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Most signal averaging processes used for cardiac signals align successive waveforms using a template matching process. In addition to achieving accurate temporal alignment of the signals, this operation must also ensure that the signal average comprises signals of the same morphology. For P wave signal averaging, systems designed for QRS complex averaging are often used, with the template acquisition window shifted to include the P wave. Theoretically, with this technique, variations in P wave morphology could reduce the high frequency content of the signal. We tested this hypothesis by comparing the performance of a selective P wave averaging system with a conventional system, based on template matching by cross-correlation over a fixed acquisition window, on identical P wave recordings from 15 subjects. The selective system identifies variations in P wave morphology and generates up to five candidate templates for averaging. Subsequently, the most frequently matched template over a 100-beat sample is used for averaging. Only P waves with the same morphology as this template are averaged. Selective averaging mainly increased the measured high frequency P wave energy, without affecting P wave duration after high pass filtering at 40 Hz, (Duration: 157(4)ms selective vs 155(4) nonselective. Energy 80-150 Hz: 1.77(0.28), microV2.s selective vs 1.61(0.3) microV2.s non selective, P < 0.01). These observations confirm that nonselective P wave averaging can reduce apparent P wave energy, especially at high frequency. Before meaningful studies of the value of frequency domain analysis of the P wave can be performed, it is important that signal averaging systems of sufficient fidelity are utilized.

OBJECTIVE: To examine the hypothesis that the anatomic equivalents of the fast and slow pathways identified in patients with atrioventricular (AV) nodal tachycardia may be universal and represent the principal sites of atrial input into the normal compact AV node. METHODS: 15 patients undergoing complete AV junction ablation for paroxysmal atrial fibrillation were studied. Radiofrequency energy was delivered first in the anterior "fast pathway" position so as to prolong the atrium to bundle of His (AH) interval by over 50% of baseline (protocol 1) and then to the "slow pathway" position using the anatomical technique (protocol 2). RESULTS: Ablation protocol 1 resulted in prolongation of AH interval in all patients. Subsequent lesions at the level of the coronary sinus produced complete heart block in four patients, and in five caused a further increase in AH interval above that produced by protocol 1. Four of these latter patients developed complete block after delivery of RF energy slightly anterior to the level of the coronary sinus os, as did three further patients in whom ablation at the level of the coronary sinus had no effect. In four patients complete heart block could not be achieved by protocol 2. CONCLUSIONS: A discrete anterior "fast" pathway and a posterior "slow" pathway or network of posterior pathways form the principal inputs to the compact AV node in most patients with atrial fibrillation. The absence of dual AV nodal physiology in the majority of these patients may be related to the functional properties of the individual components of this posterior network.

OBJECTIVE--To determine whether lead adjustment formulas for correcting QT dispersion measurements are appropriate in patients after myocardial infarction. DESIGN--Retrospective analysis of QTc dispersion measurements in 461 electrocardiograms (ECGs). Data are presented as uncorrected QTc dispersion "adjusted" for a number of measurable leads and coefficient of variation of QTc intervals for ECGs in which between six and 12 leads had a QT interval that could be measured accurately. PATIENTS--Patients were drawn from the placebo arm of the second Leicester Intravenous Magnesium Intervention Trial. Some 163 patients who subsequently died and an equal number of known survivors had ECGs recorded on day 2 or 3 of acute myocardial infarction. ECGs were also available in 135 of these patients from at least 1 month postinfarct. RESULTS--The most common lead in which a QT interval measurement was omitted was aVR (n = 176), the least common lead was V3 (n = 13). The longest QTc interval measured was most usually in lead V4 (n = 72) and the shortest in lead V1 (n = 67). As the number of measurable leads decreased there was a small, nonsignificant increase in QTc dispersion from 12 lead to eight lead ECGs (mean (SD) 100 (35.5) v 109.5 (47.9) ms). Lead adjusted QTc dispersion (QTc dispersion/square root of the number of measurable leads) showed a large, significant increase when the number of measurable leads decreased from 12 to eight (28.9 (10.3) v 38.7 (16.1) ms, P < 0.001). A similar trend was seen for coefficient of variation of QTc intervals (standard deviation of QTc intervals/mean QTc interval 64.3 (2.19) v 8.45 (3.94)%, P < 0.001). CONCLUSIONS--Lead adjustment formulas for QT dispersion are not appropriate in patients with myocardial infarction. Large differences in lead adjusted QTc dispersion are produced, dependent on the number of measurable leads, for very small differences in QTc dispersion. It is recommended that QT dispersion is presented as unadjusted QT and QTc dispersion, stating the mean (SD) of the number of leads in which a QT interval was measured.

To investigate the pharmacokinetics of the pharmacologically active metabolites of sibutramine (metabolites 1 and 2) in healthy young and elderly volunteers following a single oral dose of sibutramine.This was an open, parallel-group study completed by 12 young (six male, six female; mean age 24.0 years) and 12 elderly (six male, six female; mean age 70.3 years) healthy volunteers. Blood samples were taken at intervals up to 48 h post-dose. Plasma concentrations of metabolites were determined using HPLC-MS. Model-independent pharmacokinetic parameters of the two metabolites were compared for the two age groups.The similarity of the plasma profiles of the two desmethyl metabolites showed that despite the possibility of reduced hepatic function due to age, the rate and extent of formation of these was the same in both young and elderly, i.e. sibutramine metabolism was not impaired in elderly subjects. There were also no significant differences in elimination of metabolite 2 between groups, although the elderly group showed a slight trend for a reduction in k(el).The pharmacokinetics of the two pharmacologically active metabolites of sibutramine (metabolites 1 and 2) were not significantly different between the young and elderly groups in this study. Based on this information, a similar dosing regimen would be appropriate for both the young and elderly.

Background—Survival was prolonged in selected patients with sustained ventricular arrhythmias who received implantable cardioverter defibrillators (ICDs) in the antiarrhythmics versus implantable defibrillators (AVID) study. The Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant in ventricular arrhythmias (MAVERIC) registry is a population based trial. Objective—To determine the number of patients who satisfy the AVID criteria because of the high cost of ICDs. Design—Observational study, based on a continuing trial. Setting—All coronary care units in the Midlands region in the United Kingdom (population 9.1 million). Patients—Patients presenting to a coronary care unit with sustained ventricular arrhythmias not related to an acute myocardial infarction are entered onto the registry. Those who consent to the MAVERIC study are randomised to receive either empirical amiodarone or electrophysiologically guided treatment. Demographic data, details of clinical presentation, and echocardiographic findings are collected. These data have been used to calculate the number of patients who satisfy the AVID criteria and would benefit from ICD implantation. The financial implications have been calculated for the region and nationally. Results—132 patients were entered onto the registry during the first five months of the MAVERIC study; 69 patients fulfilled the AVID criteria. Extrapolation of these data over a 12 month period suggests implantation of at least 166 new ICDs (compared with 23 implants in 1996). This would increase the UK ICD implant rate from five to at least 18 per million of the population, costing the National Health Service £24.1 million per annum. Conclusion—Application of the AVID criteria in the UK will cause a great increase in the ICD implant rate, with serious financial implications. Keywords: AVID study; MAVERIC trial; implantable cardioverter defibrillator; economics; arrhythmias

Aims MAVERIC was a randomised clinical trial designed to test the possibility of prospectively identifying patients who would benefit most from the implantable cardioverter-defibrillator (ICD) by electrophysiology (EP) study in the context of secondary prevention of sudden cardiac death (SCD) through comparing EP-guided interventions (anti-arrhythmic drugs, coronary revascularization, and ICD) against empirical amiodarone therapy. Methods Two hundred and fourteen survivors of sustained ventricular tachycardia (VT), ventricular fibrillation (VF) or SCD were randomized to either treatment strategy, pre-stratified for haemodynamic status at index event, and followed up for a median of 5 years. Results Of the 106 amiodarone arm patients, 89 (84%) received the drug and 5 (5%) received an ICD after crossing over. Of the 108 EP arm patients, 31 (29%) received an ICD, 46 (43%) received anti-arrhythmic drugs only (mainly amiodarone or sotalol) and 18 (17%) received coronary revascularization but no ICD. No significant differences in survival or arrhythmia recurrence existed between the two treatment arms after 6 years. However, ICD recipients had a lower mortality than non-ICD recipients, regardless of allocated treatment (hazard ratio = 0.54, p =0.0391). Conclusions Prospective selection of patients to receive the ICD by EP study did not improve survival compared with empirical amiodarone therapy among survivors of VT, VF or SCD, whereas ICD implantation improved survival regardless of allocated treatment. On this basis, routine EP study has no role in the management of such patients, who should be offered empirical ICD therapy according to the results of other secondary prevention ICD trials.

Background—Survival was prolonged in selected patients with sustained ventricular arrhythmias who received implantable cardioverter defibrillators (ICDs) in the antiarrhythmics versus implantable defibrillators (AVID) study. The Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant in ventricular arrhythmias (MAVERIC) registry is a population based trial. Objective—To determine the number of patients who satisfy the AVID criteria because of the high cost of ICDs. Design—Observational study, based on a continuing trial. Setting—All coronary care units in the Midlands region in the United Kingdom (population 9.1 million). Patients—Patients presenting to a coronary care unit with sustained ventricular arrhythmias not related to an acute myocardial infarction are entered onto the registry. Those who consent to the MAVERIC study are randomised to receive either empirical amiodarone or electrophysiologically guided treatment. Demographic data, details of clinical presentation, and echocardiographic findings are collected. These data have been used to calculate the number of patients who satisfy the AVID criteria and would benefit from ICD implantation. The financial implications have been calculated for the region and nationally. Results—132 patients were entered onto the registry during the first five months of the MAVERIC study; 69 patients fulfilled the AVID criteria. Extrapolation of these data over a 12 month period suggests implantation of at least 166 new ICDs (compared with 23 implants in 1996). This would increase the UK ICD implant rate from five to at least 18 per million of the population, costing the National Health Service £24.1 million per annum. Conclusion—Application of the AVID criteria in the UK will cause a great increase in the ICD implant rate, with serious financial implications. Keywords: AVID study; MAVERIC trial; implantable cardioverter defibrillator; economics; arrhythmias

The incidence of atrial fibrillation in patients with atrioventricular block (AVB) appears increased over that for the unpaced population even if atrioventricular synchrony is maintained by dual chamber pacing. To assess whether atrial fibrillation in these patients might be due to concurrent abnormality in atrial activation we performed signal averaged P wave (SAPW) recordings in 15 patients with dual chamber pacemakers implanted for AVB and compared the results to those from 21 unpaced controls. The median (range) age was 69 (53-89) years for patients and 60 (51-78) years for controls. Eleven patients and 12 controls were male. All patients were pacing in VDD mode at the time of study. SAPW recordings were obtained using our previously reported selective P wave averaging system. We measured P wave duration after high pass filtering at 40 Hz, the rate of change of P wave voltage over time (spatial velocity) and low and high frequency spectral energy after Fourier transformation of the P wave signal. We found increased P wave duration, mean spatial velocity and lower frequency energy in patients with AVB compared to controls [duration, 144 (5) vs. 134 (2) ms, p0.05; mean spatial velocity, 5.6 (0.4) vs. 4.6 (0.1) mV/s, p0.05; energy 20-150 Hz, 57.4 (8.2) vs. 36.3 (2.8) muV2.s, p0.01. All values mean (SEM)]. These results suggest that the increased incidence of atrial fibrillation in patients paced for AVB may be related to intrinsic abnormalities of atrial activation and not solely to the pacing mode. Ensuring sequential atrioventricular pacing in these patients may not completely abolish the increased incidence of atrial fibrillation.

OBJECTIVE: To assess the reproducibility of time and frequency domain variables derived from the signal averaged P wave. DESIGN: Longitudinal within patient study. SETTING: Regional cardiothoracic centre. PATIENTS: 20 patients (10 with documented paroxysmal atrial fibrillation and 10 normal controls) were studied on three occasions to assess the reproducibility of repeated signal averaged P wave recordings. Digital P wave recordings were made on a further 10 patients on a single occasion and the recordings signal averaged twice in order to assess the reproducibility of the averaging system itself in the absence of biological variation. MAIN OUTCOME MEASURES: P wave duration, spatial velocity, and energies contained in frequency bands from 20, 30, and 60-150 Hz of the P wave spectrum were measured after P wave specific signal averaging. Coefficients of reproducibility were calculated for paired signal averaged P waves derived by signal averaging the same digital recordings on two separate occasions, for recordings performed in the same patients immediately after each other ("back to back") and those performed one week apart. RESULTS: System reproducibility when the same digital P wave recordings were signal averaged on two separate occasions was high (< 11% for all variables). For P wave duration the coefficient of reproducibility was 11.4% for back to back recordings and 13.1% for those one week apart. The reproducibility of spatial velocity and P wave energy was low. Variation in P wave morphology was noted when successive P waves from the same subject were examined. If recordings with the same P wave morphology were analysed the reproducibility of spatial velocity and P wave energy improved but remained significantly poorer than that for P wave duration. CONCLUSIONS: P wave duration is reproducible within subjects in the short and medium term. Frequency domain and spatial velocity analysis are poorly reproducible, due more to spontaneous variation in P wave morphology than to instability of the signal averaging process. This may limit the utility of signal averaged P wave variables other than duration for the prediction of atrial arrhythmia.

OBJECTIVE: To define the clinical value of the signal averaged P wave (SAPW) and to compare it with the standard electrocardiogram (ECG), echocardiogram, and clinical assessment for the prediction of atrial fibrillation after coronary bypass grafting (CABG). DESIGN: Prospective validation cohort study. SETTING: Regional cardiothoracic centre. PATIENTS: 201 unselected patients undergoing first elective CABG were recruited over six months. Patients requiring concomitant valve surgery were excluded. MAIN OUTCOME MEASURES: Age, sex, cardiothoracic ratio, and cardioactive drugs were noted. P wave specific SAPW recordings, ECG, and M mode echocardiograms from which left atrial diameter was measured were performed within 24 hours of surgery. Filtered P wave duration (SAPWD), spatial velocity, and energy were calculated from the SAPW. From the ECG, lead II P wave duration, P terminal force in lead V1, total P wave duration, and isoelectric interval were measured. Patients had Holter monitoring for 48 hours postoperatively and daily ECGs until discharge. RESULTS: Two patients died (1%) and 10 were unsuitable for analysis (5%). Of the remaining 189, 51 (27%) had atrial fibrillation (AF) lasting > 1 hour at a mean of 2 (0.5 to 7) days after CABG. Of the variables examined, only SAPWD (AF group 148 (SD 12), v 142 (14) ms, P = 0.008) and male sex (AF group 96%, v 78%, P < 0.01) were significantly different. A prospectively defined SAPWD of > 141 ms predicted atrial fibrillation with positive and negative predictive accuracies of 34% and 83%. Logistic regression analysis identified both male sex and SAPWD as significant independent predictors of postoperative atrial fibrillation. CONCLUSIONS: Signal averaged P wave duration was a better predictor of atrial fibrillation after coronary bypass grafting than standard electrocardiographic or echocardiographic criteria. The predictive value of this test is such that it is likely to be useful in the design of prospective trials of prophylactic antiarrhythmic treatment but is of limited use using current techniques in the clinical management of individual patients.

We studied the dynamics of QT dispersion over the first few days of myocardial infarction and during coronary angioplasty. Ten patients with anterior myocardial infarction and an equal number with inferior infarction had electrocardiograms (ECGs) recorded on admission to hospital (day 1), on the subsequent 2 days (day 2, 3), and prior to discharge (day 6). Ten patients undergoing therapeutic coronary angioplasty were studied; ECGs were recorded prior to, during, and after balloon inflation. Simultaneous 12-lead ECGs were scanned into a personal computer; specially designed software skeletonised and joined each image. The images were then available for user-interactive measurement of QT dispersion. Mean (S.D.) QTc dispersion on day 1 of acute myocardial infarction was 107 (44.8) ms, rose further over the next 48 h, reaching a maximum on day 3 (QTc dispersion, 162.3 (64.8) ms, P < 0.01), and was falling by hospital discharge (QTc dispersion, 117.4 (67.4) ms). There was no difference in QT dispersion measurement during coronary angioplasty. It is unlikely that acute ischaemia plays an important role in the dynamic changes seen in QT dispersion over the first few days of myocardial infarction. These rapid changes in QT dispersion have important implications in the design of any study of QT dispersion after myocardial infarction, and in comparison of studies.

This study investigated interobserver (two observers) and intrasubject (two measurements) reproducibility of QT dispersion from abnormal electrocardiograms in patients with previous myocardial infarction, and compared a user-interactive with an automatic measurement system. Standard 12-lead electrocardiograms, recorded at 25 mm. s−1, were randomly chosen from 70 patients following myocardial infarction. These were scanned into a personal computer, and specially designed software skeletonized and joined each image. The images were then available for user-interactive (mouse and computer screen), or automatic measurements using a specially designed algorithm. For all methods reproducibility of the RR interval was excellent (mean absolute errors 3–4 ms, relative errors 0·3–0·5%). Reproducibility of the mean QT interval was good; intrasubject error was 6 ms (relative error 1·4%), interobserver error was 7 ms (1·8%), and observers' vs automatic measurement errors were 10 and 11 ms (2·5, 2·8%). However QTc dispersion measurements had large errors for all methods; intrasubject error was 12 ms (17·3%), interobserver error was 15 ms (22·1%), and observers' vs automatic measurement were errors 30 and 28 ms (35·4, 31·9%). QT dispersion measurements rely on the most difficult to measure QT intervals, resulting in a problem of reproducibility. Any automatic system must not only recognize common T wave morphologies, but also these more difficult T waves, if it is to be useful for measuring QT dispersion. The poor reproducibility of QT dispersion limits its role as a useful clinical tool, particularly as a predictor of events.

OBJECTIVE--To investigate the effects of low dose sotalol on the signal averaged surface P wave in patients with paroxysmal atrial fibrillation. DESIGN--A longitudinal within patient crossover study. SETTING--Cardiac departments of a regional cardiothoracic centre and a district general hospital. PATIENTS--Sixteen patients with documented paroxysmal atrial fibrillation. The median (range) age of the patients was 65.5 (36-70) years; 11 were men. MAIN OUTCOME MEASURES--Analysis of the signal averaged P wave recorded from patients not receiving antiarrhythmic medication and after 4-6 weeks' treatment with sotalol. P wave limits were defined automatically by a computer algorithm. Filtered P wave duration and energies contained in frequency bands from 20, 30, 40, 60, and 80 to 150 Hz of the P wave spectrum expressed as absolute values (P20, P30, etc) and as ratios of high to low frequency energy (PR20, PR30, etc) were measured. RESULTS--No difference in P wave duration was observed between the groups studied (mean (SEM) 149 (4) without medication and 152 (3) ms with sotalol). Significant decreases in high frequency P wave energy (for example P60: 4.3 (0.4) v 3.3 (0.3) microV2.s, P = 0.003) and energy ratio (PR60: 5.6 (0.5) v 4.7 (0.6), P = 0.03) were observed during sotalol treatment. These changes were independent of heart rate. CONCLUSIONS--Treatment with low dose sotalol reduces high frequency P wave energy but does not change P wave duration. These results are consistent with the class III effect of the drug and suggest that signal averaging of the surface P wave may be a useful non-invasive measure of drug induced changes in atrial electrophysiology.

QTc Dispersion. Introduction: QTc dispersion has traditionally been calculated from all 12 leads of a standard electrocardiogram (ECG). It is possible that alternative, quicker methods using fewer than 12 leads could be used to provide the same information. Methods and Results: We have previously shown a difference in QTc dispersion from ECGs recorded at least 1 month after myocardial infarction between patients who subsequently died and long-term survivors. In the current study, we recalculated QTc dispersion in these ECGs using different methods to determine if the observed difference in QTc dispersion measurements between the two groups, as calculated from 12-lead ECGs, persisted when using smaller sets of leads. QTc dispersion was recalculated by four methods: (1) with the two extreme QTc intervals excluded: (2) from the six precordial leads; (3) from the three leads most likely to contribute to QTc dispersion (aVF, V1V4); and (4) from the three quasi-orthogonal leads (aVF, I, V). For each of the 270 12-lead ECGs examined, a mean of 9.9 leads (SD 1.5 leads) had a QT interval analyzed; the QT interval could not be accurately measured in the remaining leads. Using the standard 12-lead measurement of QTc dispersion, there was a difference in the fall in QTc dispersion from early to late ECG between the groups: 9.1 (SD 60.8) msec for deaths versus 34.4 (55.2) msec for survivors (P = 0.016). This difference in QTc dispersion between early and late ECGs was maintained using either three-lead method (quasi-orthogonal leads: -2.6 [56.2] msec for deaths vs 26.9 [54.3] msec for survivors [P = 0.003]; “likeliest” leads: 8.6 [64.9] msec vs 29.5 [50.2] msec [P = 0.05]), but not when using the other two methods (precordial leads: 19.1 [55.5] msec vs 22 [50.8] msec [P = 0.76]; extreme leads removed: 9.2 [50.1] msec vs 21.8 [42] msec [P = 0.13]). Conclusion: QTc dispersion calculated from three leads may be as useful a measurement as QTc dispersion calculated from all leads of a standard ECG. Its advantages over the standard measurement are its simplicity and the lack of problems with lead adjustment.

A random sample of 200 East Anglian general practitioners was surveyed to establish current trends in the management of hypertension, including measurement of blood pressure (BP), patient investigation, treatment and follow-up. A total of 125 (62.5%) completed questionnaires was returned. Responses were used to assess the range of self-reported management practice and the extent of conformity with the British Hypertension Society guidelines. Although there was a broad spectrum of reported practice, many respondents adhered closely to the guidelines in relation to BP measurement, use of non-pharmacological treatment, treatment goals, choice of drug and patient investigation. Not surprisingly, the greatest disparity between reported and recommended practice occurred in areas where guidelines have only recently become available: treatment of isolated systolic hypertension and of the elderly hypertensive. Here, the survey provides a useful baseline against which to monitor future changes in management.

BACKGROUND Although the use of physical signs for the diagnosis of ventricular tachycardia (VT) was described in the early 1900s, their value in this role has never been systematically assessed. METHODS AND RESULTS Using a blinded, randomized protocol, we examined the ability of 26 clinicians to detect ventriculoatrial (VA) dissociation during cardiac pacing in 21 patients with both atrial and ventricular pacing wires in situ after successful ablation of accessory pathways. In protocol 1 (10 patients), pacing was randomized to either ventricular pacing alone (simulating VT) or to atrioventricular sequential pacing (simulating supraventricular tachycardia or VT with intact VA conduction) at rates of 150 or 180 beats per minute. Each patients was examined by four clinicians blinded to the pacing mode. Clinicians were asked to make a diagnosis of "VA association" or "VA dissociation" after examining the patient for variability of the arterial pulse, jugular venous pulse (JVP), and first heart sound. In protocol 2 (11 patients), randomization of pacing mode was performed between examination of each of the three physical signs so that the value of each sign was assessed individually. In protocol 1, a diagnosis of VA dissociation (VT) was made in 21 of 40 observations, with a specificity of 75%, sensitivity of 70%, and a positive predictive value (PPV) of 71%. In protocol 2, from a total of 132 observations (44 for each sign), the sensitivity, specificity, and PPV for a diagnosis of VT were as follows: arterial pulse, 61%, 71%, 70%; JVP, 96%, 75%, 82%; and first heart sound, 58%, 100%, 100%. CONCLUSIONS It is concluded that, in patients with a regular tachycardia of uncertain origin, clinically detectable variations in the first heart sound and JVP are highly specific and sensitive indicators, respectively, of a diagnosis of VT. Assessment of the arterial pulse is of little value in this role.

Adenosine has been proposed as a useful diagnostic agent in patients with narrow complex regular tachycardia of uncertain origin. Its effects are usually transient owing to its extremely short plasma half life and, as a consequence, it is thought to be safer than other drugs used in the acute treatment of such arrhythmias. However, adenosine had a proarrhythmic effect when administered to a patient in order to confirm the diagnosis of atrial flutter. As expected, a transient increase in atrioventricular block was seen but this was followed by a doubling of the ventricular rate and haemodynamic compromise requiring immediate DC cardioversion. It is postulated that the secondary catecholamine-mediated effects of adenosine were responsible for this phenomenon.

Insulin dissolved in aqueous or methanolic buffer was iodinated to give preparations containing an average of between one and five iodine atoms per insulin monomer. The resultant preparations were fragmented in various ways and the ratio of tyrosine to monoiodotyrosine and di-iodotyrosine was determined in each fragment. This has allowed the distribution of iodine between the combined A-chain tyrosine residues and the individual B-chain tyrosine residues to be determined. The hormonal activity of each of these iodinated insulin preparations was measured from their effect on the production of 14CO2 from [1-14C]glucose by isolated adipose cells. The results were interpreted as meaning that the iodination of tyrosine residue A19 or B16 leads to the inactivation of insulin. Speculations are made about the nature of an interaction between insulin and a receptor site on the target tissue.

The total cost of performing diagnostic tests in a hospital laboratory during one year was assessed. The largest single item of expenditure was the cost of the salaries of the technical staff, while the cost of reagents (including radiopharmaceuticals) was relatively small. The total costs of carrying out diagnostic tests are much higher than is often recognised by those who request them. The use of relatively expensive, commercially available assay kits saves time and gives good value for money. It may be worth taking this into account when planning hospital budgets.

1. 1. The association with rat retina, diaphragm and epididymal fat of 131I from [131I]iodoinsulin and of 125I from [125I]iodoalbumin or [125I]iodide have been compared and the effect on glucose uptake during a subsequent incubation without insulin has been measured. 2. 2. 131I association wit all tissues continued to increase throughout the duration of the experiments, but 125I association quickly reached a relatively constant level. tendency for glucose uptake increase with 131I association was noted up to a maximum level of association. 3. 4. It was concluded that insulin enters the extracellular fluid rapidly and then enters into association with the tissue in a manner yet unknown 4. 5. It was concluded that some of this insulin association was directly related to physiological action, but there must be a second type of association of which the significance is not understood.

IT has never been possible to prove directly that iodinated insulin molecules and normal insulin molecules are biologically indistinguishable. This is partly because of the heterogeneous nature of iodo-insulin preparations and partly because the notorious insensitivity of insulin bio-assays makes it difficult to detect small losses of biological activity. In view of the increasing use of iodine-131 iodo-insulin as a radioactive tracer for insulin it is important to know that they behave identically. In these experiments the biological activities of various iodine-131 iodo-insulin preparations have been compared with the average number of iodine atoms per insulin molecule. A sudden drop in biological activity has been observed when the degree of iodination exceeds about 3 atoms iodine/mol. By integrating these results with existing knowledge1,2 on the probable degree of heterogeneity of various iodo-insulin preparations indirect evidence has been obtained that iodine-131 iodo-insulin is a valid tracer for the natural hormone, provided that it is not too heavily iodinated.