The intercalated disc of monkey myocardial cells and Purkinje fibers as revealed by scanning electron microscopy

The intercalated discs of working myocardium and Purkinje fibers of the monkey heart were examined by scanning and transmission electron microscopy. The NaOH/ultrasonication technique resulted in the digestion of connective tissue and a separation of the intercellular junctions of intercalated discs, such that these could be visualized three-dimensionally. The intercalated discs of ventricular myocytes, atrial myocytes and Purkinje fibers vary considerably in number and configuration, as do the intercalated discs of the three different layers of the ventricular myocardium. Myocytes in the subepicardial, middle and subendocardial layers of the ventricle have 1-3, 4-5 and 5-6 intercalated discs at the end of these cells, respectively, Those in the endocardial layer are characterized by the presence of small laterally-placed intercalated discs. Atrial myocytes and Purkinje fibers usually only have 1-2 intercalated discs, Individual intercalated discs in ventricular myocytes have complicated stairs with 10-30 steps and corresponding risers, while those of atrial myocytes and Purkinje fibers have simple stairs with 1-3 steps and risers, Steps equivalent to the plicate segments are characterized by densely-packed microplicae and finger-like microprojections which greatly increase surface area in vertricular myocytes, Microprojections in atrial myocytes and Purkinje fibers are sparse by comparison, Risers equivalent to the interplicate segments containing large gap junctional areas are most numerous in left ventricular myocytes, followed by right ventricular myocytes, Purkinje fibers and atrial myocytes in decreasing order. The geometric arrangement of the various types of myocytes may be related with impulse propagation. Large intercalated discs of cell trunks and series branches may participate in longitudinal propagation, while small laterally-placed ones may be the site of transverse propagation.

Mild myocardial infarction - A classification problem in epidemiologic studies

In studies assessing the trends in coronary events, such as the World Health Organization (WHO) MONICA Project (multinational MONItoring of trends and determinants of CArdiovascular disease), the main emphasis has been on coronary deaths and non-fatal definite myocardial infarctions (MI). It is, however, possible that the proportion of milder MIs may be increasing because of improvements in treatment and reductions in levels of risk factors. We used the MI register data of the WHO MONICA Project to investigate several definitions for mild non-fatal MIs that would be applicable in various settings and could be used to assess trends in milder coronary events. Of 38 populations participating in the WHO MONICA MI register study, more than half registered a sufficiently wide spectrum of events that it was possible to identify subsets of milder cases. The event rates and case fatality rates of MI are clearly dependent on the spectrum of non-fatal MIs, which are included. On clinical grounds we propose that the original MONICA category ''non-fatal possible MI'' could bt:divided into two groups: ''non fatal probable MI'' and ''prolonged chest pain.'' Non-fatal probable MIs are cases, which in addition to ''typical symptoms'' have electrocardiogram (EGG) or enzyme changes suggesting cardiac ischemia, but not severe enough to fulfil the criteria for non-fatal definite MI In more than half of the MONICA Collaborating Centers, the registration of MI covers these milder events reasonably well. Proportions of non-fatal probable MIs vary less between populations than do proportions of non fatal possible MIs. Also rates of non-fatal probable MI are somewhat more highly correlated with rates of fatal events and non-fatal definite MI. These findings support the validity of the category of non-fatal probable MI. In each center the increase in event rates and the decrease in case-fatality due to the inclusion of non-fatal probable MI was lar er for women than men. For the WHO MONICA Project and other epidemiological studies the proposed category of non-fatal probable MIs can be used for assessing trends in rates of milder MI. Copyright (C) 1997 Elsevier Science Inc.

Isolated limb perfusion with melphalan for human melanoma xenografts in the hindlimb of nude rats: A surviving animal model

We have established a surviving model of isolated limb perfusion using xenografts of the human melanoma cell line MM 96L injected subcutaneously into the hindlimb of a nude rat, The femoral artery and vein were cannulated via the left renal artery and vein and the hind limb was isolated using tourniquets. The limb was perfused with Krebs Heinseleit buffer at 37 degrees C containing 4.7% bovine serum albumin at a constant flow rate of 4 mi per min for 30-60 min with 100% survival of the animals, Tumour vascularization and blood flow were demonstrated using vascular casts and [Cr-51]-microspheres. Following the addition of melphalan (15 or 100 mu g/ml), drug concentrations in the perfusate, tissues and systemic circulation were determined using high pressure liquid chromatography (HPLC), Systemic leakage, assessed using [I-125]albumin and melphalan and detected by a gamma-counter and HPLC respectively, was <0.5%. The melphalan concentration and tissue flow rate in the tumour deposits were 40 and 30% respectively, when compared with the surrounding subcutaneous tissue, At a dose of 15 mu g/ml, melphalan caused a reduction in tumour growth after 60 min perfusion, and a significant reduction in tumour size was seen when the melphalan dose was 100 mu g/ml. The surviving nude rat model of isolated limb perfusion for recurrent melanoma will allow examination of optimal perfusion conditions, along with the pharmacokinetics, pharmacodynamics and efficacy of melphalan and other drugs.

The impact of diabetes on survival among patients with first myocardial infarction

OBJECTIVE - The purpose of this paper is to estimate the impact of diabetes on survival among patients with first acute myocardial infarction, using data from the World Health Organization (WHO) Monitoring Trends and Determinants of Cardiovascular Disease (MONICA) Project in Newcastle, New South Wales, Australia. RESEARCH DESIGN AND METHODS - The WHO MONICA Project is a community-based surveillance system that monitors coronary heart disease morbidity and mortality. All patients with suspected coronary events were observed for 28 days after the onset of symptoms. RESULTS - Of 5,322 patients with acute myocardial infarction and no previous history of ischemic heart disease (3,643 men and 1,679 women), 333 men (9%) and 224 women (13%) had a history of diabetes. The age-adjusted 28-day case fatality for women with diabetes (25%) was significantly higher than for women without diabetes (16%); relative risk 1.56 (95% CI: 1.19-2.04). The difference for men was also significant (25% with diabetes and 20% without diabetes); relative risk 1.25 (95% CI: 1.02-1.53). Age-specific case fatality increased significantly with age in both men and women without diabetes, but systematic age effects were not so apparent in patients with diabetes. Case fatality significantly decreased over the study period in patients without diabetes, but not among the diabetic patients. CONCLUSIONS - The increased risk of death in the diabetic patients remained after accounting for their poorer risk factor profiles; even if they reached the hospital alive, diabetic patients were also less likely to survive than nondiabetic patients. The relative impact of diabetes on survival is greater in women than in men.

Melphalan dosing regimens for management of recurrent melanoma by isolated limb perfusion: Application of a physiological pharmacokinetic model based on melphalan distribution in the isolated perfused rat hindlimb

The optimal dosing schedule for melphalan therapy of recurrent malignant melanoma in isolated limb perfusions has been examined using a physiological pharmacokinetic model with data from isolated rat hindlimb perfusions (IRHP), The study included a comparison of melphalan distribution in IRHP under hyperthermia and normothermia conditions. Rat hindlimbs were perfused with Krebs-Henseleit buffer containing 4.7% bovine serum albumin at 37 or 41.5 degrees C at a flow rate of 4 ml/min. Concentrations of melphalan in perfusate and tissues were determined by high performance liquid chromatography with fluorescence detection, The concentration of melphalan in perfusate and tissues was linearly related to the input concentration. The rate and amount of melphalan uptake into the different tissues was higher at 41.5 degrees C than at 37 degrees C. A physiological pharmacokinetic model was validated from the tissue and perfusate time course of melphalan after melphalan perfusion. Application of the model involved the amount of melphalan exposure in the muscle, skin and fat in a recirculation system was related to the method of melphalan administration: single bolus > divided bolus > infusion, The peak concentration of melphalan in the perfusate was also related to the method of administration in the same order, Infusing the total dose of melphalan over 20 min during a 60 min perfusion optimized the exposure of tissues to melphalan whilst minimizing the peak perfusate concentration of melphalan. It is suggested that this method of melphalan administration may be preferable to other methods in terms of optimizing the efficacy of melphalan whilst minimizing the limb toxicity associated with its use in isolated limb perfusion.

The effects of perfusion conditions on melphalan distribution in the isolated perfused rat hindlimb bearing a human melanoma xenograft

An isolated rat hindlimb perfusion model carrying xenografts of the human melanoma cell line MM96 was used to study the effects of perfusion conditions on melphalan distribution. Krebs-Henseleit buffer and Hartmann's solution containing 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 were used as perfusates. Melphalan concentrations in perfusate, tumour nodules and normal tissues were measured using high-performance liquid chromatography (HPLC). Increasing the perfusion flow rates (from 4 to 8 mi min(-1)) resulted in higher tissue blood flow (determined with Cr-51-labelled microspheres) and melphalan uptake by tumour and normal tissues. me distribution of melphalan within tumour nodules and normal tissues was similar for both Krebs-Henseleit buffer and Hartmann's solution; however, tissue concentrations of melphalan were significantly higher for a perfusate containing 2.8% dextran 40 than for one containing 4.7% BSA. The melphalan concentration in the tumour was one-third of that found in the skin if the perfusate contained 4.7% BSA. In conclusion, this study has shown that a high perfusion flow enhances the delivery of melphalan into implanted tumour nodules and normal tissues, and a perfusate with low melphalan binding (no albumin) is preferred for maximum uptake of drug by the tumour.

Can ECG changes predict the long-term outcome in patients admitted to hospital for suspected acute myocardial infarction?

7,028 patients with suspected acute myocardial infarction and discharged alive from hospital were followed in a 10-year community-based study. The long-term prognosis was relatively good if the electrocardiograms (ECGs) were normal (5-year all-cause death rate 5%), poor with uncodable ECGs showing rhythm or conduction disturbances (37%), and intermediate with new Q wave, new ST elevation, new T wave inversion or ischemic ECG (17-21%), and with new ST depression (27%). Similar patterns were found for ischemic cardiac death and reinfarction. The long-term prognosis of patients with suspected acute myocardial infarction is relatively good if the ECGs are normal and poor if ECGs are uncodable. ST depression may be a marker for a worse long-term outcome.

Underuse of beta-blockers following myocardial infarction: a tale of two cities

Aims: To measure factors associated with underuse of beta-blocker therapy after myocardial infarction (MI). Methods: The Newcastle and Perth collaborating centres of the World Health Organization (WHO) MONICA project (to MONItor trends and determinants of Cardiovascular disease) systematically evaluated all patients admitted to hospital in their respective regions with possible MI. A total of 1766 patients in Newcastle and 4503 patients in Perth, discharged from hospital after confirmed MI from 1985 to 1993, were studied, Rates of beta-blocker use before and after hospital discharge were evaluated and correlates of beta-blocker use determined. Results: Beta-blocker use was similar in Newcastle and Perth before MI (21% of patients in each centre). During hospital admission, beta-blocker therapy was initiated nearly twice as frequently in Perth compared with Newcastle (66 vs 36%, respectively) and more patients were discharged from hospital on beta-blockers in Perth (68%) than in Newcastle (45%). The main factors associated with underuse of beta-blockers in multivariate analysis were geographical centre (odds ratio (OR) for Newcastle compared with Perth 0.3 95% confidence interval (CI) 0.3-0.3), a history of previous MI (OR 0.6, 95% CI 0.5-0.7), admission to hospital in earlier years (OR 0.4, 95% CI 0.3-0.4 for years 1985-87 compared with years 1991-93), diabetes (OR 0.6, 95% CI 0.5-0.8) and the concomitant use of diuretics (OR 0.5, 95% CI 0.4-0.6) and calcium antagonists (OR 0.6, 95% CI 0.5-0.8). Conclusions: Underuse of beta-blockers after MI was strongly related to hospital prescribing patterns and not to community use of beta-blockers. Underuse occurred in patients with diabetes and in patients with left ventricular dysfunction, patients who stand to benefit most from beta-blocker use following MI.

MRI based diffusion and perfusion predictive model to estimate stroke evolution

In this study we present a novel automated strategy for predicting infarct evolution, based on MR diffusion and perfusion images acquired in the acute stage of stroke. The validity of this methodology was tested on novel patient data including data acquired from an independent stroke clinic. Regions-of-interest (ROIs) defining the initial diffusion lesion and tissue with abnormal hemodynamic function as defined by the mean transit time (MTT) abnormality were automatically extracted from DWI/PI maps. Quantitative measures of cerebral blood flow (CBF) and volume (CBV) along with ratio measures defined relative to the contralateral hemisphere (r(a)CBF and r(a)CBV) were calculated for the MTT ROIs. A parametric normal classifier algorithm incorporating these measures was used to predict infarct growth. The mean r(a)CBF and r(a)CBV values for eventually infarcted MTT tissue were 0.70 +/-0.19 and 1.20 +/-0.36. For recovered tissue the mean values were 0.99 +/-0.25 and 1.87 +/-0.71, respectively. There was a significant difference between these two regions for both measures (P

Randomized controlled trial of two cigarette quit programmes in coronary care patients after acute myocardial infarction

Background: Tobacco cessation after acute myocardial infarction (AMI) substantially improves outcome but how effective individual programmes are needs to be established. To date, few studies have examined this factor. Aims: To assess the outcome of two smoking cessation programmes after AMI. Methods: One hundred and ninety-eight current smokers admitted to coronary care with an AMI participated in a randomized controlled study comparing two outpatient tobacco interventions, the Stanford Heart Attack Staying Free (SF) programme and a Usual Care (UC) programme. Results: Log-rank analyses revealed that patients in the SF programme were retained longer (P < 0.001) and had higher cotinine validated abstinence rates (P < 0.001) compared with patients in the UC programme. Twelve months after intervention, 39% of the SF programme compared with 2% of the UC programme demonstrated cotinine validated tobacco cessation, representing a significant reduced relapse rate in the SF programme (chi (2), P < 0.001). Conclusions: The SF smoking cessation programme initiated in hospital can significantly reduce smoking rates at 12 months after myocardial infarction. Although superior to the UC quit programme, Australian outcomes were lower than the American programme originators' published outcomes.

Using postoperative cardiac troponin-I (cTi) levels to detect myocardial ischaemia in patients undergoing vascular surgery

Background, Cardiac complications occur commonly in vascular surgery patients. Diagnosis of cardiac complications is difficult because of the inaccuracies associated with traditional cardiac enzyme measurements. CTi, a highly sensitive and specific marker of myocardial injury, may be able to detect cardiac complications with greater ease and accuracy. Methods. The study prospectively examined 100 consecutive patients who underwent major vascular surgery between 6/7/98 and 31/12/98 at the Royal Brisbane Hospital. Daily measurements of cTi, creatine kinase (CK), creatine kinase MB (CKMB), CKMB index, renal function and haemoglobin were taken for three postoperative days. One postoperative electrocardiograph (ECC) was taken. An extensive cardiac history was taken. Intraoperative and postoperative events were recorded. Findings. There were 100 patients, 18 patients (18%) had a cTi elevation. On the basis of classical diagnostic criteria, 15 patients (15%) suffered one or more cardiac complication (either myocardial infarction, congestive cardiac failure, unstable angina or atrial fibrillation), One patient (1%) who had a cTi elevation died. CTI elevation occurred in five patients (5%) who were not diagnosed with cardiac complications based on traditional criteria. Despite not meeting specific diagnostic criteria for cardiac complications, all patients showed signs and symptoms that could be attributed to myocardial ischaemia, Every patient who developed congestive cardiac failure or atrial fibrillation had a cTi elevation. A Chi-square analysis revealed a significant association between cTi elevation and postoperative cardiac complications. Four variables contributed small but significant amounts of unique variance to the prediction of peak cTi on linear regression analysis. These were peak CKMB index, postoperative congestive cardiac failure, postoperative chest pain and postoperative cardiac complications. Conclusions. Routine cTi monitoring of postoperative vascular patients would be an effective and inexpensive way to detect patients with cardiac complications. The relationship between postoperative cTi elevation and significant coronary artery disease remains to be shown, (C) 2001 The international Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved.

Alteplase: descendancy in myocardial infarction, ascendancy in stroke

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in Mi. Alteplase is most effective when given early in Mi and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in Mi can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard Mi treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in Mi. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.