Comparison of the Agilent, ROMA/NimbleGen and Illumina platforms for classification of copy number alterations in human breast tumors.

BACKGROUND: Microarray Comparative Genomic Hybridization (array CGH) provides a means to examine DNA copy number aberrations. Various platforms, brands and underlying technologies are available, facing the user with many choices regarding platform sensitivity and number, localization, and density distribution of probes. RESULTS: We evaluate three different platforms presenting different nature and arrangement of the probes: The Agilent Human Genome CGH Microarray 44 k, the ROMA/NimbleGen Representational Oligonucleotide Microarray 82 k, and the Illumina Human-1 Genotyping 109 k BeadChip, with Agilent being gene oriented, ROMA/NimbleGen being genome oriented, and Illumina being genotyping oriented. We investigated copy number changes in 20 human breast tumor samples representing different gene expression subclasses, using a suite of graphical and statistical methods designed to work across platforms. Despite substantial differences in the composition and spatial distribution of probes, the comparison revealed high overall concordance. Notably however, some short amplifications and deletions of potential biological importance were not detected by all platforms. Both correlation and cluster analysis indicate a somewhat higher similarity between ROMA/NimbleGen and Illumina than between Agilent and the other two platforms. The programs developed for the analysis are available from http://www.ifi.uio.no/bioinf/Projects/. CONCLUSION: We conclude that platforms based on different technology principles reveal similar aberration patterns, although we observed some unique amplification or deletion peaks at various locations, only detected by one of the platforms. The correct platform choice for a particular study is dependent on whether the appointed research intention is gene, genome, or genotype oriented.

Transcriptional response to ionizing radiation in human radiation sensitive cell lines.

BACKGROUND AND PURPOSE: Radiation is a common treatment of cancer, but some patients show severe side effects when exposed to small doses of radiation. The aim of this study was to explore the underlying cause of radiation sensitivity in a group of radiation sensitive patients. MATERIALS AND METHODS: Lymphoblastoid cell lines from 5 normal individuals, 4 Ataxia Telangiectasia (AT), and 12 non-AT radiation sensitive (RS) patients were irradiated. RNA was isolated before and after radiation and hybridized to 15k cDNA microarrays and gene expression was recorded. RESULTS AND CONCLUSION: The RS cell lines showed an expression phenotype different from both the AT and normal cell lines. Six of the RS cell lines had a distinct expression profile before radiation. This implies that the RS patients are a heterogeneous group, but that six of the patients may have a common cause of radiation sensitivity.

Long QT syndrome patients may faint due to neurocardiogenic syncope.

AIMS: Syncope in long QT syndrome (LQTS) is expected to be due to Torsades de Pointes ventricular tachycardia (TdP). Often these patients faint in situations with emotional stress. The aim of the present study was to evaluate whether neurocardiogenic syncope occurs in LQTS. METHODS AND RESULTS: Ten untreated consecutive LQTS patients (age 11-72 years, median 37.5 years, five males and five females from five different families (one KvLQT1 mutation, two HERG mutations in three families and one without established genetic background)) were examined by a head-up tilt-table test (HUT). If syncope did not occur within 25 min, the patient received 0.25 mg nitroglycerine sublingually and the HUT was continued for 20 min. Nine out of 10 patients had a positive HUT. The syncope resulted from a combined vasodepressor and bradycardiac response. There were no cases of TdP. No syncope occurred in a 42-year-old asymptomatic male LQTS patient with a borderline prolonged QTc of 0.45 s and a HERG mutation. In 11 of 21 patients referred for syncope without LQTS a positive HUT was found (P < 0.10). CONCLUSION: Syncope in LQTS can be of neurocardiogenic origin and is not necessarily due to TdP. The reason for neurocardiogenic syncope in LQTS is unknown, but involvement of the autonomic nervous system outside the heart is possible.

Heart rate variability and n-3 fatty acids in patients with chronic renal failure--a pilot study.

Patients with chronic renal failure (CRF) often have autonomic cardiac dysfunction, which can be assessed by measuring heart rate variability (HRV). This dysfunction prediposes the patients to sudden cardiac death. This study describes 24-hour HRV in patients with CRF compared to HRV in patients with a previous myocardial infarction (MI). Furthermore, associations between HRV in patients with CRF and the content of n-3 polyunsaturated fatty acids (PUFA) in cell membranes were examined, because n-3 PUFA may improve HRV. Twenty-nine patients with CRF treated with dialysis were enrolled. A 24-hour Holter recording was obtained at baseline and the HRV variables, RR (= mean of all normal RR intervals during the 24-hour recording) and SDNN (= standard deviation of all normal RR intervals in the entire 24-hour recording) were analyzed. Also, granulocyte fatty acid composition was determined. The patients were allocated to dietary supplementation with either 5.2 g of n-3 PUFA or a placebo oil (olive oil) daily for 12 weeks in a double-blind design. At the end of the supplementation period the Holter recording and blood sampling were repeated. At baseline the CRF patients' mean SDNN ws 86 ms compared to 118 ms (p < 0.01) in patients with a previous MI. After supplementation with either n-3 PUFA or placebo a highly significant correlation was observed between the content of n-3 PUFA in cell membranes and HRV (r = 0.71, p < 0.01). Furthermore, when the patients were dichotomized according to their mean SDNN, it was found, that those with the highest SDNN had a higher content of n-3 PUFA in cell membranes compared to those with the lowest SDNN (7.8% vs 4.2%, p < 0.05). In conclusion, HRV was decreased in CRF patients indicating a cardiovascular autonomic dysfunction. The positive correlation between the n-3 PUFA content in cell membranes and HRV suggests that the effects of an increased intake of n-3 PUFA in CRF patients should be further studied.

[n-3 polyunsaturated fatty acids, heart rate variability and ventricular arrhythmias in post-AMI-patients. A clinical controlled trial]. / n-3 polyumaettede fedtsyrer, hjertefrekvensvariabilitet og ventrikulaere arytmier hos post-AMI-patienter. Et klinisk kontrolleret studie.

There is evidence for an antiarrhythmic effect of n-3 polyunsaturated fatty acids (n-3 PUFA) in animals. The aim of the present study was to investigate the effect of dietary n-3 PUFA on ventricular arrhythmias and heart rate variability (HRV) in patients with a previous myocardial infarction. Fifty-five patients were randomized to receive either 5.2 g of n-3 PUFA daily for 12 weeks or placebo in a double blind, placebo-controlled study. Prior to randomization a 24-hour Holter recording was obtained, and this was repeated at the end of the study. The major end-points were the number of ventricular extrasystoles (VE)/24 hours and the 24-hour HRV. A non-significant decrease in VE/24 hours was found in both the n-3 PUFA group and among controls after dietary supplementation, whereas HRV significantly increased after n-3 PUFA compared to both baseline values (p = 0.04) and to controls (p = 0.01). The present study therefore supports the hypothesis that n-3 PUFA may have an anti-arrhythmic effect in humans.

Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction.

To elucidate a possible antiarrhythmic effect of long-chained n-3 polyunsaturated fatty acids, heart rate variability was assessed in 52 patients with a previous myocardial infarction and left ventricular dysfunction. The content of n-3 polyunsaturated fatty acids in platelets was closely associated with the patient's fish-consuming habits, and a significant positive correlation was observed between the n-3 fatty acid docosahexaenoic acid and heart rate variability.

The prognostic value of exercise testing early after myocardial infarction in patients treated with thrombolytics.

Exercise testing early post AMI was evaluated as a predictor of reinfarction in patients treated with thrombolytics. AMI patients exercise-tested prior to discharge were included in the study (n = 178). The patients were followed for 2.9 +/- 0.9 years (mean +/- 1 SD) for the development of new cardiac events defined as cardiac death or reinfarction. Cox regression analysis of clinical and exercise test variables showed that there was significant predictive value of treating heart failure with drugs from two or more therapeutic groups (P < 0.001; hazard ratio 9.4 (3.1-28.2) (estimate and 95% confidence interval)), such as those with a previous history of myocardial infarction (P = 0.001; hazard ratio 4.0 (1.7-9.6)) and of significant ST depression (P = 0.029; hazard ratio 2.5 (1.1-5.7)). Significant ST depression could be substituted by the delta ST/delta HR index (P = 0.042; hazard ratio 2.8 (1.2-6.8)). The exercise test had independent but limited prognostic value in AMI patients treated with thrombolytics. The delta ST/delta HR index did not improve the predictive value of the exercise test.

Proatrial natriuretic polypeptide (31-67) in healthy individuals: day-to-day variation and influence of sex and age.

N-terminal parts of proatrial natriuretic polypeptide have been proposed to be sensitive and specific markers of congestive heart failure (CHF). A prerequisite for use of a clinical marker is knowledge of day-to-day variation and dependence on age and sex. Immunoreactive N-terminal proatrial natriuretic polypeptide (31-67) (ir-N-ANP(31-67)) was measured in a clinically relevant population of healthy individuals. A total of 21 females (mean age 52 years, range 42-76) and 26 males (mean age 54 years, range 42-73), without cardiovascular disease, were included in the study. No correlation was found between ir-N-ANP(31-67) and sex. A statistically significant positive linear correlation (ir-N-ANP pmol 1(-1) = 182+ (8.2 x age in years) (p = 0.004) was found between age and ir-N-ANP(31-67). For the youngest subjects (42 years) the expected mean ir-N-ANP(31-67) was 530 pmol 1(-1), and for the oldest subjects (76 years) it was 800 pmol 1(-1). For all the subjects, the median ir-N-ANP(31-67) was found to be 626 pmol 1(-1) (range 300-1151). The day-to-day variation was studied and no significant difference was found in the plasma concentration of two samples taken 2-5 days apart. Of the individual day-to-day variation, 95% would be expected to be in the interval from -244 to 188 pmol 1(-1) (mean +/- 2 x SD). We conclude that ir-N-ANP(31-67) rises with age. The age-dependent rise in ir-N-ANP(31-67) is modest, but should be taken into consideration in order to use ir-N-ANP(31-67) as a diagnostic marker of CHF. The day-to-day variation is found to be rather high and cannot be neglected if N-ANP(31-67) is to be used as a marker of asymptomatic heart failure.

[Tilt test--part of examination in syncope]. / Vippetest--et led i udredningen af synkope.

Approximately three percent of all emergency room contacts are caused by syncopes. Despite thorough neurological and cardiological examination, more than 40% of all cases are never given a clear diagnosis. These might be caused by neurally mediated hypotension and bradycardia. Head-up tilt table test (HUT), done by the Westminster standard, provokes vasovagal syncope (VVS) in patients with recurrent unexplained syncope. VVS is believed to be caused by triggering the Bezold-Jarish reflex. Several treatments have been suggested. None of these treatments have been promising. By HUT the patient can be made aware of prodromic symptoms and be given instructions to prevent syncope. HUT is useful in the investigation of unexplained syncope.

[Tilt-induced vasovagal syncope]. / Vippeinduceret vasovagal synkope.

In a patient with recurrent unexplained syncope, a case of tilt-induced vasovagal syncope is presented. In a 60 degrees head-up tilt table test, the patient developed complete AV-block and hypotension with loss of postural tonus. After treatment with a B-receptor blocker the head-up tilt table test was better tolerated. The importance of instructions to recognize prodromic symptoms to prevent syncope is underlined. No obvious benefits of medical therapy have been found.