Publications by authors named "Klaus Lenz"

44 Publications

Grouping of UVCB substances with new approach methodologies (NAMs) data.

ALTEX 2021 9;38(1):123-137. Epub 2020 Oct 9.

Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA.

One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (unknown or variable composition, complex reaction products and biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, could be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data were used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of repre­sentative substances in each group for testing when needed, and to fill data gaps by read-across.
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http://dx.doi.org/10.14573/altex.2006262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900923PMC
October 2020

Laparoscopic Versus Open Liver Resection for Benign Tumors and Lesions: A Case Matched Study with Propensity Score Matching.

J Laparoendosc Adv Surg Tech A 2019 Dec 31;29(12):1518-1525. Epub 2019 Oct 31.

Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Germany.

In recent years, minimally invasive surgical approaches have gained an increasingly important role in hepatobiliary surgery. The aim of this study was to investigate the safety and potential benefits of laparoscopic liver resection (LLR) compared with open liver resection (OLR) for benign liver tumors and lesions. Between January 2009 and December 2017, 182 patients underwent liver resection for benign liver tumors and lesions at our center. After exclusion of 15 patients, the remaining 167 patients were divided into LLR group ( = 54) and OLR group ( = 113) and were compared with regard to perioperative outcomes. To overcome selection bias, a 1:1 propensity score matching (PSM) was performed. In addition, patients undergoing major hepatectomy were divided into major-LLR and major-OLR groups and perioperative outcomes evaluated. After PSM, 35 patients were included in the OLR group and 35 patients in the LLR group. The LLR group had a significantly shorter median intensive care unit (ICU) stay (LLR: 1 [0-4] days; OLR: 1 [0-3] days;  = .009) and median hospital stay (length of stay [LOS]) (LLR: 7 [4-14] days; OLR: 10 [5-16] days;  < .001). There were no statistically significant differences in postoperative complications graded as Clavien-Dindo ≥III (LLR: 11.4%; OLR: 2.9%;  = .375) in both groups. Postoperative 90-day mortality was 0% in both groups. When comparing major-LLR ( = 8) with major-OLR ( = 59), patients in the major-LLR group had a significantly longer median operation time (major-LLR: 403 [240-501] minutes; major-OLR: 221.5 [111-529] minutes;  < .001), but a significantly shorter median LOS (major-LLR: 7 [5-14] days; major-OLR: 9 [7-129] days;  = .013). The rate of major complications (Dindo Classification ≥III) for major-LLR was 0% and for major-OLR it was 16.9% ( = .207). Our case-matched study demonstrates shorter ICU and hospital stay using laparoscopic techniques while maintaining high-quality perioperative outcomes. Based on our findings, we suggest preferring the LLR over OLR for benign liver tumors and lesions regardless of the resection extent.
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http://dx.doi.org/10.1089/lap.2019.0427DOI Listing
December 2019

Predictive MGMT status in a homogeneous cohort of IDH wildtype glioblastoma patients.

Acta Neuropathol Commun 2019 06 5;7(1):89. Epub 2019 Jun 5.

Department of Neurosurgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.

Methylation of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter is predictive for treatment response in glioblastoma patients. However, precise predictive cutoff values to distinguish "MGMT methylated" from "MGMT unmethylated" patients remain highly debated in terms of pyrosequencing (PSQ) analysis. We retrospectively analyzed a clinically and molecularly very well-characterized cohort of 111 IDH wildtype glioblastoma patients, who underwent gross total tumor resection and received standard Stupp treatment. Detailed clinical parameters were obtained. Predictive cutoff values for MGMT promoter methylation were determined using ROC curve analysis and survival curve comparison using Log-rank (Mantel-Cox) test. MGMT status was analyzed using pyrosequencing (PSQ), semi-quantitative methylation specific PCR (sqMSP) and direct bisulfite sequencing (dBiSeq). Highly methylated (> 20%) MGMT correlated with significantly improved progression-free survival (PFS) and overall survival (OS) in our cohort. Median PFS was 7.2 months in the unmethylated group (UM, < 10% mean methylation), 10.4 months in the low methylated group (LM, 10-20% mean methylation) and 19.83 months in the highly methylated group (HM, > 20% mean methylation). Median OS was 13.4 months for UM, 17.9 months for LM and 29.93 months for HM. Within the LM group, correlation of PSQ and sqMSP or dBiSeq was only conclusive in 51.5% of our cases. ROC curve analysis revealed superior test precision for survival if additional sqMSP results were considered (AUC = 0.76) compared to PSQ (cutoff 10%) alone (AUC = 0.67). We therefore challenge the widely used, strict PSQ cutoff at 10% which might not fully reflect the clinical response to alkylating agents and suggest applying a second method for MGMT testing (e.g. MSP) to confirm PSQ results for patients with LM MGMT levels if therapeutically relevant.
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http://dx.doi.org/10.1186/s40478-019-0745-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549362PMC
June 2019

Performance of specific immunoglobulin E tests for diagnosing occupational asthma: a systematic review and meta-analysis.

Occup Environ Med 2019 04 25;76(4):269-278. Epub 2019 Feb 25.

European Society for Environmental and Occupational Medicine (EOM), Berlin, Germany.

Objectives: To determine the test performance parameters for the retrievable range of high-molecular-weight (HMW) and low-molecular-weight (LMW) occupational allergens and to evaluate the impact of allergenic components and the implementation of measures for test validation.

Methods: A protocol with predefined objectives and inclusion criteria was the basis of an electronic literature search of MEDLINE and EMBASE (time period 1967-2016). The specific inhalation challenge and serial peak flow measurements were the reference standards for the specific IgE (sIgE) test parameters. All of the review procedures were reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Results: Seventy-one studies were selected, and 62 entered meta-analysis. Pooled pairs analysis indicated a sensitivity of 0.74(95% CI 0.66 to 0.80) and specificity of 0.71(95% CI 0.63 to 0.77) for HMW allergens and a sensitivity of 0.28(95% CI 0.18 to 0.40) and specificity of 0.89(95% CI 0.77 to 0.95) for LMW allergens. Component-specific analysis improved the test parameters for some allergens. Test validation was handled heterogeneously among studies.

Conclusion: sIgE test performance is rather satisfactory for a wide range of HMW allergens with the potential for component-specific approaches, whereas sensitivity for LMW allergens is considerably lower, indicating methodological complications and/or divergent pathomechanisms. A common standard for test validation is needed.
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http://dx.doi.org/10.1136/oemed-2018-105434DOI Listing
April 2019

Cryoballoon ablation in the elderly: one year outcome and safety of the second-generation 28mm cryoballoon in patients over 75 years old.

Europace 2018 05;20(5):772-777

Charité Universitaetsmedizin Berlin, Campus Benjamin Franklin, Department of Cardiology, Hindenburgdamm 30, 12203, Berlin, Germany.

Aims: The efficacy of the second-generation cryoballoon (CB) ablation in patients with atrial fibrillation (AF) has been demonstrated previously. Data on the efficacy of CB ablation in elderly patients is missing. The aim of this study was to evaluate the long-term success rate of pulmonary vein isolation (PVI) in patients ≥75 years vs. <75 years using the second-generation 28mm CB.

Methods And Results: Eighty patients [n = 40 ≥75 years (Group 1); n = 40 <75 years (Group 2)] with paroxysmal [n = 37 (46%) or persistent (n = 43 (54%)] AF were included. Median follow-up was 12 [6;18] months (Group 1 vs. 13 [6;27]) months (Group 2; P = 0.8). PVI was performed in all patients using cryoablation. Follow-up was obtained using 24h-Holter monitoring or via an implanted loop recorder or pacemaker. CHA2DS2VASc-Score (Group 1: 4 [4;5] vs. Group 2: 2 [1;3], P < 0.001) and HASBLED-Score (Group 1: 2 [2;3] and Group 2: 2 [1;3], (P = 0.009)) differed significantly between the two groups. Mean fluoroscopy time was 22.9 [16.3;31.9] in Group 1 and 24.5 [19.1;30.6] in Group 2 (P = 0.75), and mean procedure time was 125 min [105;151] in Group 1 and 130.5 min [117.5;147.3] in Group 2 (P = 0.66). Arrhythmia recurrence was similar in Group 1 and Group 2 (12/40 (30%) vs. 10/40 (25%) (P = 0.62). One transient ischaemic attack occurred in Group 2. No further major complications were documented in this patients cohort.

Conclusion: CB ablation in patients ≥75 years has favourable success rates and similar complication rates compared with patients <75 years.
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http://dx.doi.org/10.1093/europace/eux128DOI Listing
May 2018

Long-term follow up of 3 T MRI-detected brain lesions after percutaneous catheter-based left atrial appendage closure.

Catheter Cardiovasc Interv 2018 08 8;92(2):327-333. Epub 2018 May 8.

Department of Cardiology, Charité - Universitätsmedizin Berlin, University Hospital, Berlin, Germany.

Background: Left atrial appendage closure (LAAC) for stroke prevention is an increasingly performed intervention.

Aims: This prospective study aims to evaluate the incidence of long-term magnetic resonance imaging (MRI)-detected brain lesions as well as potential changes of neurocognitive function after percutaneous LAAC.

Methods: Brain MRI at 3 T was performed within 24 hr before and after LAAC. A follow-up MRI was carried out after three months. Neuro-cognitive examination using the National Institutes of Health Stroke Scale (NIHSS) score and the Montreal Cognitive Assessment (MoCA) Test was performed.

Results: Successful device implantation was achieved in all 25 patients (age 74.6 ± 10.2 years, male = 17) using the Amulet (n = 20), Occlutech (n = 3), or a Lambre (n = 2) device. In 12/25 (48%) patients, acute brain lesions (ABL) were detected after LAAC. A three-month follow-up MRI was performed in seven patients, and no new ABLs were seen. In 5/7 (71%) patients, there were no residual changes from the ABLs detectable. However, the FLAIR sequence was still positive in two patients. After LAAC, there were no significant differences in the MoCA-test (mean 24.3 ± 4.5 vs. 23.5 ± 4.5; P = 0.1) and the NIHSS-score (mean 0.9 ± 1.6 vs. 1.2 ± 1.8; P = 0.1). This was the same at the three-month follow-up (MoCA-test 23.5 ± 4.5 vs. 23.8 ± 2.7; P = 0.3; NIHSS-score 1.2 ± 1.8 vs. 1.0 ± 0.8; P = 0.4).

Conclusion: While new MRI-detected brain lesions are commonly observed after percutaneous LAAC, ABLs were no longer detectable in 71% of the patients at the three-month follow-up. There were no significant changes in neurocognitive function after LAAC and at the three-month follow-up.
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http://dx.doi.org/10.1002/ccd.27611DOI Listing
August 2018

[Effects of Bilingualism on Cognitive Functions in Early Childhood].

Prax Kinderpsychol Kinderpsychiatr 2018 Jan;67(1):2-17

Charité Universitätsmedizin - Berlin Klinik für Audiologie und Phoniatrie Augustenburger Platz 1 13353 Berlin Deutschland Klinik für Audiologie und Phoniatrie - Charité Universitätsmedizin - Berlin.

Effects of Bilingualism on Cognitive Functions in Early Childhood Studies have revealed advantages in cognitive functions among children with bilingualism. In this study we investigate cognitive functions in monolingual and bilingual preschool children taking socioeconomic status into account. The study population consists of 40 monolingual (German) children (M = 5.0 ± 0.4) and 23 bilingual (German/English) children (M = 5.1 ± 0.6). A neuropsychological test battery was conducted. The analyses revealed better performance for bilingual children. However, significant group differences were only found with respect to phonological short-term memory. Controlling for socioeconomic status, intelligence and balanced bilingualism, only slight advantages in cognitive performance were found for bilingual children. Due to high socioeconomic status in both groups, we suppose a ceiling effect. Children's development might be extensively promoted in upper class families and therefore bilingualism may not have additional impact on cognitive functions in these children.
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http://dx.doi.org/10.13109/prkk.2018.67.1.2DOI Listing
January 2018

Left atrial appendage angiography is associated with the incidence and number of magnetic resonance imaging-detected brain lesions after percutaneous catheter-based left atrial appendage closure.

Heart Rhythm 2018 01;15(1):3-8

Department of Cardiology, Charité-Universitätsmedizin Berlin, University Hospital, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Partner Site Berlin, Germany.

Background: Percutaneous catheter-based left atrial appendage closure (LAAC) is a procedure being increasingly performed in patients with atrial fibrillation and high bleeding risk.

Objective: The purpose of this study was to evaluate the incidence of magnetic resonance imaging (MRI)-detected acute brain lesions (ABLs) as well as potential changes in neurocognitive function after percutaneous LAAC in patients with atrial fibrillation.

Methods: Brain MRI at 3 T was performed within 24 hours before and after LAAC along with neurologic (National Institutes of Health Stroke Scale [NIHSS] score) and cognitive (Montreal Cognitive Assessment [MoCA] test) assessment. Acquired MRI sequences included high-resolution diffusion-weighted imaging as well as fluid-attenuated inversion recovery.

Results: Successful device implantation was achieved in all 23 patients (age 74.1 ± 10.5 years; 16 male) using the Amulet (n = 18), Occlutech (n = 3), or LAmbre (n = 2) device. Thirty-seven ABLs were detected by MRI in 12 of 23 patients (52%) after LAAC. The number of periprocedural LAA angiographies was significantly higher in patients with ABL than in those without ABL (1.67 ± 0.65 vs 1.18 ± 0.41; P = .048) and was associated with a higher number of ABL (ρ = 0.615; P = .033). Compared to pre-LAAC assessment, post-LAAC MoCA and NIHSS scores revealed similar results. After LAAC, MoCA test (mean 24.1 ± 4.6 vs 23.2 ± 4.6; P = .09) and NIHSS score (mean 1.0 ± 1.7 vs 1.2 ± 1.8; P = .1) were similar between patients with and those without ABL, respectively.

Conclusion: MRI-detected ABLs are commonly observed after percutaneous LAAC. The number of LAA angiographies is significantly associated with the number of ABLs; however, the clinical implications of ABL have yet to be determined.
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http://dx.doi.org/10.1016/j.hrthm.2017.11.015DOI Listing
January 2018

Apixaban, rivaroxaban, and dabigatran use in patients undergoing catheter ablation for atrial fibrillation using the second-generation cryoballoon.

Clin Cardiol 2017 Nov 28;40(11):1095-1099. Epub 2017 Aug 28.

Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

Background: Data are limited on the safety of periprocedural anticoagulation with novel oral anticoagulants (NOACs) in patients undergoing pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB) for the treatment of atrial fibrillation.

Hypothesis: We hypothesized that the incidence of acute periprocedural complications in patients undergoing PVI do not differ between patients treated with VKA compared to NOACs.

Methods: In 200 consecutive patients (mean age, 64.3 _ 10.6 years; female, n = 83) with symptomatic atrial fibrillation, PVI using the second-generation 28-mm CB was performed. In patients treated with NOACs, the medication was stopped the day of the procedure and continued the evening after the procedure with a reduced dosage. Patients treated with phenprocoumon were continued on uninterrupted phenprocoumon with a target INR of 2 to 3. If INR was <2, bridging with low-molecular-weight heparin was performed.

Results: Forty-seven of 200 patients (23.5%) were treated with a vitamin K antagonist (VKA) and 55 (27.5%) were treated with apixaban, 67 (33.5%) with rivaroxaban, and 31 (15.5%) with dabigatran. Seven (3.5%) major complications occurred in the overall population. Major bleeding complications did not differ significantly between the 2 groups (P = 0.23). One patient taking VKA had a pericardial tamponade at the end of the procedure; 2 patients treated with apixaban developed a groin hematoma requiring surgical intervention. Transient ischemic attack occurred in 1 patient of the apixaban and rivaroxaban group.

Conclusions: Apixaban, rivaroxaban, and dabigatran, compared with uninterrupted VKA, did not show a higher risk for major bleeding or ischemic complications in patients undergoing PVI using the second-generation CB.
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http://dx.doi.org/10.1002/clc.22782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490573PMC
November 2017

Two years outcome in patients with persistent atrial fibrillation after pulmonary vein isolation using the second-generation 28-mm cryoballoon.

Heart Rhythm 2016 09 27;13(9):1817-22. Epub 2016 May 27.

Department of Cardiology, Campus Benjamin Franklin, Charité Universitaetsmedizin Berlin, Berlin, Germany.

Background: The efficacy of the second-generation cryoballoon (CB) in patients with paroxysmal atrial fibrillation (AF) has been demonstrated previously. Data on the efficacy of CB ablation in patients with persistent AF are sparse.

Objective: The aim of this study was to evaluate the 2-year success rate of pulmonary vein isolation in patients with persistent AF using the second-generation CB.

Methods: Fifty consecutive patients (mean age 64.6 ± 9.9 years; 19 women [38%]) with persistent AF were included in this analysis. The mean follow-up period was 22 ± 11 months. All patients were ablated using the second-generation 28-mm CB. Isolation of the pulmonary veins was confirmed using a spiral mapping catheter. In all patients, follow-up was obtained using 24-hour Holter monitoring or via interrogation of an implanted loop recorder or pacemaker.

Results: The mean left atrial diameter was 43.6 ± 5.6 mm, the mean CHA2DS2-VASc score was 2.8 ± 1.5, and the mean HAS-BLED score was 2.1 ± 1.2. The mean fluoroscopy time was 25.8 ± 9 minutes, and the mean procedural time was 146.4 ± 37.8 minutes. After 22 ± 11 months, the frequency of arrhythmia recurrence was 22 of 50 (44%) in the overall group (paroxysmal AF 6 of 22 [27%]; persistent AF 16 of 22 [73%]). No major complications occurred. Aneurysma spurium not requiring surgical intervention occurred in 1 (2%) patient. No phrenic nerve palsy was observed.

Conclusion: Two years' results after pulmonary vein isolation using the second-generation CB in patients with persistent AF are promising. The clinical success rate appears to be similar to the reported success rates of radiofrequency ablation for the treatment of persistent AF.
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http://dx.doi.org/10.1016/j.hrthm.2016.05.022DOI Listing
September 2016

Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study.

PLoS One 2016 28;11(1):e0147968. Epub 2016 Jan 28.

Clinical and Experimental Multiple Sclerosis Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS).

Objective: To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection.

Methods: Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls.

Results: The median (range) number of γ-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL.

Conclusion: γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731473PMC
July 2016

Erratum to: Severe back pain in elite athletes: a cross-sectional study on 929 top athletes of Germany.

Eur Spine J 2016 Mar;25(3):973

Büttner-Janz Spinefoundation, Charité Universitätsmedizin Berlin, Meinekestraße 6, 10719, Berlin, Germany.

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http://dx.doi.org/10.1007/s00586-015-4295-1DOI Listing
March 2016

Severe back pain in elite athletes: a cross-sectional study on 929 top athletes of Germany.

Eur Spine J 2016 Apr 3;25(4):1204-10. Epub 2015 Sep 3.

Büttner-Janz Spinefoundation, Charité Universitätsmedizin Berlin, Meinekestraße 6, 10719, Berlin, Germany.

Purpose: The cross-sectional study evaluates the incidence, localization, treatment, and influencing factors of back pain (BP) in Germany's elite athletes.

Methods: An online questionnaire was sent out to 3564 top athletes. We used the VAS to identify the intensity of BP and SPSS for statistical analyses.

Results: 929 athletes responded. 514 (55.3%) had BP within the last 12 months, mainly located in the lumbar spine (n = 293, 56.1%). The average pain intensity was 5.75/10. Back-affecting exercise and additional burdens (e.g. at their place of work) did not increase the intensity of BP. When dividing the athletes into two groups according to the BP intensity, BP did not correlate with gender, age or BMI.

Conclusion: At least every tenth athlete suffers temporarily from low BP at a level at which spine surgery could be the only option to relieve the pain. BP occurs independently of back-affecting training and additional stress. Further evaluation is needed to identify factors for avoiding severe BP in top athletes.
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http://dx.doi.org/10.1007/s00586-015-4210-9DOI Listing
April 2016

Assessment of the Biological Effects of Welding Fumes Emitted From Metal Active Gas and Manual Metal Arc Welding in Humans.

J Occup Environ Med 2015 Aug;57(8):845-50

From the Institute for Occupational and Social Medicine (Ms Dewald, Dr Gube, Dr Baumann, Dr Bertram, Ms Kossack, Prof Dr Kraus, and Dr Brand); ISF-Welding and Joining Institute (Mr Lenz and Prof Dr Resigen), RWTH Aachen University, Germany.

Objective: Emissions from a particular welding process, metal inert gas brazing of zinc-coated steel, induce an increase in C-reactive protein. In this study, it was investigated whether inflammatory effects could also be observed for other welding procedures.

Methods: Twelve male subjects were separately exposed to (1) manual metal arc welding fumes, (2) filtered air, and (3) metal active gas welding fumes for 6 hours. Inflammatory markers were measured in serum before, and directly, 1 and 7 days after exposure.

Results: Although C-reactive protein concentrations remained unchanged, neutrophil concentrations increased directly after exposure to manual metal arc welding fumes, and endothelin-1 concentrations increased directly and 24 hours after exposure. After exposure to metal active gas and filtered air, endothelin-1 concentrations decreased.

Conclusions: The increase in the concentrations of neutrophils and endothelin-1 may characterize a subclinical inflammatory reaction, whereas the decrease of endothelin-1 may indicate stress reduction.
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http://dx.doi.org/10.1097/JOM.0000000000000495DOI Listing
August 2015

Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status.

Eur Arch Otorhinolaryngol 2016 Aug 31;273(8):2157-69. Epub 2015 Jul 31.

Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

Data indicate a better prognosis for human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). HPV and p16 detection are established markers for HPV-related HNSCC. Both are accepted as survival-independent predictors. Previous studies investigating the survival in HNSCC patients depending on HPV(+/-) and p16(+/-) status consistently found discordant results with p16(-)/HPV(+) and p16(+)/HPV(-). However, no meta-analysis regarding the survival according to combined HPV/p16 status has been performed yet. The objective of this study was to discriminate the impact of combined HPV(+/-) and p16(+/-) status on survival. Data sources were identification and review of publications assessing survival of the distinct subgroups with both p16 and HPV investigated in HNSCC until February, 2015. A meta-analysis was performed to classify survival and clinical outcomes. 18 out of 397 articles (4424 patients) were eligible for the meta-analysis. The percent proportion of the subgroups was 25 % for HPV(+)/p16(+), 61.2 % for HPV(-)/p16(-), 7.1 % for HPV(-)/p16(+) and 6.8 % for HPV(+)/P16(-). The meta-analysis showed a significantly improved 5-year overall survival (OS), 5-year disease-free survival and their corresponding hazard ratio for HPV(+)/p16(+) HNSCC in comparison to HPV(-)/p16(-), HPV(+)/p16(-) and HPV(-)/p16(+). The 5-year OS of the HPV(-)/p16(+) subgroup was intermediate while HPV(+)/p16(-) and HPV(-)/p16(-) HNSCC had the shortest survival. With current therapeutic strategies, survival of patients with HNSCC is better if associated with HPV(+)/p16(+) or HPV(-)/p16(+). Clinical trials are needed to confirm the distinct survival pattern and to investigate possible differences in survival for HPV(+)/p16(-) and HPV(-)/p16(+) HNSCC. To further differentiate p16(+) HNSCC, HPV testing may be advisable.
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http://dx.doi.org/10.1007/s00405-015-3728-0DOI Listing
August 2016

Human biomonitoring of aluminium after a single, controlled manual metal arc inert gas welding process of an aluminium-containing worksheet in nonwelders.

Int Arch Occup Environ Health 2015 Oct 18;88(7):913-23. Epub 2015 Jan 18.

Medical Faculty, Institute for Occupational Medicine and Social Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Purpose: Several existing field studies evaluate aluminium welding works but no thoroughly controlled exposure scenario for welding fume has been described yet. This study provides information about the uptake and elimination of aluminium from welding fumes under controlled conditions.

Methods: In the Aachen Workplace Simulation Laboratory, we are able to generate welding fumes of a defined particle mass concentration. We exposed 12, until then occupationally unexposed participants with aluminium-containing welding fumes of a metal inert gas (MIG) welding process of a total dust mass concentration of 2.5 mg/m(3) for 6 h. Room air filter samples were collected, and the aluminium concentration in air derived. Urine and plasma samples were collected directly before and after the 6-h lasting exposure, as well as after 1 and 7 days. Human biomonitoring methods were used to determine the aluminium content of the samples with high-resolution continuum source atomic absorption spectrometry.

Results: Urinary aluminium concentrations showed significant changes after exposure compared to preexposure levels (mean t(1) (0 h) 13.5 µg/L; mean t(2) (6 h) 23.5 µg/L). Plasma results showed the same pattern but pre-post comparison did not reach significance.

Conclusions: We were able to detect a significant increase of the internal aluminium burden of a single MIG aluminium welding process in urine, while plasma failed significance. Biphasic elimination kinetic can be observed. The German BAT of 60 µg/g creatinine was not exceeded, and urinary aluminium returned nearly to baseline concentrations after 7 days.
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http://dx.doi.org/10.1007/s00420-015-1020-7DOI Listing
October 2015

Human biomonitoring of chromium and nickel from an experimental exposure to manual metal arc welding fumes of low and high alloyed steel.

Ann Occup Hyg 2015 May 15;59(4):467-80. Epub 2014 Dec 15.

1.Institute for Occupational Medicine and Social Medicine, RWTH Aachen University, Pauwelsstr. 30 D-52074, Aachen, Germany.

Objectives: The uptake and elimination of metals from welding fumes is currently not fully understood. In the Aachen Workplace Simulation Laboratory (AWSL) it is possible to investigate the impact of welding fumes on human subjects under controlled exposure conditions. In this study, the uptake and elimination of chromium or chromium (VI) respectively as well as nickel was studied in subjects after exposure to the emissions of a manual metal arc welding process using low or high alloyed steel.

Methods: In this present study 12 healthy male non-smokers, who never worked as welders before, were exposed for 6h to welding fumes of a manual metal arc welding process. In a three-fold crossover study design, subjects were exposed in randomized order to either clean air, emissions from welding low alloyed steel, and emissions from welding high alloyed steel. Particle mass concentration of the exposure aerosol was 2.5mg m(-3). The content of chromium and nickel in the air was determined by analysing air filter samples on a high emission scenario. Urine analysis for chromium and nickel was performed before and after exposure using methods of human biomonitoring.

Results: There were significantly elevated chromium levels after exposure to welding fumes from high alloyed steel compared to urinary chromium levels before exposure to high alloyed welding fumes, as well as compared to the other exposure scenarios. The mean values increased from 0.27 µg l(-1) to 18.62 µg l(-1). The results were in good agreement with already existing correlations between external and internal exposure (German exposure equivalent for carcinogenic working materials EKA). The variability of urinary chromium levels was high. For urinary nickel no significant changes could be detected at all.

Conclusions: Six-hour exposure to 2.5mg m(-3) high alloyed manual metal arc welding fumes lead to elevated urinary chromium levels far higher (7.11-34.16 µg l(-1)) than the German biological exposure reference value (BAR) of 0.6 µg l(-1) directly after exposure. On the other hand mean urinary nickel concentrations slightly increased, but did not exceed background levels due to lower bioavailability. We could underline with our single exposure experiment that a welding work related chromium exposure can be measured immediately after the work shift, while the same is not possible for nickel exposure due to lower nickel bioavailability. The data provide useful information for real occupational welding work places.
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http://dx.doi.org/10.1093/annhyg/meu104DOI Listing
May 2015

Antioxidants in Asian-Korean and caucasian skin: the influence of nutrition and stress.

Skin Pharmacol Physiol 2014 26;27(6):293-302. Epub 2014 Jun 26.

Center of Experimental and Applied Cutaneous Physiology, Department of Dermatology, Venerology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: The antioxidant status of the human skin provides protection against the destructive action of free radicals. Most antioxidants cannot be synthesized by the human organism itself, but have to be ingested with a healthy nutrition rich in fruit and vegetables. The Korean cuisine is known to be one of the healthiest worldwide. This binational study investigated the cutaneous carotenoid concentrations in German subjects, South Korean subjects and immigrant Korean subjects resident in Germany and examined whether dietary- and lifestyle-related differences are reflected in the cutaneous carotenoid concentrations.

Methods: Measurements of the carotenoid concentrations of 714 healthy volunteers were performed using a non-invasive spectroscopic measurement system based on reflectance spectroscopy.

Results: In the present study South Korean residents showed a significantly higher antioxidant status than both native German residents and Korean immigrants living in Germany (p < 0.001). The first generation of Korean immigrants to Germany over the age of 50 mostly preserved Korean dietary habits, showing significantly higher concentrations (p < 0.001) than the German-born second and third Korean generations under the age of 50.

Conclusion: The results of the study indicate that a healthy nutrition alone does not provide a high antioxidant status unless the stress exposure can be reduced simultaneously.
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http://dx.doi.org/10.1159/000361053DOI Listing
March 2015

Biological effects of emissions from resistance spot welding of zinc-coated material after controlled exposure of healthy human subjects.

J Occup Environ Med 2014 Jun;56(6):673-7

From the Institute for Occupational and Social Medicine (Drs Gube and Brand and Mr Lenz) and ISF-Welding and Joining Institute (Mr Lenz and Dr Reisgen), RWTH Aachen University, Germany.

Objective: Do emissions from a resistance spot welding process of zinc-coated materials induce systemic inflammation in healthy subjects after exposure for 6 hours?

Methods: Twelve healthy male subjects were exposed once for 6 hours either to filtered ambient air or to welding fume from resistance spot welding of zinc-coated material (mass concentration approximately 100 μg m). Biological effects were measured before, after, and 24 hours after exposure.

Results: At the concentrations used in this study, however, the suspected properties of ultrafine particles did not lead to systemic inflammation as reflected by high-sensitivity C-reactive protein or other endpoint parameters under consideration.

Conclusions: Ultrafine particles from a resistance spot welding process of zinc-covered materials with a number concentration of about 10 cm and a mass concentration of about 100 μg m did not induce systemic inflammation.
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http://dx.doi.org/10.1097/JOM.0000000000000170DOI Listing
June 2014

Multiple sclerosis: the elevated antibody response to Epstein-Barr virus primarily targets, but is not confined to, the glycine-alanine repeat of Epstein-Barr nuclear antigen-1.

J Neuroimmunol 2014 Jul 16;272(1-2):56-61. Epub 2014 Apr 16.

Institute for Medical Immunology, Charité - Universitätsmedizin Berlin, Germany.

Patients with multiple sclerosis (MS) have elevated antibodies against Epstein-Barr virus (EBV), but data on the epitope-resolved specificity of these antibodies are scarce. Using a peptide microarray containing 1465 peptides representing 8 full-length EBV proteins, we identified higher (p<0.001) antibody reactivities to 39 EBV-peptides in MS patients (n=29) compared to healthy controls (n=22). Seventeen of the 39 peptides were from EBNA-1 and 13 located within the glycine-alanine repeat of EBNA-1. Further reactivities were directed against EBNA-3, EBNA-4, EBNA-6, VP26, and LMP1. Thus, antibodies against EBV in MS patients primarily target, but are not confined to, the glycine-alanine repeat of EBNA-1.
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http://dx.doi.org/10.1016/j.jneuroim.2014.04.005DOI Listing
July 2014

[Systematics of somatoform disorders in children and adolescents].

Prax Kinderpsychol Kinderpsychiatr 2013 ;62(9):639-53

Klinik für Psychiatrie, Psychotherapie und Psychosomatik des Kindes- und Jugendalters, Charité - Universitätsmedizin Berlin.

Somatoform disorders in children and adolescents are common and can cause significantly reduced wellbeing and quality of life. Considerable subjective impairment leads to a high number of doctors' visits, which along with a reoccurrence of negative findings, often results in a sense of helplessness in the patient and a lack of trust towards the physician. The criteria for somatoform disorders are illustrated based on the classification scheme ICD-10 and in consideration of the DSM-V. Referring to Noeker (2008) the special role of the parents for the development of somatoform disorders is explained. The typical clinical profile of somatoform disorders in children and adolescents is described. As a diagnostic instrument the newly developed Screening for Somatoform Disorders in Children and Adolescents (SOMS-CA) (Winter, Pfeiffer, Köberle, Lenz, Lehmkuhl, 2008) is introduced. Furthermore it is demonstrated that patients with somatoform disorders are seen predominantly within consulting and liaison services of the paediatric clinic. The importance of interdisciplinary cooperation between paediatrics and child and adolescent psychiatry and -psychotherapy in early diagnosis and introduction of appropriate treatment is highlighted.
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March 2014

Relationship between welding fume concentration and systemic inflammation after controlled exposure of human subjects with welding fumes from metal inert gas brazing of zinc-coated materials.

J Occup Environ Med 2014 Jan;56(1):1-5

From the Institute for Occupational and Social Medicine (Drs Brand, Bauer, Gube, and Kraus) and ISF-Welding and Joining Institute (Mr Lenz and Dr Reisgen), Aachen University of Technology, Aachen, Germany; and Institution for Statutory Accident Insurance and Prevention in the Woodworking and Metalworking Industry (Dr Spiegel-Ciobanu), Hannover, Germany.

Objectives: It has been shown that exposure of subjects to emissions from a metal inert gas (MIG) brazing process of zinc-coated material led to an increase of high-sensitivity C-reactive protein (hsCRP) in the blood. In this study, the no-observed-effect level (NOEL) for such emissions was assessed.

Methods: Twelve healthy subjects were exposed for 6 hours to different concentrations of MIG brazing fumes under controlled conditions. High-sensitivity C-reactive protein was measured in the blood.

Results: For welding fumes containing 1.20 and 1.50 mg m zinc, high-sensitivity C-reactive protein was increased the day after exposure. For 0.90 mg m zinc, no increase was detected.

Conclusions: These data indicate that the no-observed-effect level for emissions from a MIG brazing process of zinc-coated material in respect to systemic inflammation is found for welding fumes with zinc concentrations between 0.90 and 1.20 mg m.
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http://dx.doi.org/10.1097/JOM.0000000000000061DOI Listing
January 2014

[Investigation of practicability of OPD-CA for patients with migration background].

Prax Kinderpsychol Kinderpsychiatr 2013 ;62(4):285-99

Universitätsmedizin Berlin, Klinik für Psychiatrie, Psychotherapie und Psychosomatik des Kindes- und Jugendalters, Berlin.

32 clinical patients (5-15 years) were diagnosed with an OPD-CA interview-manual (Winter, 2004). To investigate practicability of OPD-CA for patients with migration background (N = 14) a comparison with patients without migration background (N = 18) was carried out. There were patients with different ethnical backgrounds. The OPD-CA covers the axes prerequisites for treatment, interpersonal relation, structure and conflicts. Both groups showed equal prerequisites for treatment, interpersonal relation and conflicts. Significant differences were rated in structure: Patients with migration background have fewer skills in control as well as self- and object-perception. The interpretation of these results remained unsettled and suggested a careful use of the axis structure of OPD-CA for patients with migration background. The replication with a larger sample in a multicultural team of therapists and raters would be important.
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http://dx.doi.org/10.13109/prkk.2013.62.4.285DOI Listing
August 2013

Number size distribution of fine and ultrafine fume particles from various welding processes.

Ann Occup Hyg 2013 Apr 1;57(3):305-13. Epub 2012 Oct 1.

Institute for Occupational and Social Medicine, RWTH Aachen University, Pauwelsstr. 30, D-52074 Aachen/Germany.

Studies in the field of environmental epidemiology indicate that for the adverse effect of inhaled particles not only particle mass is crucial but also particle size is. Ultrafine particles with diameters below 100 nm are of special interest since these particles have high surface area to mass ratio and have properties which differ from those of larger particles. In this paper, particle size distributions of various welding and joining techniques were measured close to the welding process using a fast mobility particle sizer (FMPS). It turned out that welding processes with high mass emission rates (manual metal arc welding, metal active gas welding, metal inert gas welding, metal inert gas soldering, and laser welding) show mainly agglomerated particles with diameters above 100 nm and only few particles in the size range below 50 nm (10 to 15%). Welding processes with low mass emission rates (tungsten inert gas welding and resistance spot welding) emit predominantly ultrafine particles with diameters well below 100 nm. This finding can be explained by considerably faster agglomeration processes in welding processes with high mass emission rates. Although mass emission is low for tungsten inert gas welding and resistance spot welding, due to the low particle size of the fume, these processes cannot be labeled as toxicologically irrelevant and should be further investigated.
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http://dx.doi.org/10.1093/annhyg/mes070DOI Listing
April 2013

[Use of operationalized psychodynamic diagnostics in childhood and adolescence in patients with somatic diseases].

Psychother Psychosom Med Psychol 2012 Jul 9;62(7):259-65. Epub 2012 Jul 9.

Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Charité Universitätsmedizin Berlin.

Psychodynamic findings based on the Operationalized Psychodynamic Diagnostics in Childhood and Adolescence (OPD-CA) in patients with Anorectal Malformations (ARM) in comparison to psychiatric patients were presented focussing the psychic structure. Patients with ARM had significant better psychic structure especially with regard to coping with conflicts and communication of affects. Furthermore typical findings were generated: Patients with ARM had better treatment conditions and more positive relationships. Still they had fewer hypotheses about their disease and greater living burden. Structural strengthes facilitate acceptance and integration of the disease. Nonetheless more attention should be paid to child-oriented psychoeducation for development of age-appropriate hypotheses about the disease. Facing living burden, psychological-psychiatric support should be offered to patients with ARM.
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http://dx.doi.org/10.1055/s-0032-1314784DOI Listing
July 2012

The dissociative adsorption of hydrogen on defect-'free' Pt(111).

J Phys Condens Matter 2010 Aug 13;22(30):304006. Epub 2010 Jul 13.

MESA + Institute for Nanotechnology, University of Twente, Enschede, The Netherlands.

The interaction of hydrogen with an (almost) defect-free Pt(111) surface (step density ∼ 0.1%) is revisited in a combined thermal energy atom scattering/thermal desorption spectroscopy (TEAS/TDS) study. We propose a novel kinetic precursor-mediated adsorption/desorption model for hydrogen/Pt(111) to reconcile seemingly conflicting results, such as extremely different dissociative adsorption kinetics at 25 and 155 K. Up to a perpendicular energy of (at least) 60 meV, highly relevant for hydrogenation reactions, the initial sticking probability scales with perpendicular energy to the power 1.9. This atypical behaviour is attributed to probing larger corrugation amplitudes at higher normal energy, leading to scattering of hydrogen into a dynamic precursor prior to dissociation and thus to increased trapping. Scrutiny of the data demonstrates that only a small minority of the surface sites (most probably steps) is active in dissociation. The observed decay of the heat of adsorption with coverage indicates strong repulsion between hydrogen atoms. The TDS-spectra of hydrogen from the defect-'free' Pt(111) consist definitively of a single (β(2)-)peak in contrast to the frequently measured double (β(1), β(2)-)peak structure and at variance with the yet widely accepted conjecture that repulsive interactions lead to double (β(1), β(2)-)peak structures in TDS-spectra. TDS-spectra simulated by applying the micro-reversibility principle and using TEAS-data are in agreement with the experimental ones. The TEAS-data, probing hydrogen whilst on the surface, are thus consistent with TDS-data, probing hydrogen after leaving the surface.
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http://dx.doi.org/10.1088/0953-8984/22/30/304006DOI Listing
August 2010

[Clinical and empirical findings with the OPD-CA].

Prax Kinderpsychol Kinderpsychiatr 2011 ;60(1):41-59

Charité-Universitätsmedizin Berlin, Klinik für Psychiatrie, Psychisomatik und Psychotherapie des Kindes- und Jugendalters.

60 clinical patients (5-17 years) were diagnosed with an interview-manual of OPD-CA (Winter, 2004). For clinical validity a comparison of patients with internal (N=17) and external disorders (N=19) was shown. References for clinical validity resulted from the comparison of the groups, especially for the axes "conflict" and "prerequisites for treatment". Patients with internal disorders showed the conflict desire for care versus autarchy significantly more often than patients with external disorders. On the other hand patients with external disorders displayed the conflict submission versus control significantly more often. Significant differences were also found for the axis "prerequisites for treatment". Patients with internal disorders had better "prerequisites for treatment" in the domains experience of illness and the prerequisites for therapy. For the axes "interpersonal relation", "structure" and "prerequisites for treatment" satisfactory data for validity and reliability were found. The clinical validity points to the usefulness of OPD-CA-manual for psychodynamic diagnostics in childhood and adolescence.
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http://dx.doi.org/10.13109/prkk.2011.60.1.41DOI Listing
March 2011

The dissociative adsorption of hydrogen on Pt(111): actuation and acceleration by atomic defects.

J Chem Phys 2011 Feb;134(7):074703

Solid State Physics MESA+ Institute for Nanotechnology, University of Twente, Enschede, The Netherlands.

The dissociation of hydrogen at atomic surface defects is the strongly dominant, if not the decisive, step in the chain of events eventually leading to chemisorbed H-atoms on Pt(111). This holds for perpendicular kinetic energies of the gas phase molecules from 8 to 60 meV, i.e., covering the range relevant to hydrogenation reactions. This insight has been gained in the present study in which we reversibly varied the defect density on one and the same crystal in a controlled way. Information has been derived from measuring the adsorption kinetics as a function of coverage. Two distinct adsorption channels are distinguished. The first, indirect one, prevails at lower H-coverage and involves capture into a non-accommodated molecular precursor state followed by dissociation at step sites as described in our recent paper. The second one, dominant at higher coverage and non-negligible defect densities, obeys second order Langmuir kinetics. Here the dissociative adsorption takes place directly at step sites with a cross section of 0.24 unit cells (initial sticking probability 24% of the step density). These results are consistent with thermally programmed desorption data: the direct channel is responsible for the emergence of the low temperature peak in thermal desorption spectroscopy, usually denoted with β(1), while the indirect channel is represented by the β(2) state. The dependence on the perpendicular component of the hydrogen kinetic energy is distinctly different for the two channels: the indirect one shows power law behavior with an exponent 1.9 ± 0.1, while the direct one shows no perpendicular energy dependence at all.
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http://dx.doi.org/10.1063/1.3530286DOI Listing
February 2011

Severe affective and behavioural dysregulation is associated with significant psychosocial adversity and impairment.

J Child Psychol Psychiatry 2011 Jun 11;52(6):686-95. Epub 2010 Oct 11.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité-Universitätsmedizin Berlin, Germany.

Background: Recently, a highly heritable behavioral phenotype of simultaneous deviance on the Anxious/Depressed, Attention Problems, and Aggressive Behavior syndrome scales has been identified on the Child Behavior Checklist (CBCL-Dysregulation Profile, CBCL-DP). This study aims to investigate psychosocial adversity and impairment of the CBCL-DP.

Methods: A total of 9024 patients aged 4-18 years were assessed using the CBCL, and the axes V and VI of ICD-10.

Results: ANOVA revealed significant differences regarding psychosocial adversity and impairment between patients with CBCL-DP phenotype and the clinical control group, patients with attention problems, and patients with attention problems and additional anxious/depressed symptoms as assessed by the CBCL. Patients with CBCL-DP showed significant psychosocial adversity and impairment. However, in most cases patients with aggressive behavior showed equal psychosocial adversity as patients with CBCL-DP.

Conclusions: Findings suggest the CBCL-DP phenotype to be associated with significant psychosocial adversity and impairment either as a cause or an effect of the syndrome. Clinicians should carefully address psychosocial adversity and impairment with particular attention to the adversity and impairment of adolescents with CBCL-DP.
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http://dx.doi.org/10.1111/j.1469-7610.2010.02322.xDOI Listing
June 2011