Medizin - Open Access LMU - Teil 19/22

Recruitment of 53BP1 to chromatin flanking double strand breaks (DSBs) requires γH2AX/MDC1/RNF8-dependent ubiquitination of chromatin and interaction of 53BP1 with histone H4 methylated on lysine 20 (H4K20me). Several histone methyltransferases have been implicated in 53BP1 recruitment, but their quantitative contributions to the 53BP1 response are unclear. We have developed a multi-photon laser (MPL) system to target DSBs to subfemtoliter nuclear volumes and used this to mathematically model DSB response kinetics of MDC1 and of 53BP1. In contrast to MDC1, which revealed first order kinetics, the 53BP1 MPL-DSB response is best fitted by a Gompertz growth function. The 53BP1 MPL response shows the expected dependency on MDC1 and RNF8. We determined the impact of altered H4K20 methylation on 53BP1 MPL response kinetics in mouse embryonic fibroblasts (MEFs) lacking key H4K20 histone methyltransferases. This revealed no major requirement for the known H4K20 dimethylases Suv4-20h1 and Suv4-20h2 in 53BP1 recruitment or DSB repair function, but a key role for the H4K20 monomethylase, PR-SET7. The histone methyltransferase MMSET/WHSC1 has recently been implicated in 53BP1 DSB recruitment. We found that WHSC1 homozygous mutant MEFs reveal an alteration in balance of H4K20 methylation patterns; however, 53BP1 DSB responses in these cells appear normal.

In a recent paper, Horder and colleagues (Horder et al., 2010, J Psychopharmacol 25: 1277–1288) have suggested that the mainproblem in the Kirsch analysis is methodological. We argue that the results are similar irrespective of the method used. In our opinion the data suggest that placebo and drug effects are non-additive: antidepressants act independently of depression severity, while the placebo effect is present only in milder cases. While the response in the placebo group is due to unstable ‘noise’ and ‘artefacts’, the medication effect is reliable, valid and stable.

Aim: To identify possible associations between muscular pain and headache in adolescents in a large population-based sample.

Methods: Grammar school students were invited to fill in a questionnaire on headache and associated lifestyle factors. Headache was classified according to the German version of the International Classification of Headache Disorders (2nd edition). Muscular pain was assessed via denoting affected areas in schematic drawings of a body and via provoked muscular pain on controlled movements of head, neck and shoulder regions.

Results: Prevalence of any headache within the previous 6 months exceeded 80%. In all subjects muscular pain or pain on movement was most prominent in the neck and shoulder region, ranging from 9% to 27% in the non-headache population to up to 63% for individuals with migraine or mixed migraine and tension-type headache (TTH). Frequency of muscular pain increased significantly with growing chronicity of TTH.

Interpretation: A strong association between muscle pain in the neck/shoulder region and headache was observed, pointing to the importance of muscular pain for headache in adolescents. Also, in this age group muscular pain appears to be of particular importance in chronic TTH and – unexpectedly – in migraine, which is the most important new finding in our study.

Sleep has strong links to the symptomology of fibromyalgia syndrome (FMS), a diffuse musculoskeletal pain disorder. Information about the involvement of the circadian clock is, however, sparse. In this study, 1548 individuals with FMS completed an online survey containing questions on demographics, stimulant consumption, sleep quality, well-being and subjective pain, chronotype (assessed by the Munich ChronoType Questionnaire, MCTQ), and FMS impact. Chronotype (expressed as the mid-sleep-point on free days, corrected for sleep deficit on workdays, MSFsc) significantly correlated with stress-ratings, so-called “memory failures in everyday life,” fatigue, FMS impact, and depression but not with anxiety. When chronotypes were categorized into 3 groups (early, intermediate, late), significant group differences were found for sum scores of perceived stress, memory failures in everyday life, fatigue, FMS impact, and depression but not anxiety, with late chronotypes being more affected than early chronotypes. Sleepiness ratings were highest in early chronotypes. Challenges of sleep quality and subjective pain were significantly increased in both early and late chronotypes. The results show that according to their reports, late chronotypes are more affected by fibromyalgia.

B cells and antibodies constitute an important element in different inflammatory diseases of the central nervous system (CNS). Autoantibodies can serve as a biomarker to identify disease subgroups and may in addition contribute to the pathogenic process. One candidate autoantigen for multiple sclerosis (MS) is myelin oligodendrocyte glycoprotein (MOG). MOG is localized at the outermost surface of myelin in the CNS and has been the focus of extensive research for more than 30 years. Its role as an important autoantigen for T cells and as a target of demyelinating autoantibodies has been established in several variants of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The literature regarding antibodies to MOG in MS patients is confusing and contradictory. Recent studies, however, have described high levels of antibodies to conformationally correct MOG in pediatric acquired demyelination, both acute disseminated encephalomyelitis (ADEM) and MS. In adult MS, such antibodies are rarely found and then only at low levels. In this review, we summarize key findings from animal models and patient studies, discuss challenges in detecting anti-MOG antibodies in patients and present recent approaches to identifying new autoantigens in MS.

Objectives: Children with severe cerebral palsy (CP) commonly have gastrointestinal (GI) dysfunction. Whey-based enteral formulas have been postulated to reduce gastroesophageal reflux (GOR) and accelerate gastric emptying (GE). The authors investigated whether whey-based (vs casein-based) enteral formulas reduce GOR and accelerate GE in children who have severe CP with a gastrostomy and fundoplication.

Methods: Thirteen children received a casein-based formula for 1 week and either a 50% whey whole protein (50% WWP) or a 100% whey partially hydrolyzed protein (100% WPHP) formula for 1 week. Reflux episodes, gastric half-emptying time (GE t1/2), and reported pain and GI symptoms were measured.

Results: Whey formulas emptied significantly faster than casein (median [interquartile range (IQR)] GE t1/2, 33.9 [25.3-166.2] min vs 56.6 [46-191] min; P = .033). Reflux parameters were unchanged. GI symptoms were lower in children who received 50% WWP (visual analog symptom score, median [IQR], 0[0-11.8]) vs 100% WPHP (13.0 [2.5-24.8]) (P = .035).

Conclusion: This pilot study shows that in children who have severe CP with a gastrostomy and fundoplication, GE of the whey-based enteral formula is significantly faster than casein. The acceleration in GE does not alter GOR frequency, and there appears to be no effect of whey vs casein in reducing acid, nonacid, and total reflux episodes. The results indicate that enteral formula selection may be particularly important for children with severe CP and delayed GE. (JPEN J Parenter Enteral Nutr. 2012;36:118S-123S)

Background: No data are available about the sports activity of patients with bone-conserving short-stem hip implants. Hypothesis: Patients can return to a good level of sports activity after implantation of a short-stem hip implant.

Study Design: Case series; Level of evidence, 4.

Methods: The sports activity level of 68 patients (76 hips) after short-stem hip arthroplasty was assessed for a minimum of 2 years after implantation. In addition to the clinical examination, a detailed evaluation of the patients’ sports pattern was obtained. Furthermore, the results were analyzed with regard to gender (female and male) and age (<=55 and >55 years).

Results: After a mean of 2.7 years, patients showed a Harris Hip Score (HHS) of 93.6, a Western Ontario and McMaster Universities Arthritis Index (WOMAC) score of 9.5, and a University of California, Los Angeles (UCLA) activity score of 7.6, with each individual participating on average in 3.5 different disciplines after surgery compared with 3.9 before surgery. High-impact activities decreased significantly postoperatively, whereas low-impact activities increased significantly. The duration of the sports activities remained stable, while the frequency actually increased. In contrast, men participated preoperatively in more sports than women (4.3 men vs 3.3 women). However, because of a pronounced decrease in high-impact activities by men, both genders participated in an equal number of sports postoperatively (3.5 men vs 3.5 women). Finally, 45% (n = 31) reported at least one activity that they missed. Most of them were disciplines with an intermediate- or high-impact level.

Conclusion: Patients with a short-stem hip implant can return to a good level of activity postoperatively. Participation in sports almost reached similar levels as preoperatively but with a shift from high- to low-impact activities. This seems desirable from a surgeon’s point of view but should also be communicated to the patient before hip replacement

Background: Graft hypertrophy is the most common complication of periosteal autologous chondrocyte implantation (p-ACI).

Purpose: The aim of this prospective study was to analyze the development, the incidence rate, and the persistence of graft hypertrophy after matrix-based autologous chondrocyte implantation (mb-ACI) in the knee joint within a 2-year postoperative course.

Study Design: Case series; Level of evidence, 4.

Methods: Between 2004 and 2007, a total of 41 patients with 44 isolated cartilage defects of the knee were treated with the mb-ACI technique. The mean age of the patients was 35.8 years (standard deviation [SD], 11.3 years), and the mean body mass index was 25.9 (SD, 4.2; range, 19-35.3). The cartilage defects were arthroscopically classified as Outerbridge grades III and IV. The mean area of the cartilage defect measured 6.14 cm2 (SD, 2.3 cm2). Postoperative clinical and magnetic resonance imaging (MRI) examinations were conducted at 3, 6, 12, and 24 months to analyze the incidence and course of the graft.

Results: Graft hypertrophy developed in 25% of the patients treated with mb-ACI within a postoperative course of 1 year; 16% of the patients developed hypertrophy grade 2, and 9% developed hypertrophy grade 1. Graft hypertrophy occurred primarily in the first 12 months and regressed in most cases within 2 years. The International Knee Documentation Committee (IKDC) and visual analog scale (VAS) scores improved during the postoperative follow-up time of 2 years. There was no difference between the clinical results regarding the IKDC and VAS pain scores and the presence of graft hypertrophy.

Conclusion: The mb-ACI technique does not lead to graft hypertrophy requiring treatment as opposed to classic p-ACI. The frequency of occurrence of graft hypertrophy after p-ACI and mb-ACI is comparable. Graft hypertrophy can be considered as a temporary excessive growth of regenerative cartilage tissue rather than a true graft hypertrophy. It is therefore usually not a persistent or systematic complication in the treatment of circumscribed cartilage defects with mb-ACI.

Background: In line with patient-centered health care, it is necessary to understand patients’ perceptions of health. How stroke survivors perceive their health at different time points after stroke and which factors are associated with these feelings provide important information about relevant rehabilitation targets. Objective. This study aimed to identify the independent factors of health-related quality of life (HRQoL) from a biopsychosocial perspective using the methods of multivariate regression at 3 different time points poststroke. Methods. Included in the study were 99 patients from stroke units with diagnosed first-ever stroke. At admission and at 6 weeks, 3 months, and 1 year poststroke, HRQoL was assessed using the EuroQoL-5D Visual Analogue Scale (EQ-5D VAS). Consequences in Body Functions and Activities and Participation, and Environmental Factors were documented using 155 categories of the International Classification of Functioning, Disability and Health (ICF) Core Set for Stroke. Results. For a period of 1 year, problems with recreation and leisure, personality functions, energy and drive functions, and gait pattern functions were repeatedly associated with worse HRQoL. Whereas Body Functions and Activities and Participation explained more than three-fourths of the variances of HRQoL at 6 weeks and 3 months (R2 = 0.80-0.93), the variation at 1 year was best explained by either Body Functions or Environmental Factors (R2 = 0.51).

Conclusions. The results indicate the importance of Body Functions and Activities and Participation (mainly personality functions and recreation and leisure) on HRQoL within 3 months poststroke, but increased impact of Environmental Factors on HRQoL at 1 year.

Summary

In this study, we analyzed vitamin D receptor (VDR) expression and survival in a breast cancer patient cohort of 82 breast

cancer patients. Immunohistochemical analysis was possible in 91.5% of the patients (75/82). Staining was evaluated using the

semi-quantitative assay according to Remmele and Stegner (immunoreactivity score [IRS]). IRS 0–1 was negative/very low, IRS

2–4 was moderate to high, and IRS 6–12 was high. Statistical analysis was performed by Spearman’s correlation test (p<0.05

significant). Overall survival was analyzed using Kaplan-Meier estimations. Only 6 patients had a negative IRS. Moderate IRS

values were present in 20 patients. Most of the patients had a high IRS (49). For survival analysis, data were dichotomized

(IRS 0–4: negative to moderate and IRS 6–12: high VDR expression). In univariate analysis, VDR expression showed significant

differences in progression-free survival (PFS) and overall survival (OS). Patients with high IRS scores showed significantly better

PFS and OS than patients with moderate/negative IRS scores for VDR expression. Tumor size was significantly correlated to

PFS. When analyzed separately, the three different IRS groups showed significant differences in VDR expression. The present

data suggest that VDR expression in breast cancer tissue may be of clinical significance, and the results provide evidence that

VDR may be a factor with prognostic relevance. (J Histochem Cytochem 60:121–129, 2012).

Keywords: breast cancer, vitamin D receptor, immunohistochemistry, prognosis