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1.  Protease-Activated Receptor-2 Regulates the Innate Immune Response to Viral Infection in a Coxsackievirus B3–Induced Myocarditis 
This study sought to evaluate the role of protease-activated receptor-2 (PAR2) in coxsackievirus B3 (CVB3)–induced myocarditis.
An infection with CVB3 leads to myocarditis. PAR2 modulates the innate immune response. Toll-like receptor-3 (TLR3) is crucial for the innate immune response by inducing the expression of the antiviral cytokine interferon-beta (IFNβ).
To induce myocarditis, wild-type (wt) and PAR2 knockout (ko) mice were infected with 105 plaque-forming units CVB3. Mice underwent hemodynamic measurements with a 1.2-F microconductance catheter. Wt and PAR2ko hearts and cardiac cells were analyzed for viral replication and immune response with plaque assay, quantitative polymerase chain reaction, Western blot, and immunohistochemistry.
Compared with wt mice, PAR2ko mice and cardiomyocytes exhibited a reduced viral load and developed no myocarditis after infection with CVB3. Hearts and cardiac fibroblasts from PAR2ko mice expressed higher basal levels of IFNβ than wt mice did. Treatment with CVB3 and polyinosinic:polycytidylic acid led to higher IFNβ expression in PAR2ko than in wt fibroblasts and reduced virus replication in PAR2ko fibroblasts was abrogated by neutralizing IFNβ antibody. Overexpression of PAR2 reduced the basal IFNβ expression. Moreover, a direct interaction between PAR2 and Toll-like receptor 3 was observed. PAR2 expression in endomyocardial biopsies of patients with nonischemic cardiomyopathy was positively correlated with myocardial inflammation and negatively with IFNβ expression and left ventricular ejection fraction.
PAR2 negatively regulates the innate immune response to CVB3 infection and contributes to myocardial dysfunction. The antagonism of PAR2 is of therapeutic interest to strengthen the antiviral response after an infection with a cardiotropic virus.
PMCID: PMC4077621  PMID: 23871888
interferon beta; myocarditis; protease-activated receptor 2; Toll-like receptor 3
2.  Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation 
After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients.
We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively.
By comparing two recently proposed naïve T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naïve B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively.
We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia.
PMCID: PMC3751290  PMID: 23941115
Allogeneic hematopoietic stem cell transplantation; Acute leukemia; Simultaneous TREC/KREC quantification assay; Monitoring immune reconstitution
3.  Development of a clinical trial to determine whether watchful waiting is an acceptable alternative to surgical repair for patients with oligosymptomatic incisional hernia: study protocol for a randomized controlled trial 
Trials  2012;13:14.
Incisional hernia is a frequent complication in abdominal surgery. This article describes the development of a prospective randomized clinical trial designed to determine whether watchful waiting is an acceptable alternative to surgical repair for patients with oligosymptomatic incisional hernia.
This clinical multicenter trial has been designed to compare watchful waiting and surgical repair for patients with oligosymptomatic incisional hernia. Participants are randomized to watchful waiting or surgery and followed up for two years. The primary efficacy endpoint is pain/discomfort during normal activities as a result of the hernia or hernia repair two years after enrolment, as measured by the hernia-specific Surgical Pain Scales (SPS). The target sample size of six hundred thirty-six patients was calculated to detect non-inferiority of the experimental intervention (watchful waiting) in the primary endpoint. Sixteen surgical centers will take part in the study and have submitted their declaration of commitment giving the estimated number of participating patients per year. A three-person data safety monitoring board will meet annually to monitor and supervise the trial.
To date, we could find no published data on the natural course of incisional hernias. To our knowledge, watchful waiting has never been compared to standard surgical repair as a treatment option for incisional hernias. A trial to compare the outcome of the two approaches in patients with oligosymptomatic incisional hernias is urgently needed to provide data that can facilitate the choice between treatment options. If watchful waiting was equal to surgical repair, the high costs of surgical repair could be saved. The design for such a trial is described here.
This multicenter trial will be funded by the German Research Foundation (DFG). The ethics committee of the Charité has approved the study protocol. Approval has been obtained from ten study sites at time of this submission. The electronic Case Report Forms have been created. The first patient was to be randomized November 14th, 2011. An initiation meeting took place in Berlin January 9th, 2012.
Trial Registration NCT01349400
PMCID: PMC3305376  PMID: 22314130
oligosymptomatic incisional hernia; watchful waiting; surgical repair; prospective randomized trial
4.  Attachment style contributes to the outcome of a multimodal lifestyle intervention 
Background & Aims
The long-term success of life-style interventions in the treatment of obesity is limited. Although psychological factors have been suggested to modify therapeutic effects, specifically the implications of attachment styles and the patient-therapist relationship have not been examined in detail yet.
This study included 44 obese patients who participated in a one-year multimodal weight-reduction program. Attachment style was analyzed by the Adult Attachment Prototype Rating (AAPR) inventory and its relation to a one-year weight reduction program was studied. The patient-therapist-relationship was assessed using the Helping Alliance Questionnaire.
Attachment style was secure in 68% of participants and insecure (preoccupied and dismissing) in 32%. Interestingly a significantly higher weight-reduction was found in securely (SAI) compared to insecurely attached individuals (UAI; p < 0.05). This estimation correlated positively also to the quality of helping alliance (p = 0.004).
The frequency of insecure attachment in obese individuals was comparable to that of the normal population. Our data suggest a greater weight-reduction for SAI than for UAI, and the patient-therapist relationship was rated more positively. The conclusion can be drawn that a patient's attachment style plays a role in an interdisciplinary treatment program for obesity and has an influence on the effort to lose weight.
PMCID: PMC3296567  PMID: 22300715
attachment style; obesity; patient-therapist relationship; weight reduction
5.  Delay in diagnosis of muscle disorders depends on the subspecialty of the initially consulted physician 
New therapeutic strategies in muscular dystrophies will make a difference in prognosis only if they are begun early in the course of the disease. Therefore, we investigated factors that influence the time to diagnosis in muscle dystrophy patients.
A sample of 101 patients (mean age 49 years; range 19-80; 44% women) with diagnosed muscle dystrophies from neurological practices and the neuromuscular specialty clinic in Berlin, Germany, was invited to participate. Time from first consultation to diagnosis, subspecialty of physician, and sociodemographic data were assessed with self-report questionnaires. The association between time to diagnosis and potential predictors (subspecialty of initially consulted physician, diagnoses, gender, and age at onset) was modeled with linear regression analysis.
The mean time span between first health-care contact and diagnosis was 4.3 years (median 1). The diagnostic delay was significantly longer if patients were initially seen by a non-neurological specialist compared to a general practitioner (5.2 vs. 3.5 years, p = 0.047). Other factors that were independently associated with diagnostic delay were female gender and inherited muscle disease.
Action to improve clinical awareness of muscle diseases in non-neurological specialists is needed.
PMCID: PMC3112398  PMID: 21542919
6.  The Shine-Through Masking Paradigm Is a Potential Endophenotype of Schizophrenia 
PLoS ONE  2010;5(12):e14268.
To understand the genetics of schizophrenia, a hunt for so-called intermediate phenotypes or endophenotypes is ongoing. Visual masking has been proposed to be such an endophenotype. However, no systematic study has been conducted yet to prove this claim. Here, we present the first study showing that masking meets the most important criteria for an endophenotype.
Methodology/Principal Findings
We tested 62 schizophrenic patients, 39 non-affected first-degree relatives, and 38 healthy controls in the shine-through masking paradigm and, in addition, in the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST). Most importantly, masking performance of relatives was significantly in between the one of patients and controls in the shine-through paradigm. Moreover, deficits were stable throughout one year. Using receiver operating characteristics (ROC) methods, we show that the shine-through paradigm distinguishes with high sensitivity and specificity between schizophrenic patients, first-order relatives and healthy controls.
The shine-through paradigm is a potential endophenotype.
PMCID: PMC3000331  PMID: 21151559
7.  Circadian Intraocular Pressure Profiles in Chronic Open Angle Glaucomas 
To evaluate circadian intraocular pressure (IOP) profiles in eyes with different types of chronic open-angle glaucoma (COAG) and normal eyes.
This study included 3,561 circadian IOP profiles obtained from 1,408 eyes of 720 Caucasian individuals including glaucoma patients under topical treatment (1,072 eyes) and normal subjects (336 eyes). IOP profiles were obtained by Goldmann applanation tonometry and included measurements at 7 am, noon, 5 pm, 9 pm, and midnight.
Fluctuations of circadian IOP in the secondary open-angle glaucoma (SOAG) group (6.96±3.69 mmHg) was significantly (P<0.001) higher than that of the normal pressure glaucoma group (4.89±1.99 mmHg) and normal eyes (4.69±1.95 mmHg); but the difference between the two latter groups was not significant (P=0.47). Expressed as percentages, IOP fluctuations did not vary significantly among any of the study groups. Inter-ocular IOP difference for any measurement was significantly (P<0.001) smaller than the profile fluctuations. In all study groups except the SOAG group, IOP was highest at 7 am, followed by noon, 5 pm, and finally 9 pm or midnight. In the SOAG group, mean IOP measurements did not vary significantly during day and night.
In contrast to normal eyes and eyes with primary open-angle glaucoma under topical antiglaucoma treatment, eyes with SOAG under topical treatment do not show the usual circadian IOP profile in which the highest IOP values occur in the morning, and the lowest in the evening or at midnight. These findings may have implications for timing of tonometry. Fluctuation of circadian IOP was highest in SOAG compared to other types of open angle glaucomas.
PMCID: PMC3380677  PMID: 22737337
Intraocular Pressure; Amplitude; Profile; Fluctuation; Chronic Open Angle Glaucoma; Central Corneal Thickness
8.  Contrast-Enhancing Meningeal Lesions Are Associated with Longer Survival in Breast Cancer-Related Leptomeningeal Metastasis 
Breast Care  2008;3(2):118-123.
Leptomeningeal metastasis (LM) is a devastating complication of advanced cancer. Despite aggressive therapy survival is very poor.
Data of all breast cancer patients with LM were retrospectively analyzed (n = 27).
Median survival was 9 weeks. Patients with contrast-enhancing meningeal lesions (n = 11) detected by MRI had a median survival of 33 weeks versus 8 weeks for patients without contrast-enhancing lesions (n = 9; p = 0.0407). Patients who received systemic chemotherapy (n = 18) had a median survival of 15 weeks versus 7 weeks (n = 9; p = 0.0106). Patients undergoing radiotherapy (n = 8) had a median survival of 17 weeks as compared to 5 weeks for patients without radiotherapy (n = 18; p = 0.0188). In a multiple Cox regression analysis, lack of systemic therapy (hazard ratio, HR 89.5; p = 0.002) and negative hormone receptor status (HR 4.2; p = 0.027) emerged as significant main risk factors, together with contrast-enhancing lesion as effect modifier for systemic therapy (p = 0.03).
Contrast-enhancing meningeal lesions, systemic therapy, and radiotherapy were significantly associated with longer survival. Patients with contrast-enhancing lesions who were treated systemically had the longest survival. Evidence is increasing that systemic therapy plays an important role and should be applied in breast cancer patients with LM.
PMCID: PMC2931086  PMID: 21373215
Breast cancer; Leptomeningeal metastases; Carcinomatous meningitis; Neoplastic meningitis; Intrathecal chemotherapy
9.  Preconceptional factors associated with very low birthweight delivery in East and West Berlin: a case control study 
BMC Public Health  2002;2:10.
Very low birthweight, i.e. a birthweight < 1500 g, is among the strongest determinants of infant mortality and childhood morbidity. To develop primary prevention approaches to VLBW birth and its sequelae, information is needed on the causes of preterm birth, their personal and social antecedents, and on conditions associated with very low birthweight. Despite the growing body of evidence linking sociodemographic variables with preterm delivery, little is known as to how this may be extrapolated to the risk of very low birthweight.
In 1992, two years after the German unification, we started to recruit two cohorts of very low birthweight infants and controls in East and West Berlin for a long-term neurodevelopmental study. The present analysis was undertaken to compare potential preconceptional risk factors for very low birthweight delivery in a case-control design including 166 mothers (82 East vs. 84 West Berlin) with very low birthweight delivery and 341 control mothers (166 East vs. 175 West).
Multivariate logistic regression analysis was used to assess the effects of various dichotomous parental covariates and their interaction with living in East or West Berlin. After backward variable selection, short maternal school education, maternal unemployment, single-room apartment, smoking, previous preterm delivery, and fetal loss emerged as significant main effect variables, together with living in West Berlin as positive effect modificator for single-mother status.
Very low birthweight has been differentially associated with obstetrical history and indicators of maternal socioeconomic status in East and West Berlin. The ranking of these risk factors is under the influence of the political framework.
PMCID: PMC117217  PMID: 12095425

Results 1-9 (9)