this SNP were associated with different C1q serum levels in healthy controls (P = 0·006). Interestingly, this SNP was also associated significantly in genome-wide association studies (GWAS) from the North American Rheumatoid Arthritis Consortium study, confirming the association with RA [OR = 0·83 (0·69-1·00), P = 0·043]. Combined analysis, including integrated data from six GWAS studies, provides support for the genetic association. Genetic variants in C1q are correlated with C1q levels and may be a risk for the development of RA.

The major risk alleles of age-related macular degeneration (AMD) in CFH do not play a major role in rheumatoid arthritis (RA).

Because activation of the alternative pathway (AP) of the complement system is an important aspect of both age-related macular degeneration (AMD) and rheumatoid arthritis (RA), we wished to address the question whether genetic risk factors of the AP inhibitor complement factor H (CFH) for AMD would also be risk factors for RA. For this purpose we genotyped single nucleotide polymorphisms (SNPs) in a Dutch set of RA patients and controls. Similarly, a meta-analysis using a Spanish cohort of RA as well as six large genome-wide association studies (GWAS) studies was performed. For these SNPs we analysed more than 6000 patients and 20,000 controls. The CFH variants, I62V, Y402H, IVS1 and IVS10, known to associate strongly with AMD, did not show a significant association with the risk of developing RA despite a strong statistical power to detect such differences. In conclusion, the major risk alleles of AMD in CFH do not have a similar effect on developing RA.

Modulation of disease risk according to a cathepsin D / apolipoprotein E genotype in Parkinson's disease.

Aspartyl protease Cathepsin D (CTSD) has been suggested to play a role in the pathogenesis of sporadic Alzheimer's disease (AD) due to interference with protein degradation mechanisms. A C224T (A38V) polymorphism in exon 2 of the CTSD gene is reported to be associated with an increased risk for AD. The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of this polymorphism in PD. Using association studies in 457 German PD patients and 340 controls we found no evidence for direct association between the CTSD genotype and PD. However, stratification for the apolipoprotein E (APOE) epsilon4 allele suggests a protective effect of the CTSD T-allele in PD (OR = 0.24, p = 0.002). Our findings suggest interference of CTSD and APOE polymorphisms in the pathogenesis of PD, in the sense of modulating disease risk.

Predicting time on the waiting list for HLA matched corneal grafts.

Recent studies report the beneficial effect of HLA matching for the long-term prognosis of penetrating keratoplasty (KP). This improvement in prognosis, however, has to be weighed against the additional waiting time while a HLA compatible graft is found. Precise estimation of this additional waiting period is a prerequisite for informed consent on the waiting policy. A mathematical model based on survival analysis and HLA haplotype frequencies was used to estimate time on the waiting list for each of 1400 HLA typed patients registered at the Lions Cornea Bank North Rhine Westfalia (NRW). Additionally, the waiting period for each patient was retrospectively determined. Both values were tested for correlation. This analysis was performed for acceptance of up to two mismatches on HLA-A, -B and -DR. The median predicted waiting period was compatible with the median waiting period in retrospective simulation. Correlation of both entities was statistically significant also. Predicted time on the waiting list as derived from the patient's HLA genotype and a comprehensive database of HLA haplotype frequencies is thus a valuable tool for management of HLA-matching in KP.

Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations.

Multiple sclerosis (MS) is an autoimmune disease displaying different clinical courses. In this multifactorial disease complex environmental as well as genetic predisposition factors contribute to the disease manifestation. Following the candidate gene approach we analysed several genes of the NFkappaB cascade, which are prime candidates for MS because of their involvement in almost all immunological reactions. MS association was excluded for the NFKB1 and NFKB3 genes, which show remarkably low degrees of polymorphism. The genes of NFkappaB inhibitors exhibit more sequence variations. In the IKBL gene a predisposing allele was identified (13.1% vs 7.5% in the control group, P < 0.001). This difference in the allelic distribution was even increased in the group of MS patients with a relapsing remitting course of the disease (14.9%, P < 0.0001). A protecting allele was found in the NFKBIA promotor for the patients with primary progressive MS (15.4% vs 28.4% in the control group, P < 0.01). Given predisposing alleles increase MS risk dramatically in certain combinations.

Nuclear coat and viruslike particles in the midgut epithelium of Glossina morsitans sspp.

The ultrastructural aspects of the nuclear coat formation in midgut epithelial cells of pupae and adult flies of G. morsitans sspp. are described. Out of four different species of Glossina examined, this peculiar structure was only found in G. morsitans sspp. Three different types of viruslike particles were found in midgut epithelial cells. One type which is of the same kind of particle found in the salivary glands, lies inside of cytoplasmic vesicles. Two other types of particles were detected in the nuclei.

Quantitative ultrastructural investigations of the life cycle of Trypanosoma brucei: a morphometric analysis.

The quantitative ultrastructure of the developmental stages of Trypanosoma brucei brucei in its vector Glossina morsitans was studied by morphometric analysis. Values from ectoperitrophic midgut forms, proventricular forms, epimastigote and metacyclic forms in the salivary gland are compared with results from bloodstream forms, published previously. Significant differences in the volume densities of the trypanosome's single mitochondrion, of microbody-like organelles and in the surface densities of inner and outer mitochondrial membranes were found throughout the whole life cycle. A great increase in volume density of the mitochondrion was observed after transfer to the insect host; reduction took place during metacyclic development. Parallel to the biogenesis of the mitochondrion a reduction of microbodies was found in proventricular forms and there was a great increase in metacyclic forms concomitant with the regression of the mitochondrion. Metacyclic forms had a close quantitative morphologic similarity to bloodstream forms. The results are discussed in connection with changes in structure and in oxidative metabolism.