Reproducibility of Computerized Measurements of QT Interval from Multiple Leads at Rest and During Exercise

Background: Accurate measurement of the QT interval is important for diagnosing long QT syndrome (LQTS), and in research on determinants of ventricular repolarization time. We tested automatic analysis of QT intervals from multiple ECG leads on chest. Methods: Eleven healthy volunteers and 10 genotyped LQTS patients were tested at rest and during exercise with a bicycle ergometer twice 1–31 months apart. Electrocardiograms were recorded with the body surface potential mapping system, and 12 precordial channels were selected for analysis. Averaged QT peak and QT end intervals were determined with an automated algorithm, and the difference QT end minus QT peak (Tp‐e) was calculated. Repeatability was assessed by coefficient of variation (CV) between measurements. Results: Within one test at rest the QT end intervals were highly repeatable with CV 0.6%. In repeated tests CV was 4.4% for QT end interval and 3.5% when the QT interval was corrected for heart rate. In exercise test at specified heart rates, mean CV was 3.0% for QT end and 2.9% for QT peak interval. The CV of Tp‐e interval was 10.2% at rest, and 9.3% in exercise test. Reproducibility was comparable between healthy subjects and LQTS patients. Conclusions: The BSPM system with automated analysis produced accurate and highly repeatable QT interval measurements. Reproducibility was adequate also over prolonged time periods both at rest and in exercise stress test. The method can be applied in studying duration of ventricular repolarization time in different physiologic and pharmacologic interventions.     

Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves.

AIMS: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive. METHODS AND RESULTS: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2,328S, Q4,201R, and V4,653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 microg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2,328S and V4,653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca(2+) release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca(2+) release events as Ca(2+) sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca(2+) release events at lower concentrations of cAMP than cells transfected with wild-type RyR2. CONCLUSION: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca(2+) waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT.     

The effects of training, immobilization and remobilization on musculoskeletal tissue

Compared with the knowledge on immobilization, the effects of remobilization on musculoskeletal tissues have not been well established. What is sure is that remobilization and rehabilitation of any component of the musculoskeletal tissues require much more time than the time needed to cause the immobilization atrophy. With intensive rehabilitation, the functional properties of skeletal muscles can be improved significantly even years after the injury and following immobilization, but no study has shown whether full recovery is possible and whether these rehabilitated muscles are able to respond normally to further training. Experimental studies have given evidence that slow-twitch muscle fibres have better capacity for recovery than fast-twitch fibres, most likely due to better circulation and higher protein turnover. Also evidence has been given that fibre regeneration is possible through satellite cell activation and myotube formation. Very little is known, however, about the effects of age, gender or the level of preimmobilization muscle performance on the restoration capacity. Also the fate of the marked structural changes (for example, connective tissue accumulation) induced by immobilization is unknown. Tendon and ligament tissues are likely to respond appropriately to remobilization, resulting in acceleration of collagen synthesis and fibril neoformation. However, there is a strong suspicion that remobilized tendons and ligaments will not achieve all the biochemical and biomechanical properties of their healthy counterparts. Specifically, the amount of weak type III collagen has been shown to be overrepresented in these tissues instead of mature, strong type I collagen. It is not known whether this is an important risk factor for ruptures during later activity. The effects of remobilization on muscle-tendon junction and proprioceptive organs are not known. It would not be surprising if the serious structural changes induced by immobilization were unrestorable. In the literature dealing with immobilization and remobilization, cartilage degeneration is always a major concern, because not only too strenuous training or immobilization, but also unskilful remobilization may activate this process leading finally to osteoarthrosis. Bone may be one of the best components of musculoskeletal tissues to respond to remobilization, probably because the immobilization atrophy of bone is largely quantitative (osteoporosis) only. The prerequisites for bony recovery are that the follow-up time is long enough (months) and that immobilization has not exceeded about 6 months, the time limit between active and inactive (irreversible) osteoporosis. Prevention of the atrophying effects of immobilization can be very successful if performed properly. According to present knowledge, there are many methods for the purpose, including preimmobilization training early, controlled mobilization; optimal positioning of the immobilized joint; muscular training during immobilization; early weightbearing; exercise with the nonimmobilized extremity; and electrical stimulation. Lots of education and information will be needed, however, before these methods are deeply rooted in the daily routines of the attending physicians, physical therapists, athletic trainers and other persons involved in the treatment of musculoskeletal problems.     

Presence of human papillomavirus DNA and abnormal p53 protein accumulation in lung carcinoma.

BACKGROUND: In some carcinomas inactivation of the tumour suppressor gene product p53, either by point mutation or indirectly by the human papillomavirus (HPV), has been suggested as two alternative routes to malignant transformation. To test this hypothesis in lung tumours, 43 lung carcinomas were analysed by in situ hybridisation and polymerase chain reaction (PCR) for the presence of HPV DNA, and the results were compared with p53 protein immunohistochemical analysis. METHODS: The presence of HPV DNA in lung carcinoma was detected by nucleic acid in situ hybridisation for HPV types 6, 11, 16, 18, 31, and 33 using nonradioactively labelled DNA probes. Polymerase chain reaction (PCR) analysis was performed on all cases showing positive HPV DNA labelling by in situ hybridisation and in an additional 13 negative cases. Abnormal nuclear accumulation of the p53 protein was revealed by immunohistochemistry using the avidin-biotin-peroxidase complex method and a CM-1 polyclonal anti-human p53 antibody and a monoclonal mutation-specific Pab 240 p53 antibody. RESULTS: HPV DNA was found by in situ hybridisation in 13 lung carcinomas (30%). In all these cases subtype-specific HPV DNA could also be detected by PCR. Abnormal p53 protein accumulation was seen in 21 of the 43 carcinomas (49%), of which 18 were HPV negative. Twelve (57%) of the CM-1 positive cases were also positive for the mutation-specific antibody Pab 240. There was an obvious inverse relationship between the presence of papilloma viral DNA and abnormal p53 protein accumulation. CONCLUSIONS: p53 plays an important part in the development of lung carcinomas and, in some cases, HPV may contribute to it by binding and inactivating the p53 protein.     

Polymeric genes MEL8, MEL9 and MEL10 — new members of α-galactosidase gene family in Saccharomyces cerevisiae

Summary We used a combination of genetic hybridization analysis and electrokaryotyping with radioactively labelled MEL1 gene probe hybridization to isolate and identify seven polymeric genes for the fermentation of melibiose in strain CBS 5378 of Saccharomyces cerevisiae (syn. norbensis). Four of the MEL genes, i.e. MEL3, MEL4, MEL6 and MEL7, were allelic to those found in S. cerevisiae strain CBS 4411 (syn. S. oleaginosus) whereas three genes, i.e. MEL8, MEL9 and MEL10 occupied new loci. Electrokaryotyping showed that all seven MEL genes in CBS 5378 were located on different chromosomes. The new MEL8, MEL9 and MEL10 genes were found on chromosomes XV, X/XIV and XII, respectively.     

Prognostic value of various staging and grading systems in proximal colon cancer.

OBJECTIVE: To compare the ability of various methods of staging and grading to predict survival in proximal colon cancer. DESIGN: Retrospective study. SETTING: University hospital, Finland. SUBJECTS: 153 patients with primary proximal colon cancer. MAIN OUTCOME MEASURES: Staging by four classification systems, grading by two grading systems, and survival analysis based on Kaplan-Meier survival curves. RESULTS: In all staging systems the survival curves of different stages differed significantly from each other. The modified Dukes' classification was still the best predictor of survival. Grade of tumours had no significant effect on long term survival, but short term survival was affected adversely by the presence of anaplastic tissue. Tumours with no mucin had a worse prognosis than those that produced mucin. All staging methods were superior to either of the histological grading systems tested as prognosticators. Tumour depth correlated with the operator's clinical impression of radicality of operation, and also predicted survival. CONCLUSION: The clinicopathological modified Dukes' staging system was the most powerful prognosticator in proximal colonic cancer and its use in clinical practice should continue. Even a small amount of anaplastic tissue (> or = 5%) had an adverse effect on short term survival.     

Patency of the infarct-related coronary artery — a pertinent factor in late recovery of myocardial fatty acid metabolism among patients receiving thrombolytic therapy?

The decrease in mortality among patients receiving thrombolytic therapy for myocardial infarction is greater than would be expected from the improvement in left ventricular contractile function alone; thus some additional advantage of recanalization of the infarctrelated coronary artery probably exists. Changes in the post-infarction myocardial metabolic state with respect to artery patency have not been studied with a gamma camera previously. A single-photon emission tomography scan using the fatty acid analogue para-¹²³I-iodophenylpentadecanoic acid was performed at rest before hospital discharge on nine patients with first anterior myocardial infarction. All patients had received intravenous thrombolytic therapy at the beginning of the insult. The semiquantitative analysis of the left ventricle included a total of 44 segments in each patient. The test was repeated 3 months later, with the patients divided into two groups: six patients had an angiographically patent left anterior descending coronary artery (group A), and three an occluded artery (group B). In group A the number of myocardial segments with abnormal (<70% of maximum) fatty acid uptake was initially 20.2±4.7 (mean±SD) and was reduced to 11.3±6.1 during the follow-up (95% confidence interval of the decrease 16.0–1.7 segments). In group B the number of these aberrant segments was fairly constant (21.7±13.1, initial test, and 21.3±13.3, retest). Our preliminary results suggest that even when thrombolytic therapy fails to prevent myocardial infarction, myocardial fatty acid metabolism has a better change of recovering if the relevant coronary artery has regained its patency. This finding emphasizes the need for further study to establish whether a direct link exists between myocardial metabolic state and patient survival after infarction.