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Aims: More precise characterization of risk factors for occurring ventricular arrhythmia in patients (pts) with primary prevention implantable cardioverter-defibrillator (ICD) therapy is critical. We sought to investigate whether biomarkers of nitric oxide metabolism can predict the occurrence of ventricular tachyarrhythmias and might be used as risk markers in these pts.Methods and Results: Plasma levels of l-arginine (Arg), asymmetric dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), monomethyl l-arginine, and nitrite/nitrate were examined in 106 consecutive pts (mean age 65 years, 97 male, mean LV-EF 24 ± 6%), with ischaemic (n= 82) or non-ischaemic cardiomyopathy (n= 24) who underwent ICD implantation for primary prevention of SCD. Appropriate ICD intervention was assessed during a mean follow-up of 344 days, and occurred in 18 of 106 (17%) pts. Asymmetric dimethylarginine plasma levels were significantly higher in pts with appropriate ICD intervention compared with those without any ICD intervention (0.564 ± 0.083 μmol/L vs. 0.513 ± 0.088 μmol; P= 0.027). The Arg/ADMA ratio was found lower in pts with appropriate ICD intervention than in those without ICD intervention (144.71 ± 32.50 vs. 175.29 ± 41.29; P= 0.002). Univariate Cox regression showed that ADMA (P = 0.028) and the Arg/ADMA ratio (P = 0.003) were associated with a higher incidence of appropriate ICD intervention. In a multivariable Cox regression analysis, an ADMA concentration above the 50th centile was independently associated with appropriate ICD intervention, revealing a hazard ratio (HR) of 4.21 (CI 95 %: 1.14-15.63; P = 0.028, Table 4). An Arg/ADMA ratio below the 25th centile had a HR of 3.83 (1.360-10.87; P = 0.011).Conclusion: Asymmetric dimethylarginine and the Arg/ADMA ratio seem to be new biomarkers for the prediction of ventricular tachycardia/ventricular fibrillation episodes and of appropriate ICD intervention in pts with left ventricular ejection fraction dysfunction (LV-EF ≤ 35%), suggesting a value for risk stratification in these pts. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80-90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.

Background: Nonsteroidal anti-inflammatory drugs, low-dose aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors and corticosteroids increase the risk of gastroduodenal bleeding., Aim: To determine in a retrospective cohort study the contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients taking these drugs., Methods: Among patients with peptic ulcer disease diagnosed by endoscopy from 01/2004 to 12/2014 (N = 1719, 60% males, age 65.8 ± 14.5), 56.9% had peptic ulcer bleeding (cases) and 43.1% uncomplicated peptic ulcer disease (controls). Demographics, intake of nonsteroidal anti-inflammatory drugs, aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, proton pump inhibitors and corticosteroids were documented. H. pylori status was determined by histology, rapid urease test or serology. Adjusted odds ratios (OR) were estimated by logistic regression analysis., Results: Helicobacter pylori infection increased the risk of peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users (OR = 2.91, 95% CI = 1.71-4.98 and OR = 2.23, 95% CI = 1.52-3.28, respectively), but not in patients on anticoagulants, selective serotonin reuptake inhibitor or corticosteroid therapy. H. pylori-positive status substantially increased the risk of peptic ulcer bleeding in patients on non-aspirin antiplatelet agents (OR = 4.37, 95% CI = 1.28-14.99), concomitant aspirin/nonsteroidal anti-inflammatory drug intake (OR = 5.85, 95% CI = 1.68-20.36) and combined antiplatelet therapy (OR = 8.43, 95% CI = 1.09-65.17). After further adjustment for proton pump inhibitor intake, H. pylori infection was still a risk factor for peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users., Conclusions: Helicobacter pylori infection increases the risk of peptic ulcer bleeding in peptic ulcer disease patients on nonsteroidal anti-inflammatory drugs, aspirin and non-aspirin antiplatelet agents. H. pylori-positive patients on combined antiplatelet therapy carry the highest risk for peptic ulcer bleeding., (© 2018 John Wiley & Sons Ltd.)

Purpose: Currently, no reliable data are available concerning the type and frequency of symptoms in premenopausal women with uterine myomas., Methods: 2296 women were examined by means of vaginal ultrasound for the presence of myomas in seven gynaecological outpatient departments in Germany. From this population, 1314 premenopausal women between the ages of 30 and 55 years were evaluated to determine the type and frequency of myoma-related symptoms and their relationship to anamnestic factors, and the number, size, and location of the myomas. Standardised questionnaires were used to record the symptoms., Results: Prevalence: In almost every second premenopausal woman (n = 639; 48.6%), uterine myomas were diagnosed. The frequency of myomas increased continuously with age and was highest in women between 46 and 50 years (65.2%). Age itself was found to be the main risk factor for the presence of myomas (p < 0.001)., Symptoms: 54.3% (n = 347) of the women suffered from myoma-related symptoms. The four main symptoms were identified as: Heavy menstrual bleeding (40.7%), dysmenorrhoea (28.2%), lower abdominal pain (14.9%), and intermenstrual bleeding (14.1%). In the majority of cases, the symptoms occurred simultaneously. Determinants for symptoms: Symptoms did not follow a clear age-related trend, whilst the number and size of the myomas did determine the presence of symptoms. The main influencing factor for the presence of intermenstrual bleeding was the location of the myomas., Conclusions: The high prevalence of uterine myomas highlights the importance of the diagnosis uterine myomas in standard gynaecological practice: The presence of only one myoma caused symptoms in 46.5% and small myomas of up to 2 cm in diameter resulted in symptoms in 39.5%.

Background: Eosinophilic oesophagitis (EoE) and gastro-oesophageal reflux disease (GERD) present with overlapping symptomatology and it is challenging to distinguish EoE from GERD clinically before endoscopy., Aim: To investigate the prognostic value of a set of clinical symptoms and laboratory values in patients with EoE and GERD., Methods: In this prospective, single-centre, observational study, we compared clinical and laboratory data from 202 patients with EoE or GERD (10 relevant characteristics). Those characteristics showing potential significance in a univariate analysis were then included in a multivariate analysis., Results: The set of 10 characteristics (10-marker set) was able to distinguish between EoE and GERD with good reliability (correct assignment, i.e. agreement with subsequent EGD, of 94.4%). Reduction of the set to the six statistically and clinically most relevant markers continued to give good reliability (88.9%), and further stepwise reduction led to four-marker sets comprising history of atopy, history of food impaction, proton pump inhibitor refractory symptoms and either immunoglobulin E or peripheral eosinophilia, with correct assignment rates of 91.3% and 85.1% respectively., Conclusions: We have developed a simple and easily applicable clinical/laboratory marker set that helps to distinguish EoE from GERD earlier in the treatment course, thus guiding the endoscopist to perform biopsies from the oesophagus to ensure the diagnosis. The application of the scoring system is expected to diagnose EoE earlier and avoiding delay of adequate treatment., (© 2016 John Wiley & Sons Ltd.)

Objective: To assess the technical success and duration of magnetic resonance imaging (MRI)-guided freehand direct shoulder arthrography (FDSA) with near real-time imaging implemented in a routine shoulder MRI examination on an open 1.0-T MRI scanner, and to assess the learning curve of residents new to this technique., Methods: An experienced MRI interventionalist (the expert) performed 125 MRI-guided FDSA procedures, and 75 patients were treated by one of three residents without previous experience in MRI-guided FDSA. Technical success rate and duration of MRI-guided FDSA of the expert and the residents were compared. The residents' learning curves were assessed. The occurrence of extra-articular deposition and leakage of contrast media from the puncture site and the subsequent impairment of image interpretation were retrospectively analyzed., Results: Overall technical success was 97.5 %. The expert needed overall fewer puncture needle readjustments and was faster at puncture needle positioning (p < 0.01). The learning curve of the residents, however, was steep. They leveled with the performance of the expert after ≈ 15 interventions. With a minimal amount of training all steps of MRI-guided FDSA can be performed in ≤10 min., Conclusion: Magnetic resonance-guided FDSA in an open 1.0-T MRI scanner can be performed with high technical success in a reasonably short amount of time. Only a short learning curve is necessary to achieve expert level.

CD4 T cells in human infants and adults differ in the initiation and strength of their responses. The molecular basis for these differences is not yet understood. To address this the principle key molecular events of TCR- and CD28-induced signaling in naive CD4 T cells, such as Ca2+ influx, NFAT expression, phosphorylation and translocation into the nucleus, ERK activation and IL-2 response, were analyzed over at least the first 3 years of life. We report dramatically reduced IL-2 and TNFα responses in naive CD31+ T cells during infancy. Looking at the obligatory Ca2+ influx required to induce T cell activation and proliferation, we demonstrate characteristic patterns of impairment for each stage of infancy that are partly due to the differential usage of Ca2+ stores. Consistent with those findings, translocation of NFATc2 is limited, but still dependent on Ca2+ influx as demonstrated by sensitivity to cyclosporin A (CsA) treatment. Thus weak Ca2+ influx functions as a catalyst for the implementation of restricted IL-2 response in T cells during infancy. Our studies also define limited mobilization of Ca2+ ions as a characteristic property of T cells during infancy. This work adds to our understanding of infants' poor T cell responsiveness against pathogens., Competing Interests: The authors have declared that no competing interests exist.

Aim: To assess characteristics of oxyntic gastric atrophy (OGA) in autoimmune gastritis (AIG) compared with OGA as a consequence of Helicobacter pylori infection., Methods: Patients undergoing oesophagogastroduodenoscopy from July 2011 to October 2014 were prospectively included (N=452). Gastric biopsies were obtained for histology and H. pylori testing. Serum gastrin-17 (G17), pepsinogen (PG) I, PGII and antibodies against H. pylori and cytotoxin-associated gene A protein were determined in all patients. Antibodies against parietal cells and intrinsic factor were determined in patients with advanced (moderate to severe) OGA. Areas under the receiver operating characteristic curves (AUCs) were calculated for serum biomarkers and compared with histology., Results: Overall, 34 patients (8.9%) had advanced OGA by histology (22 women, age 61±15 years). Current or past H. pylori infection and AIG were present in 14/34 and 22/34 patients, respectively. H. pylori-negative AIG patients (N=18) were more likely to have another autoimmune disease (OR 6.3; 95% CI 1.3 to 29.8), severe corpus atrophy (OR 10.1; 95% CI 1.9 to 54.1) and corpus intestinal metaplasia (OR 26.9; 95% CI 5.3 to 136.5) compared with H. pylori-positive patients with advanced OGA. Antrum atrophy was present in 39% of H. pylori-negative AIG patients. The diagnostic performance of G17, PG I and PGI/II was excellent for AIG patients (AUC=0.83, 0.95 and 0.97, respectively), but limited for H. pylori-positive patients with advanced OGA (AUC=0.62, 0.75 and 0.67, respectively)., Conclusions: H. pylori-negative AIG has a distinct clinical, morphological and serological phenotype compared with advanced OGA in H. pylori gastritis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background & Aims: Malnutrition is a common, hence frequently underdiagnosed condition in patients with liver cirrhosis as well as in patients with cancer and has been shown to have a negative impact on survival in these patients. Frequently applied screening tools including anthropometric measurements or laboratory parameters to screen for malnutrition are not suitable for patients with liver cirrhosis with additional pathophysiological mechanisms leading to hypoalbuminemia and edema. Prospective data on the prevalence and prognostic impact of malnutrition in patients with HCC are scarce., Methods: Fifty-one consecutive patients with hepatocellular carcinoma were prospectively enrolled into this study and screened for malnutrition by anthropometric measurements, the MNA score, the NRS score, laboratory work-up, and BIA measurement. The results of the different screening tools were compared to each other and with the BIA assessment and correlated with the outcome of patients., Results: The calculation of a body mass index (BMI) was not suitable to identify malnourished patients with HCC. The MNA identified 19, the NRS score 17 patients at a risk for malnutrition. BIA revealed a reduction in relative body cell mass in 12 patients. Univariate Cox regression analyses identified tumor stage, MNA score, and phase angle obtained by BIA as significant factors with influence on survival. Multivariate analyses confirmed the phase angle at a cut-off of 4.8 to be an independent factor., Conclusions: A significant proportion of patients with HCC is malnourished or at risk for malnutrition. Screening questionnaires and BIA measurement are superior to pure anthropometric measurements to identify the condition that negatively influences survival. The phase angle derived from body impedance analysis is an independent prognostic factor in patients with HCC., (Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

GABAergic local circuit neurons are critical for the network activity and functional interaction of the amygdala and hippocampus. Previously, we obtained evidence for a GABAergic contribution to the hippocampal projection into the basolateral amygdala. Using fluorogold retrograde labeling, we now demonstrate that this projection indeed has a prominent GABAergic component comprising 17% of the GABAergic neurons in the ventral hippocampus. A majority of the identified GABAergic projection neurons are located in the stratum oriens of area CA1, but cells are also found in the stratum pyramidale and stratum radiatum. We could detect the expression of different markers of interneuron subpopulations, including parvalbumin and calbindin, somatostatin, neuropeptide Y, and cholecystokinin in such retrogradely labeled GABA neurons. Thus GABAergic projection neurons to the amygdala comprise a neurochemically heterogeneous group of cells from different interneuron populations, well situated to control network activity patterns in the amygdalo-hippocampal system.

Background: The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines., Methods/patients: Anonymised data of 1,080 patients from 46 centres were statistically analysed., Results: Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 µg/kg/day or 186.0 µg/m²/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ-testing. Their average IQ was 98.8 ± 13.2 points., Discussion: In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care., Conclusion: Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Purpose: To evaluate the reconstruction accuracy of brachytherapy (BT) applicators tips in vitro and in vivo in MRI-guided (192)Ir-high-dose-rate (HDR)-BT of inoperable liver tumors., Materials and Methods: Reconstruction accuracy of plastic BT applicators, visualized by nitinol inserts, was assessed in MRI phantom measurements and in MRI (192)Ir-HDR-BT treatment planning datasets of 45 patients employing CT co-registration and vector decomposition. Conspicuity, short-term dislocation, and reconstruction errors were assessed in the clinical data. The clinical effect of applicator reconstruction accuracy was determined in follow-up MRI data., Results: Applicator reconstruction accuracy was 1.6±0.5 mm in the phantom measurements. In the clinical MRI datasets applicator conspicuity was rated good/optimal in ⩾72% of cases. 16/129 applicators showed not time dependent deviation in between MRI/CT acquisition (p>0.1). Reconstruction accuracy was 5.5±2.8 mm, and the average image co-registration error was 3.1±0.9 mm. Vector decomposition revealed no preferred direction of reconstruction errors. In the follow-up data deviation of planned dose distribution and irradiation effect was 6.9±3.3 mm matching the mean co-registration error (6.5±2.5 mm; p>0.1)., Conclusion: Applicator reconstruction accuracy in vitro conforms to AAPM TG 56 standard. Nitinol-inserts are feasible for applicator visualization and yield good conspicuity in MRI treatment planning data. No preferred direction of reconstruction errors were found in vivo., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Patients (pts) with severely decreased left ventricular ejection fraction (LV-EF ≤ 35%) are at high risk for sudden cardiac death (SCD). We sought to investigate, if pts with primary prevention ICD hold alterations in enzyme-activities of the dipeptidyl-aminopeptidase IV (DPIV) and the renin-angiotensin system (RAS) before VT/VF occurrence., Methods: 57 Pts (53 male, mean age 64.9 [42-84] years, mean LV-EF 26 ± 5%) with ischemic (n=49) or non-ischemic cardiomyopathy (n=8) who had received an ICD/CRT-D for primary prevention, were included. Pts were assessed for appropriate ICD intervention for VT/VF during a mean follow-up of 365 ± 90 days. Serum levels of dipeptidyl-aminopeptidase IV (DPIV), aminopeptidase N (APN), aminopeptidase B (APB), insulin-regulated aminopeptidase (IRAP), and angiotensin-converting enzyme 2 (ACE2) were determined., Results: Pts with appropriate ICD intervention (n=16) had higher serum activities of IRAP (mean difference=12.681 pkat/mL; p=0.007), and DPIV (mean difference=117.557 pkat/mL; p=0.032) than pts without appropriate ICD intervention. Furthermore, ACE2 activity was significantly higher (median: 223.7 RFU/smL vs. 169.10 RFU/smL; p=0.037). A Cox regression analysis indicated DPIV activity >50th centile to have a hazard ratio (HR) of 5.955 (CI 95%: 1.670-21.241; p=0.006) for prediction of appropriate ICD intervention. In a multivariate Cox regression model, DPIV and IRAP >50th centile remained predictive for appropriate ICD intervention., Conclusion: Our prospective study shows that pts with primary prevention ICD, who receive appropriate ICD intervention during follow-up, can be identified by elevated activities of DPIV and several RAS proteases. Hence, theses biomarkers seem to be of prognostic relevance in a primary prevention collective. Our data has to be proven in larger cohorts., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The goal of this population-based study was to determine the impact of post-mastectomy radiation therapy on long-term overall survival (OS) of male patients with breast cancer., Patients and Methods: We investigated 20-year OS rates of 664 patients diagnosed with primary stage I-III breast cancer in former East Germany between 1970 and 1989. Patients had a radical mastectomy with axillary lymph node dissection without systemic adjuvant therapy., Results: Median follow-up time was 26.2 years (range 19-38 years). 52.4% of the patients had post-mastectomy radiotherapy. Radiotherapy showed different effects in each stage group after 20 years. Whereas there was an OS trend for radiotherapy to harm patients with stage I disease (hazard ratio (HR) 1.45; 95% confidence interval (CI) 0.98-2.15; p = 0.065), radiotherapy showed no benefit in patients with stage II disease (HR 0.82; 95% CI 0.62-1.1; p = 0.15). There was a significant survival benefit for patients with stage III disease receiving radiotherapy (HR 0.60; 95% CI 0.41-0.88; p = 0.008)., Conclusion: Post-mastectomy radiotherapy is associated with longer OS in male patients with stage III breast cancer. Male breast cancer patients at stages I and II do not seem to benefit from radiotherapy, but obsolete irradiation techniques might explain adverse long-term effects in earlier stages.

Objectives: The aims of our study were (1) to assess the feasibility, effectiveness, and safety of exclusively magnetic resonance (MR)-guided freehand percutaneous abscesses drainage using a 1.0-T open MR scanner and (2) to evaluate the optimal method to visualize drainage catheters in situ., Material and Methods: In vitro studies in a dedicated MR gelatin phantom were performed to assess visualization of 8 different sizes of drainage catheters after instillation of sole 0.9% sodium chloride (NaCl) and diluted (1.0%) or concentrated (12.0%) gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) using a T1-weighted (T1w) 2-dimensional fast field echo (FFE) and a T2-weighted single-shot (ssh) turbo spin-echo (TSE) fast dynamic sequence. The catheter artifacts were evaluated with regard to the contrast-to-noise ratio (CNR), the artifact width using the full width at half-maximum (FWHM) method, and the artifact intensity, being the product of the CNR and the FWHM. We used the general linear model procedure as the global test and the Tukey studentized range test for post hoc analysis. In vivo MR-guided freehand drainage was prospectively performed in patients with increased systemic inflammation markers and abdominal, retroperitoneal, and pelvic abscess collections. This study had been approved by the institutional review board. All patients provided written informed consent. Technical success was the primary efficacy variable. The secondary efficacy variables were visibility of the puncture needle and drainage catheter artifact, using a qualitative 5-point rating scale, intervention and procedure time, and rate of postinterventional complications., Results: The FWHM, the CNR, and the artifact intensity of the drainage catheters filled with 0.9% NaCl or diluted or concentrated Gd-DTPA increased according to the drainage catheter size in an almost linear fashion in both image weighting (all P ≤ 0.006; all R(2) ≥ 0.73). The T1w FFE sequence yielded the highest FWHM, CNR, and artifact intensity of all groups, using 12.0% Gd-DTPA instillation (all P < 0.001), and the least FWHM and artifact intensity, using 1.0% Gd-DTPA instillation (all P < 0.022; all P < 0.009). The T2w ssh TSE yielded higher FWHM, using 12.0% Gd-DTPA instillation, whereas the CNR was higher for 0.9% NaCl instillation (all P < 0.001). Magnetic-resonance-guided abscess drainage was performed in 22 patients with 24 abdominal, retroperitoneal, or pelvic abscess collections. The technical success rate of in vivo MR-guided freehand drainage was 100%. Visibility of the puncture needle was excellent (≥4.4 [0.5] points). Visibility of the drainage catheters was rated with 3.9 (0.9) and 4.5 (0.8) points using T2w ssh TSE with 0.9% NaCl and 12.0% Gd-DTPA instillation as well as 4.8 (0.5) and 4.2 (0.8) points using T1w FFE with 1.0% and 12.0% Gd-DTPA instillation, respectively. The procedure and intervention time was 52.4 (16.4) minutes (range, 28-78 minutes) and 27.4 (7.2) minutes (range, 17-40 minutes). Two minor and no major complications were recorded., Conclusions: Magnetic-resonance-guided freehand percutaneous abscesses drainage using fast dynamic sequences in an open 1-T MR scanner is feasible, effective, and safe. Visualization of drainage catheters can be facilitated by instillation of 0.9% NaCl or diluted or concentrated contrast media.

Despite some evidence of the underlying molecular mechanisms the neuronal basis of ethanol-induced effects on the neurovascular coupling that forms the BOLD (blood oxygenation level dependent) signal is poorly understood. In a recent fMRI (functional magnetic resonance imaging) study monitoring ethanol-induced changes of the BOLD signal a reduction of the amplitude and a prolongation of the BOLD signal were observed. However, the BOLD signal is assumed to consist of a complex superposition of different underlying signals. To gain insight how ethanol influences stimulus efficacy, oxygen extraction, transit time and vessel-related parameters the fMRI time series from the sensori-motor and the visual cortex were analyzed using the balloon model. The results show a region-dependent decrease of the stimulus efficacy to trigger a post-stimulus neurovascular response as well as a prolongation of the transit time through the venous compartment. Oxygen extraction, feedback mechanisms and other vessel-related parameters were not affected. The results may be interpreted as follows: the overall mechanisms of the neurovascular coupling are still acting well at the moderate ethanol level of about 0.8‰ (in particular the vessel-related parts), but the potency to evoke a neurovascular response is already compromised most obviously in the supplementary motor area responsible for complex synchronizing and planning processes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2-115) months. Median age at diagnosis was 68 (range 36-91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient's age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13-2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer.

Background and Purpose: Atrial fibrillation induces ischaemic microcirculatory flow abnormalities in the ventricle, contributing to the risk for acute coronary syndromes. We evaluated the effect of dronedarone on ventricular perfusion during rapid atrial pacing (RAP)., Experimental Approach: Coronary and fractional flow reserve (CFR/FFR) were measured in the left anterior descending artery in 29 pigs. Six received RAP, six received RAP with dronedarone (RAP/D), seven received dronedarone alone, four received RAP with amiodarone (RAP/A), and six received neither (sham). In ventricular tissue, oxidative stress/ischaemia-related gene and protein expression was evaluated by RT-PCR and Western blotting; Isoprostanes were measured by GC-MS procedures., Key Results: CFR was decreased in the RAP group, compared with other groups. FFR was not different between groups. Effective refractory period was reduced in RAP compared with RAP/D. RAP-activated PKC phosphorylation tended to be decreased by dronedarone (P= 0.055) RAP induced NOX-1 and NOX-2 protein and the mRNA for hypoxia-inducible factor-1α (HIF-1α). Dronedarone reduced the pacing-dependent increase in the expression of NOX-2 protein and of HIF-1α mRNA. The oxidative stress marker, F(2)-isoprostane, was increased by RAP and this increase was attenuated by dronedarone. Other oxidative stress/ischaemia-related genes were induced by RAP compared with sham and were decreased by dronedarone treatment. In HL1 cells, dronedarone significantly inhibited the increased phosphorylation of PKCα after oxidative stress, with an almost significant effect (P= 0.059) on that after RAP., Conclusions and Implications: Dronedarone abolished RAP-induced ventricular microcirculatory abnormalities by decreasing oxidative stress/ischaemia-related gene and protein expression in the ventricle., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Object: Venous ophthalmodynamometry is a technique used to register the pressure within the central retinal vein. Because the outflow of the central retinal vein is exposed to the intracranial pressure (ICP), the pressure of the central retinal vein may be correlated with the ICP. In the absence of adequate statistical evidence, the authors compared the pressure of the central retinal vein with results of simultaneous invasive monitoring of ICP in neurosurgical patients., Methods: The pressure within the central retinal vein was recorded in 102 patients, in whom invasive continuous monitoring of ICP had become necessary for various reasons, mostly because of suspected hydrocephalus and intracranial hemorrhage., Results: A highly significant correlation of the pressure in the central retinal vein and the intracranial cavity was confirmed statistically. An increased pressure of the central retinal vein indicated an elevated ICP, with a probability of 84.2%, whereas a normal pressure of the central retinal vein indicated a normal ICP in 92.8% of patients. Conclusions Venous ophthalmodynamometry is a valuable technique for the noninvasive assessment of ICP.

Background: To assess the value of diffusion weighted imaging (DWI) as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction ¹⁹²Ir-high-dose-rate brachytherapy (HDR-BT)., Methods: Thirty patients with a total of 43 metastases underwent CT- or MRI-guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI) including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI), 2 days after HDR-BT (early MRI) as well as after 3 months (follow-up MRI). Tumor volume (TV) and intratumoral apparent diffusion coefficient (ADC) were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearson's correlation., Results: At early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (p = 0.054) while mean tumor ADC decreased significantly by 11.4% (p < 0.001). At follow-up MRI mean TV of non-treated metastases increased by 50.8% (p = 0.027) without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (p = 0.026) while the mean ADC increased inversely by 28.6% compared to baseline values (p < 0.001; Pearson's correlation coefficient of r = -0.257; p < 0.001)., Conclusions: DWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated.

Background: The diagnosis of eosinophilic esophagitis (EoE) and differentiation from gastroesophageal reflux disease (GERD) is potentially challenging and is based upon clinical signs and endoscopic and histological features. In order to alert the endoscopist to consider EoE in patients with esophageal symptoms before performing esophagogastroduodenoscopy, we aimed to identify a set of clinical and laboratory markers for predicting EoE., Methods: The study included 43 patients with either EoE (n = 23) or GERD (n = 20). The diagnosis of EoE was based on International Consensus Criteria. Age, gender, weight loss, history of atopy, dysphagia, history of food impaction, proton pump inhibitor (PPI) refractory heartburn, odynophagia, peripheral eosinophilia, and serum IgE were analyzed. Each symptom or sign was classified as '0' (absent, normal) or '1' (present, elevated), individually analyzed and statistically evaluated among the two groups of patients. Logistic regression analysis was carried out to identify a clinically applicable marker constellation to differentiate EoE from GERD., Results: Univariate analysis identified 6 out of the 10 variables to be significant between both groups. A stepwise procedure of logistic regression led to a model in which 3 out of the initial 10 items were found to be relevant for differentiating GERD and EoE. Derived from this model, an optimal differentiation was achieved by using the following simplified equation: peripheral eosinophilia + history of food impaction + PPI refractory heartburn leading to a maximal value of 3 (1 + 1 + 1). Based on a cut-off value of ≥2, sensitivity and specificity for diagnosing EoE were 91 and 100%, respectively., Conclusion: A defined set of markers including two clinical features and one laboratory parameter is highly predictive of EoE and thus allows physicians to distinguish EoE from GERD even before upper gastrointestinal endoscopy is performed., (Copyright © 2011 S. Karger AG, Basel.)

Background: Atrial fibrillation (AF) is associated with oxidative stress within the fibrillating atrial myocardium. Experimental studies suggest that reduced levels of nitric oxide (NO) caused by down-regulation of the NO synthase (eNOS) contribute to the development of prothrombotic endocardial remodeling in AF. This study was designed to determine the endocardial expression of eNOS in atrial tissue samples from patients with and without AF., Methods: Tissue microarrays were used to analyze right atrial tissue specimens obtained from 234 patients (38 with AF; 196 with sinus rhythm) for differences in atrial eNOS expression. In selected patients, immunohistological results were confirmed by Western blotting., Results: Immunohistochemical analyses showed that eNOS is expressed by endocardial cells and myocytes. However, endocardial expression of eNOS was not independently related to AF per se. There was no difference between paroxysmal and persistent AF. Clinical factors like gender (P=.05) and coronary artery disease (P=.06) were associated with down-regulation of eNOS. Interestingly, diabetes mellitus (P=.02) was associated with an up-regulation of endocardial eNOS, whereas other risk factors for thromboembolic events did not influence eNOS levels. Multivariable analysis showed that eNOS expression is influenced by interactions between diabetes mellitus and AF (P=.09) as well as by interactions between gender and AF (P=.04). Lowest levels of eNOS were found in women with AF., Conclusion: AF does not independently effect atrial eNOS expression in humans. Due to the nonuniform regulation of endocardial eNOS expression, it appears unlikely that down-regulation of eNOS is a final common pathway for the development of prothrombotic endocardial remodeling, since classical risk factors for thromboembolic events do not reduce endocardial eNOS protein., (Copyright 2010 Elsevier Inc. All rights reserved.)

Aims: Nodal spread is the single most important prognostic factor of survival in gastric cancer patients. In this study, genes that were upregulated in the lymph node metastases of gastric cancer were identified and may serve as putative novel therapeutic target., Methods: Complementary DNA (cDNA) microarray analysis and quantitative real-time polymerase chain reaction of primary gastric carcinomas and matched lymph node metastasis were carried out. Immunohistochemistry with anti-SPARC antibodies was performed on large tissue sections of 40 cases with primary gastric carcinoma (20 diffuse, 20 intestinal) and the corresponding lymph node metastases, as well as on tissue microarrays of 152 gastric cancer cases., Results: A cDNA microarray identified SPARC as being upregulated in primary gastric carcinoma tissue and the corresponding lymph node metastasis compared with the nonneoplastic mucosa. SPARC was expressed in fibroblasts and, occasionally, in tumor cells. However, the level of immunoreactivity was particularly strong in stromal cells surrounding the tumor. The level of expression of SPARC, determined by immunohistochemistry, correlated in intestinal-type gastric cancer with the local tumor growth, nodal spread, and tumor stage according to the International Union Against Cancer., Conclusions: Our study provides transcriptional and translational evidence for the differential expression of SPARC in gastric cancer tissue. On the basis of our observations and those made by others, we hypothesize that SPARC is a promising novel target for the treatment of gastric cancer.

Aims: Patients with paroxysmal atrial fibrillation (AF) often present with typical angina pectoris and mildly elevated levels of cardiac troponin (non ST-segment elevation myocardial infarction) during an arrhythmic event. However, in a large proportion of these patients, significant coronary artery disease is excluded by coronary angiography. Here we explored the potential underlying mechanism of these events., Methods and Results: A total of 14 pigs were studied using a closed chest, rapid atrial pacing (RAP) model. In five pigs RAP was performed for 7 h (600 b.p.m.; n = 5), in five animals RAP was performed in the presence of angiotensin-II type-1-receptor (AT(1)-receptor) inhibitor irbesartan (RAP+Irb), and four pigs were instrumented without intervention (Sham). One-factor analysis of variance was performed to assess differences between and within the three groups. Simultaneous measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) before, during, and after RAP demonstrated unchanged FFR (P = 0.327), but decreased CFR during RAP (RAP: 67.7 +/- 7.2%, sham: 97.2 +/- 2.8%, RAP+Irb: 93.2 +/- 3.3; P = 0.0013) indicating abnormal left ventricular (LV) microcirculation. Alterations in microcirculatory blood flow were accompanied by elevated ventricular expression of NADPH oxidase subunit Nox2 (P = 0.039), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1, P = 0.004), and F(2)-isoprostane levels (P = 0.008) suggesting RAP-related oxidative stress. Plasma concentrations of cardiac troponin-I (cTn-I) increased in RAP (RAP: 613.3 +/- 125.8 pmol/L vs. sham: 82.5 +/- 12.5 pmol/L; P = 0.013), whereas protein levels of eNOS and LV function remained unchanged. RAP+Irb prevented the increase of Nox2, LOX-1, and F(2)-isoprostanes, and abolished the impairment of microvascular blood flow., Conclusion: Rapid atrial pacing induces AT(1)-receptor-mediated oxidative stress in LV myocardium that is accompanied by impaired microvascular blood flow and cTn-I release. These findings provide a plausible mechanism for the frequently observed cTn-I elevation accompanied with typical angina pectoris symptoms in patients with paroxysmal AF and normal (non-stenotic) coronary arteries.

Background: Heartburn is known to be common during pregnancy, however validated data on gastroesophageal reflux disease (GERD) are missing. The aim of this survey was to study the prevalence of GERD, the frequency and severity of typical GERD symptoms, and their impact on quality of life and therapeutic management in advanced pregnancy., Methods: One hundred and thirty-five consecutive pregnant women in the third trimester were included in a prospective study using validated questionnaires: RDQ, QOLRAD and a self-administered questionnaire detailing sociodemographic factors., Results: The prevalence for GERD in this unselected population was 56.3%. Among symptoms regurgitation was the most frequent with 47.3%, whereas heartburn was graded as the most severe symptom. The impact of GERD on the QOL of the pregnant women was significant (p < 0.001). 22.9% of the GERD population required medication because of severe symptoms, often reported to be insufficient for symptoms relief., Conclusion: GERD is common in late pregnancy with an important negative impact on the QOL. GERD in advanced pregnancy deserves more attention and better therapeutic management., (Copyright 2009 S. Karger AG, Basel.)

In the present study, reciprocal embryo transfers were conducted to examine genetic and maternal effects on the baseline and fear-sensitized acoustic startle response (ASR) in the two inbred strains C3H/HeN and DBA/2JHd and the outbred strain NMRI. The largest differences in the ASR were found in untreated strains (effect size 0.6). The transfer procedure per se had a significant effect on the behavior of NMRI mice resulting in a reduction in the baseline, and an increase in the fear-sensitized ASR. In contrast, there were no significant effects of the transfer procedure in the two inbred strains. Autosomal genetic effects had a stronger impact on the amplitude of the ASR (effect sizes 0.5) than sex (effect sizes 0.06) as revealed by reciprocal embryo transfer. Nevertheless, the genetic effects on the fear-sensitized ASR were somewhat more variable and strain-dependent (effect sizes 0.1-0.2). Global maternal effects were detected after embryo transfer into NMRI mothers resulting in a larger reduction of the ASR in the offspring of DBA and NMRI donors than C3H donors (effect sizes 0.1-0.2). An additional fostering procedure was introduced to dissect uterine and postnatal maternal effects in NMRI offspring. Uterine factors changed the baseline ASR of the offspring in direction of the recipient mother strain. Surprisingly, postnatal maternal effects on the ASR were contrary to the behavior of the rearing mother. In conclusion, both genetic and prenatal/postnatal maternal factors persistently influenced the ASR of the offspring, whereas the fear-sensitized ASR was mainly influenced by genetic factors. Our study shows that uterine and postnatal maternal influences deserve more attention when determining the phenotype of genetically engineered mice at least in the first generation following embryo transfer.

Accumulating evidence links calcium-overload and oxidative stress to atrial remodeling during atrial fibrillation (AF). Furthermore, atrial remodeling appears to increase atrial thrombogeneity, characterized by increased expression of adhesion molecules. The aim of this study was to assess mitochondrial dysfunction and oxidative stress-activated signal transduction (nuclear factor-kappaB [NF-kappa B], lectin-like oxidized low-density lipoprotein receptor [LOX-1], intercellular adhesion molecule-1 [ICAM-1], and hemeoxgenase-1 [HO-1]) in atrial tissue during AF. Ex vivo atrial tissue from patients with and without AF and, additionally, rapid pacing of human atrial tissue slices were used to study mitochondrial structure by electron microscopy and mitochondrial respiration. Furthermore, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunoblot analyses, gel-shift assays, and enzyme-linked immunosorbent assay (ELISA) were applied to measure nuclear amounts of NF-kappa B target gene expression. Using ex vivo atrial tissue samples from patients with AF we demonstrated oxidative stress and impaired mitochondrial structure and respiration, which was accompanied by nuclear accumulation of NF-kappa B and elevated expression levels of the adhesion molecule ICAM-1 and the oxidative stress-induced markers HO-1 and LOX-1. All these changes were reproduced by rapid pacing for 24 hours of human atrial tissue slices. Furthermore, the blockade of calcium inward current with verapamil effectively prevented both the mitochondrial changes and the activation of NF-kappa B signaling and target gene expression. The latter appeared also diminished by the antioxidants apocynin and resveratrol (an inhibitor of NF-kappa B), or the angiotensin II receptor type 1 antagonist, olmesartan. This study demonstrates that calcium inward current via L-type calcium channels contributes to oxidative stress and increased expression of oxidative stress markers and adhesion molecules during cardiac tachyarrhythmia.

Background: Increased levels of inflammatory markers are predictors of thromboembolic events during atrial fibrillation (AF). Increased endocardial expression of adhesion molecules (ie, vascular cell adhesion molecule [VCAM] and intercellular adhesion molecule [ICAM]) could be an important link between initiation of inflammatory and prothrombogenic mechanisms responsible for thrombus development at the atrial endocardium (endocardial remodeling)., Methods and Results: Tissue microarrays were used to screen right atrial tissue specimens obtained from 320 consecutive patients for differences in atrial expression of the prothrombogenic proteins VCAM-1, ICAM-1, thrombomodulin, plasminogen activator inhibitor-1, and von Willebrand factor. An in vitro organotypic human atrial tissue model and a pig model of rapid atrial pacing were used to determine the therapeutic impact of angiotensin II receptor blockade. Immunohistochemical analyses showed that all prothrombogenic proteins are expressed by endocardial cells. Using multivariable analysis, only the intensity of VCAM-1 expression was increased in patients with AF (P=0.03). Increased atrial VCAM-1 expression was confirmed by Western blotting in patients with persistent and paroxysmal AF (persistent AF 207+/-42% versus sinus rhythm 100+/-16%, P=0.028; paroxysmal AF 193+/-42%, P=0.024 versus sinus rhythm). In vitro pacing of ex vivo human atrial tissue slices confirmed that rapid activation causes VCAM-1 upregulation (mRNA and protein levels). Pacing-induced VCAM-1 expression was abolished by olmesartan. To confirm this finding in vivo, VCAM-1 expression was determined in 14 pigs after rapid atrial pacing (600 bpm). Atrial tachycardia caused an upregulation of VCAM-1 expression, which was prevented by irbesartan, consistent with the observed increase in plasma levels of angiotensin II. Alterations in the in vivo VCAM-1 expression were more pronounced in the left atrium (>5-fold compared with sham) than in the right atrium (3.5-fold compared with sham)., Conclusions: AF and rapid atrial pacing both increase endocardial VCAM-1 expression, which can be attenuated by angiotensin II receptor blockade. This provides evidence that angiotensin II plays a pathophysiological role in prothrombotic endocardial remodeling.