Aneuploidy of chromosome 8 as detected by interphase fluorescence in situ hybridization is a recurrent finding in primary and metastatic breast cancer

Previous work from our laboratory demonstrated aneuploidy for several chromosomes by interphase fluorescence in situ hybridization (FISH) in a high proportion of breast cancer specimens. In the literature, only limited data are available concerning chromosome 8 anomalies in breast cancer. To determine chromosome 8 ploidy status in primary and metastatic specimens from 81 breast cancer patients, FISH analysis with a DNA probe recognizing chromosome 8 centromeres was performed. In all primary tumor specimens (n=30), significant proportions of cells were aneuploid exhibiting gain of chromosome 8 copy numbers; in 75% of effusion specimens previously classified as malignant by cytology and/or FISH for various chromosomes (n=40), cell populations aneuploid for chromosome 8 were detected; effusions previously classified non-malignant (n=11) were diploid in 10 cases, whereas one specimen contained rare hyperdiploid cells. Among these cells complex chromosomal aneuploidy could be demonstrated by two-color FISH, suggesting malignancy. Trisomic and tetrasomic clones were predominant in the majority of samples, but a marked intratumor cytogenetic heterogeneity was observed in most cases. Primary tumors and corresponding positive axillary lymph nodes revealed similar distributions of chromosome 8 copy numbers, analogous to previous findings with other chromosomes. This implies that, by using suitable FISH probes after examination of the respective primary tumor, an efficient search for (micro)metastasis might be feasible.     

A large-scale genome-wide gene expression analysis in peripheral blood identifies very few differentially expressed genes related to antidepressant treatment and response in patients with major depressive disorder

A better understanding of the biological factors underlying antidepressant treatment in patients with major depressive disorder (MDD) is needed. We perform gene expression analyses and explore sources of variability in peripheral blood related to antidepressant treatment and treatment response in patients suffering from recurrent MDD at baseline and after 8 weeks of treatment. The study includes 281 patients, which were randomized to 8 weeks of treatment with vortioxetine (N = 184) or placebo (N = 97). To our knowledge, this is the largest dataset including both gene expression in blood and placebo-controlled treatment response measured by a clinical scale in a randomized clinical trial. We identified three novel genes whose RNA expression levels at baseline and week 8 are significantly (FDR < 0.05) associated with treatment response after 8 weeks of treatment. Among these genes were SOCS3 (FDR = 0.0039) and PROK2 (FDR = 0.0028), which have previously both been linked to depression. Downregulation of these genes was associated with poorer treatment response. We did not identify any genes that were differentially expressed between placebo and vortioxetine groups at week 8 or between baseline and week 8 of treatment. Nor did we replicate any genes identified in previous peripheral blood gene expression studies examining treatment response. Analysis of genome-wide expression variability showed that type of treatment and treatment response explains very little of the variance, a median of <0.0001% and 0.05% in gene expression across all genes, respectively. Given the relatively large size of the study, the limited findings suggest that peripheral blood gene expression might not be the best approach to explore the biological factors underlying antidepressant treatment.Subject terms: Predictive markers, Depression     

Brain temperature regulation in poor-grade subarachnoid hemorrhage patients – A multimodal neuromonitoring study

Elevated body temperature (T_core) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (T_brain) is usually higher than T_core. However, the implication of this difference (T_delta) remains unclear. We aimed to study factors associated with higher T_delta and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of T_core, T_brain, cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. T_brain was tightly correlated with T_core (r = 0.948, p < 0.01), and was higher in 73.7% of neuromonitoring time (T_delta +0.18°C, IQR −0.01 – 0.37°C). A higher T_delta was associated with better metabolic state, indicated by lower CMD-glutamate (p = 0.003) and CMD-lactate (p < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2, p < 0.001). During MD, T_delta was significantly lower (0°C, IQR −0.2 – 0.1; p < 0.001). A higher T_delta was associated with improved outcome (OR = 7.7, p = 0.002). Our study suggests that T_brain is associated with brain metabolic activity and exceeds T_core when mitochondrial function is preserved. Further studies are needed to understand how T_delta may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.     

Matrix metalloproteinases and their tissue inhibitors (TIMPs) in Plasmodium falciparum malaria: serum levels of TIMP-1 are associated with disease severity

BACKGROUND: Molecular mechanisms involved in the pathogenesis of severe malaria caused by Plasmodium falciparum are not fully understood. Matrix metalloproteinases (MMPs) are enzymes that proteolytically degrade both the extracellular matrix and nonmatrix substances with various functions in the modulation of immune response. The key inhibitors of MMPs are the tissue inhibitors of metalloproteinases (TIMPs). METHODS: We studied levels of MMP-8, MMP-9, TIMP-1, and TIMP-2 on admission and after 24 h, using an enzyme-linked immunosorbent assay, in serum specimens from 50 Gabonese children with severe malaria, 43 children with uncomplicated malaria, and 27 healthy control children. RESULTS: Serum MMP-8 and TIMP-1 levels were significantly higher in the severe malaria and uncomplicated malaria groups, compared with those in the control group (P < .001). TIMP-1 levels were significantly higher in patients with severe malaria, compared with those in patients with uncomplicated malaria (P < .001). High TIMP-1 levels were significantly correlated with malaria severity, as determined by the simplified multiorgan dysfunction score (Spearman rank-correlation coefficient, 0.55; P < .001). CONCLUSIONS: TIMP-1 is associated with signs and symptoms of severe malaria. MMP-8 levels are elevated in patients with severe or uncomplicated P. falciparum malaria. MMPs and TIMPs may be relevant in the pathogenesis of severe malaria, either as proteolytic enzymes that degrade the extracellular matrix or as effectors and regulators of the immune response.     

Improving the applicability of myocardial densitometry and parametric imaging by extended automated densogram analysis

In clinical applications the analysis of X-ray contrast densograms acquired in regions of interest (ROI's) over the myocardium is disturbed by many complex factors. For this reason we acquire redundant densogram information for quality control before extracting densitometric parameters. In our approach, initially some stable measures of quality for densograms are used to lower the influence of poor quality densograms by a quality weighted averaging. For example a shape quality measure, Q₁, is calculated using regions of optimal and minimal acceptable quality defined with respect to a prototype densogram. Not a few myocardial ROI's yield densograms that differ from single-source densograms (SSD's) due to e.g. superposition of different perfusion beds or the position of the ROI relative to the coronary sinus or stenoses. This might result in a densogram shape with oscillating or plateau behavior. For densograms of a such general shape many parameters defined in the usual way do not depend smoothly on the densogram values. The conventional definitions of some parameters (appearance time, rise time) are therefore extended for application to multi-maxima densograms as well as to SSD's. These new methods are evaluated using digitized clinical angiocardiograms and are applied to parametric imaging (pixeldensograms) in a slightly modified way. Taking into account the densogram quality, its shape and its origin results in a considerable improvement both for densitometry and parametric imaging of myocardial perfusion.Abbreviations AP appearance time - Dmax maximum density - LAO 60° left anterior oblique 60° projection - LCA left coronary artery - MIRT mean integrated rise time - MTT mean transit time - RAO 30° right anterior oblique 60° projection - RCA right coronary artery - ROI region of interest - RT rise time - SSD single-source densogram - THM time of half-maximum, tmax - time of maximum     

In Acute Myocardial Infarction Liver Parameters Are Associated With Stenosis Diameter

Detection of high-risk subjects in acute myocardial infarction (AMI) by noninvasive means would reduce the need for intracardiac catheterization and associated complications. Liver enzymes are associated with cardiovascular disease risk. A potential predictive value for liver serum markers for the severity of stenosis in AMI was analyzed.Patients with AMI undergoing percutaneous coronary intervention (PCI; n = 437) were retrospectively evaluated. Minimal lumen diameter (MLD) and percent stenosis diameter (SD) were determined from quantitative coronary angiography. Patients were classified according to the severity of stenosis (SD ≥ 50%, n = 357; SD < 50%, n = 80). Routine heart and liver parameters were associated with SD using random forests (RF). A prediction model (M10) was developed based on parameter importance analysis in RF.Age, alkaline phosphatase (AP), aspartate aminotransferase (AST), and MLD differed significantly between SD ≥ 50 and SD < 50. Age, AST, alanine aminotransferase (ALT), and troponin correlated significantly with SD, whereas MLD correlated inversely with SD. M10 (age, BMI, AP, AST, ALT, gamma-glutamyltransferase, creatinine, troponin) reached an AUC of 69.7% (CI 63.8–75.5%, P < 0.0001).Routine liver parameters are associated with SD in AMI. A small set of noninvasively determined parameters can identify SD in AMI, and might avoid unnecessary coronary angiography in patients with low risk. The model can be accessed via http://stenosis.heiderlab.de.     

Intracardiac echocardiography: an ideal guiding tool for device closure of interatrial communications.

BACKGROUND: This study sought to evaluate safety and radiation exposure when using intracardiac echocardiography (ICE) in comparison to transesophageal echocardiography (TEE) in order to guide transcatheter closure of interatrial communications. METHODS: Eighty patients (44 males, 36 females, mean age 46, SD 13 years) undergoing device closure of atrial septal defect (n=12) or patent foramen ovale (n=68) had the procedure guided by ICE (n=50, group 1) or TEE (n=30, group 2). In group 1, all procedural stages were completely guided by ICE, including imaging of the interatrial communication during balloon sizing, device unfolding and release, and during the final check for adequate positioning. In group 2, exclusive implantation of devices was guided by use of TEE. RESULTS: Especially, the spatial relationship between device and cardiac structures (e.g. the ascending aorta, the interatrial septum and the superior vena cava) was accurately demonstrated in group 1. Image resolution provided by ICE was superior to that of TEE. No severe complications, including any related to ICE, were seen. Fluoroscopy time (FT) and procedure time (PT) were shorter in group 1 than in group 2 (FT: 5.5+/-1.5 min vs. 9.3+/-1.6 min, P<0.0001; PT: 31.9+/-4.6 min vs. 38.8+/-5.8 min, P<0.01). Neither sedation nor anesthesia was required in group 1. CONCLUSIONS: ICE is a safe tool to guide device closure of interatrial communications. For the patient, procedural stress and radiation exposure are negligible. ICE can be considered the guiding tool of choice for device closure, particularly when long or repeated echocardiographic viewing is required.     

Non-Compaction-Kardiomyopathie

Isolated non-compaction of the ventricular myocardium (INVM), also known as left ventricular hypertrabeculation or spongy myocardium, belongs to the "unclassified" cardiomyopathies according to the World Health Organization. The main characteristic of this entity is a prominent trabeculation of the left ventricle with deep intertrabecular recesses communicating with the ventricular cavity. The pathomechanism of INVM is thought to be an arrest in cardiac myogenesis with persistence of embryonic myocardial morphology. The most frequent clinical manifestations include congestive heart failure, ventricular arrhythmias and systemic thromboembolic events. The therapy of INVM comprises standard medical therapy for heart failure.     

Subclinical coronary atherosclerosis is more pronounced in men and women with lower socio-economic status: associations in a population-based study. Coronary atherosclerosis and social status.

BACKGROUND: Social inequalities of manifest coronary heart diseases are well documented in modern societies. Less evidence is available on subclinical atherosclerotic disease despite the opportunity to investigate processes underlying this association. Therefore, we examined the relationship between coronary artery calcification as a sign of subclinical coronary atherosclerosis, socio-economic status and established cardiovascular risk factors in a healthy population. DESIGN: Cross-sectional. METHODS: In a population-based sample of 4487 men and women coronary artery calcification was assessed by electron beam computed tomography quantified by the Agatston score. Socio-economic status was assessed by two indicators, education and income. First, we investigated associations between the social measures and calcification. Second, we assessed the influence of cardiovascular risk factors on this association. RESULTS: After adjustment for age, men with 10 and less years of formal education had a 70% increase in calcification score compared with men with high education. The respective increase for women was 80%. For income the association was weaker (among men 20% higher for the lowest compared with the highest quartile; and among women 50% higher, respectively). Consecutive adjustment for cardiovascular risk factors significantly attenuated the observed association of socio-economic status with calcification. CONCLUSIONS: Social inequalities in coronary heart diseases seem to influence signs of subclinical coronary atherosclerosis as measured by coronary artery calcification. Importantly, cumulation of major cardiovascular risk factors in lower socio-economic groups accounted for a substantial part of this association.