Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients.

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.

Symptoms of uterine myomas: data of an epidemiological study in Germany.

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%.

Freehand direct arthrography of the shoulder using near real-time guidance in an open 1.0-T MRI scanner.

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.

T Cells of Infants Are Mature, but Hyporeactive Due to Limited Ca2+ Influx.

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.

Oxyntic gastric atrophy in Helicobacter pylori gastritis is distinct from autoimmune gastritis.

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.

Identification and Characterization of GABAergic Projection Neurons from Ventral Hippocampus to Amygdala.

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.

Clinical, Radiologic, and Legal Significance of "Extensor Response" in Posttraumatic Coma.

OBJECTIVE: The timely detection of neurologic deterioration can be critical for the survival of a neurosurgical patient following head injury. Because little reliable evidence is available on the prognostic value of the clinical sign "extensor response" in comatose posttraumatic patients, we investigated the correlation of this clinical sign with outcome and with early radiologic findings from magnetic resonance imaging (MRI). METHODS: This retrospective analysis of prospectively obtained data included 157 patients who had remained in a coma for a minimum of 24 hours after traumatic brain injury. All patients received a 1.5-T MRI within 10 days (median: 2 days) of the injury. The correlations between clinical findings 12 and 24 hours after the injury-in particular, extensor response and pupillary function, MRI findings, and outcome after 1 year-were investigated. Statistical analysis included contingency tables, Fisher exact test, odds ratios (ORs) with confidence intervals (CIs), and weighted κ values. RESULTS: There were 48 patients with extensor response within the first 24 hours after the injury. Patients with extensor response (World Federation of Neurosurgical Societies coma grade III) statistically were significantly more likely to harbor MRI lesions in the brainstem when compared with patients in a coma who had no further deficiencies (coma grade I; p = 0.0004 by Fisher exact test, OR 10.8 with 95% CI, 2.7-42.5) and patients with unilateral loss of pupil function (coma grade II; p = 0.0187, OR 2.8 with 95% CI, 1.2-6.5). The correlation of brainstem lesions as found by MRI and outcome according to the Glasgow Outcome Scale after 1 year was also highly significant (p ≤ 0.016). CONCLUSION: The correlation of extensor response and loss of pupil function with an unfavorable outcome and with brainstem lesions revealed by MRI is highly significant. Their sudden onset may be associated with the sudden onset of brainstem dysfunction and should therefore be regarded as one of the most fundamental warning signs in the clinical monitoring of comatose patients.

Accuracy of applicator tip reconstruction in MRI-guided interstitial 192Ir-high-dose-rate brachytherapy of liver tumors.

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.

Malnutrition is a prognostic factor in patients with hepatocellular carcinoma (HCC).

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.

Male breast cancer: 20-year survival data for post-mastectomy radiotherapy.

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.

Percutaneous abscess drainage using near real-time MR guidance in an open 1.0-T MR scanner: proof of concept.

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.

Enzymatic activity of DPIV and renin-angiotensin system (RAS) proteases in patients with left ventricular dysfunction and primary prevention implantable cardioverter/defibrillator (ICD).

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.

Ethanol modulates the neurovascular coupling.

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.

Identification of clinical and laboratory markers for predicting eosinophilic esophagitis in adults.

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.

Asymmetric dimethylarginine predicts appropriate implantable cardioverter-defibrillator intervention in patients with left ventricular dysfunction.

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.

Noninvasive assessment of intracranial pressure with venous ophthalmodynamometry. Clinical article.

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.

Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases.

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.

Atrial expression of endothelial nitric oxide synthase in patients with and without atrial fibrillation.

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.

Differential Expression of SPARC in Intestinal-type Gastric Cancer Correlates with Tumor Progression and Nodal Spread.

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.

Gastroesophageal reflux disease and management in advanced pregnancy: a prospective survey.

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.