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Background: Phosphorylase kinase (PhK), also known as adenosine triphosphate (ATP)-phosphorylase b phosphotransferase, integrates multiple calcium/calmodulin-dependent signalling pathways, including those involved in cell migration and cell proliferation, while coupling these pathways to glycogenolysis and ATP-dependent phosphorylation, thus ensuring continuing energy supply for these activities., Objectives: Our laboratory recently reported correlation of elevated PhK activity with psoriatic activity. This study further evaluates the significance of drug-induced suppression of PhK activity on psoriatic activity., Patients and Methods: PhK activity was assayed in four groups, each with 10 patients: (i) active untreated psoriasis; (ii) resolving psoriasis treated by calcipotriol (Dovonex(R), Bristol Myers Squibb, Princeton, NJ, U.S.A. ), a vitamin D3 analogue and an indirect inhibitor of PhK; (iii) curcumin (diferuloylmethane), a selective PhK inhibitor; and (iv) 10 normal non-psoriatic subjects., Results: PhK activity in units mg-1 protein was highest in active untreated psoriasis (1204 +/- 804.3; mean +/- SD), lower in the calcipotriol-treated group (550.7 +/- 192. 9), lower in curcumin-treated group (207.2 +/- 97.6), and lowest in normal skin (105.4 +/- 44.6). One-way analysis of variance performed on log-transformed PhK activity measure showed significant differences among the four groups, F3,36 = 48.79, P < 0.0001. Decreased PhK activity in curcumin-and calcipotriol-treated psoriasis was associated with corresponding decreases in keratinocyte transferrin receptor (TRR) expression, severity of parakeratosis and density of epidermal CD8+ T cells., Conclusions: Our results demonstrate that drug-induced suppression of PhK activity is associated with resolution of psoriatic activity as assessed by clinical, histological and immunohistochemical criteria, and support the hypothesis that effective antipsoriatic activity may be achieved through modulation of PhK activity.

The in vivo immunological events in dextran sulfate sodium (DSS) -induced colitis were evaluated. Rats were fed water (control) or 5% DSS. Colonic sections were assessed by light microscopy, Gram stain, immunohistochemistry, and electron microscopy. A progressive decline in number and increase in fragmentation of bacteria in the colonic lumen was observed over time. Luminal bacteria were the first to show heat shock protein 60 (HSP60) staining (day 3). Macrophages in close proximity to these bacteria were next to show such staining (day 6), and finally the damaged epithelial cells when colitis became severe (day 15). Ultrastructural assessment showed cell-cell contact interactions between macrophages and dendritic gammadelta T cells. An increase in the number of gammadelta T cells and ED1-positive macrophages in the affected colonic tissue over time was documented. These results suggest colonic bacteria, host macrophages, and gammadelta T cells play specific roles in the immunological reactions in DSS-induced colitis, possibly via an HSP60-mediated mechanism.

Background: Recent studies have documented a number of changing demographic features in the occurrence of Warthin's tumour (adenolymphoma) of the parotid gland. In order to analyse its epidemiology in an Asian population, a retrospective study was performed on all parotid neoplasms (n = 289) operated on between 1988 and 1998., Patients and Methods: A total of 209 consecutive patients were selected for study, 136 with pleomorphic adenomas (one bilateral) and 73 with Warthin's tumours (seven bilateral). Patients were analysed with regard to tumour incidence, age, sex and race. Smoking as an aetiological factor in the development of Warthin's tumour was also studied., Results: Warthin's tumour formed 25 per cent of parotid tumours and its ratio to pleomorphic adenomas was 1 : 1.9. Multicentricity was found in 14 patients (19 per cent). The male : female ratio for Warthin's tumours was 4.6 : 1. The proportion of Warthin's tumours did not show any increasing trend relative to pleomorphic adenomas. The racial distribution of Warthin's tumours showed an increased incidence among Chinese and a reduced incidence among Malays and Indians. The adjusted odds ratio for sex and age favouring an association between smoking and Warthin's tumour was 39.5 (95 per cent confidence interval 10.5-149. 0; P < 0.0001)., Conclusion: The incidence of Warthin's tumour is considerable among Asians although there is still male predominance. There is no rising incidence of Warthin's tumour; the trend parallels the declining smoking rate in the population. The lower incidence among ethnic groups with dark skin seems to suggest concomitant genetic factors other than environmental factors alone in histogenesis. Smokers have a 40-fold greater risk than non-smokers of developing a Warthin's tumour.

We report 6 cases of marine typhus presented to us within a period of 3 months. The diagnoses were made based on the Weil-Felix reaction in the context of supportive clinical and epidemiological features, and response to appropriate antimicrobial therapy. This review serves to remind us that murine typhus is still an important cause of acute febrile illness in Singapore, especially among the migrant Indian workers.

Objective: To understand the relationship between zinc and prostaglandin (PG) metabolisms in inducing colon cancer incidence in human and animals., Methods: Human colonic tumor and normal cells were obtained from Departments of Surgery and Pathology at the Kaiser Permanente Medical Center, Los Angeles, CA and US VA Medical Center, North Hills, CA. Rat colonic tumor and normal cells were isolated from the rats that received two injections of 50 mg/kg of Azoxymethan (AOM) in 2 weeks and then kept 30 weeks in the animal facility. Then, the effects of zinc on the PGE2 synthesis and PGE2 on zinc metabolism in tumor and normal cells were determined., Results: PGE2 concentrations in both human and AOM-induced rat colonic tumor cells increased compared to those in adjacent normal colonocytes, whereas PGF2 alpha concentrations did not change. Gene expression of inducible form of prostaglandin synthase (PGS-2) is stimulated in rat colonocytes by epidermal growth factor and by tetradecanoyl 13-phorbol acetate (a tumor promoter and mitogen) only in the presence of zinc. PGE2 binding activity of rat enterocytes was maximum at 15 microM of zinc (normal plasma zinc concentration), but PGE2 synthesis activity increased for the first 15 minutes when extracellular zinc concentrations were either higher or lower than the normal extracellular zinc concentration. However, variations in extracellular zinc concentrations did not change the rate of PGF2 alpha synthesis in the normal rat enterocytes. PGE2 significantly increased zinc uptake rates of colonic tumor cells but PGF2 alpha showed only moderate effect., Conclusions: These results suggest that zinc is required for PGS-2 gene expression, that maintaining an optimal zinc nutriture is important for normal PG synthesis of intestinal cells, and that only PGE2 synthesis mechanisms rather than PGS-2 gene expression are altered in colonic tumor cells resulting in the abnormal zinc nutriture of these cells.

Because immune mechanisms are implicated in atherogenesis, we investigated the T-lymphocyte subset and factors related to its activation after acute arterial ligation (22 ligated and 13 non-ligated specimens). Ligated arteries produced heat-shock protein 65 (hsp65) and were infiltrated with activated T cells (mostly dendritic, CD3+, CD4-, CD8-, and gamma/delta T-cell-receptor bearing). The protein was found with dendritic T cells, with immunogold-labelled hsp65 beside the dendritic processes. Thus, the immune reaction after acute arterial injury may be associated with binding and recognition of in-situ hsp65 by dendritic gamma/delta T-cells.

To determine whether abnormal activity of a calmodulin-containing enzyme which catalyses phosphorylation reactions may play a pathogenetic role in psoriasis, the presence and activity of phosphorylase kinase (PK) in human epidermis were determined in patients with untreated/active psoriasis (n = 10), treated/resolving psoriasis (n = 10), and non-psoriatic controls (n = 10). Biopsies were taken from involved and uninvolved skin for PK, organic phosphorus, and inorganic phosphate estimation, and light and electron microscopy. The enzyme was present in involved and uninvolved skin of every patient in the study. PK activity (units/mg protein) was significantly higher in active psoriasis than in resolving psoriasis and controls. PK activity correlated directly with organic phosphorus levels, and inversely with the extent of cellular glycogenolysis measured by the depletion of glycogen granules within the keratinocytes. The study demonstrates that PK is present in both psoriatic and normal epidermis, with significantly higher levels in active psoriasis. Furthermore, higher levels of PK activity, glycogenolysis and phosphorylation are associated with increased clinical psoriatic activity. We conclude that PK, a calmodulin-containing enzyme, is involved in regulating calcium-dependent phosphorylation events in human epidermis, and disturbance of its activity may play a key role in the clinical manifestations of psoriasis.

Signal transduction of many intracellular events is initiated by a minute influx of calcium ions into the cells, resulting in the formation of calcium-calmodulin complex and cAMP. Because zinc appears to have an inhibitory effect on a number of tissue reactions, it is postulated that this occurs through modulation of intracellular calcium influx. To test the hypothesis that the inhibitory effects of zinc are mediated through the calcium-calmodulin-cAMP pathway, zinc was administered by various routes to five groups of nude mice (control, intragastric, intraperitoneal, intradermal and oral groups), and calmodulin and cAMP concentrations were measured in the cytosol of epidermal cells. Calmodulin levels decreased significantly in the groups given intraperitoneal zinc (P < 0.025) and intradermal zinc (P < 0.001) injections. Significant elevations of cAMP levels were noted with intradermal zinc (P < 0.025). Overall, the relationship between calmodulin and cAMP appeared to be inversely logarithmic, with the lowest calmodulin levels associated with the highest cAMP concentrations. In addition, there was a significant trend towards a smaller calmodulin/cAMP ratio in all zinc-treated groups, except the mice fed dietary zinc. These results appear to correlate with tissue zinc levels obtained with these various forms of zinc administration. Our results therefore indicate that there is a reciprocity between epidermal calmodulin and cAMP levels, which may be modulated by external factors such as zinc.

Although inversion therapy is used increasingly as a therapy for musculoskeletal back disorders, its effects on cardiovascular function have not been systematically determined. Heart rate, blood pressure and echocardiographic measurements were performed in 20 normal male volunteers before, during and after bent-knee inversion. Compared to control measurements in the supine position, inversion significantly increased heart rate, systolic and diastolic blood pressure, rate-pressure product, systemic vascular resistance and left ventricular (LV) wall stress. Inversion also resulted in a significant decrease in LV diastolic volume, cardiac output and ejection fraction. Thus inversion produces an increase in LV afterload and myocardial oxygen demand concomitantly with a decrease in LV preload and global systolic function, and may be contraindicated in patients with cardiovascular disease.

The distribution of various glycoprotein molecules on the surface of follicular keratinocytes was studied with a panel of lectins with specificity for various sugar moieties on biopsy specimens from both bald/balding scalp and normal occipital scalp, of 23 patients with androgenetic alopecia as well as on biopsies of normal forearm skin of four patients. The most significant differences between bald and normal scalp biopsy were noted with Ulex europaeus agglutinin I (UEA I). We noted an increased (91.8% +/- 3.1; mean +/- SE) expression of UEA I binding sites on the infra-infundibular follicular keratinocytes in anagen terminal scalp hairs, compared to 28.5% +/- 5.2 in the indeterminate (anagen) hairs of balding scalps, and 23.2% +/- 6.3 in the anagen follicles of vellus fore-arm hairs. By contrast, the telogen hairs demonstrated minimal UEA I staining: 4.0% +/- 0.8, mean +/- SE in telogen scalp hairs, 1.8% +/- 0.5 in telogen hairs of balding scalps (0% in completely bald scalps, in which all the hairs were in the telogen phase), and 1.9% +/- 0.2 in telogen forearm hairs. The percentage of UEA I staining correlated with the length of the infra-infundibular follicles in all cases studied. In three cases of hair regrowth after hair growth promotors, the UEA I staining increased to 80.6% +/- 6.1 in anagen hairs and correlated with increased length of infra-infundibular follicles. Our data indicate that there are 1) marked differences between anagen and telogen follicles in UEA I binding to infra-infundibular follicular keratinocytes; 2) the percentage of UEA I staining reflects the size (length) of the infra-infundibular hair follicle; and 3) the anagen follicles of balding scalps (indeterminate hairs) show UEA I staining resembling that exhibited by anagen follicles of vellus hairs.

Microangiopathy is an essential component in diabetic vascular pathology. We report ultrastructural observations of ballooning degeneration involving isolated endothelial cells of cutaneous capillaries, while leaving adjacent endothelial cells relatively intact in six diabetic patients with early lesions of necrobiosis lipoidica induced by trauma. Focal proliferation of endothelial cells encroaching upon the vascular lumina (obliterative endarteritis) was also observed. Lectin studies on biopsy specimens of older lesions of necrobiosis lipoidica revealed paucity of dermal blood vessels. These observations enable us to gain further insight into the pathophysiological mechanisms that underlie diabetic microvascular disease.

The presence of systolic dysfunction, diastolic dysfunction, or both is an important consideration in selecting the optimal pharmacologic approach to the treatment of congestive heart failure in an individual patient. Cardiac glycosides and arterial vasodilators act only on systolic function, whereas beta 1-adrenoceptor-stimulating agents, such as beta 1 full and partial agonists, have both inotropic and lusitropic activity. Acute and chronic administration of xamoterol, a new beta 1 partial agonist, to patients with congestive heart failure has been shown to improve myocardial contractility, as indicated by increases in the peak rate of rise in left ventricular pressure, left ventricular ejection fraction, and cardiac output. Improvement in ventricular relaxation and filling, reflected by increases in the peak rate of decline in left ventricular pressure, reductions in the time constant of the decrease in isovolumic pressure, improved left ventricular compliance, and increases in the atrial contribution to diastolic filling, are other beneficial effects of xamoterol on diastolic function. Exercise capacity increases in response to xamoterol therapy, while heart rate at maximum exercise declines. Relief of the signs and symptoms of congestive heart failure and improvement in functional status have also been demonstrated in xamoterol-treated patients. The undesirable effects of beta 1 full agonists, such as tachycardia, arrhythmias, increased myocardial oxygen consumption, and effects on the peripheral vasculature, are not seen with xamoterol. The beta 1 partial agonist also causes no beta-adrenoreceptor down-regulation, a finding that may account for its sustained effectiveness with long-term therapy.

The antiarrhythmic effects of mexiletine (n = 14) were compared to procainamide (n = 16) by a double-blind parallel protocol in 30 patients (group I) with frequent premature ventricular contractions (PVCs) (greater than 20/hr), and to amiodarone by an open-label sequential approach in 25 patients (mean left ventricular ejection fraction of 32.6 +/- 13.4%) with life-threatening ventricular arrhythmias (group II) resistant to two or more conventional agents. The predetermined end point of therapy in group I patients was met in 6 of 14 (43%) given mexiletine, with 7 (50%) requiring drug discontinuation for severe gastrointestinal or central nervous system side effects and only 3 of 16 patients (19%) given procainamide, with 5 (31%) developing limiting side effects. Increases in dose led to a higher efficacy rate for PVC suppression with a corresponding increase in side effects with mexiletine; with procainamide, the higher dose was not associated with greater PVC suppression. In group II patients, mexiletine was effective in 4 (16%), with one patient discontinuing the drug during long-term therapy; mexiletine was ineffective in 16 (64%) and early side effects developed in 5 (20%). Patients not responding to or not tolerating mexiletine were given amiodarone; 20 of 21 (95%) responded with arrhythmia control after the loading dose. During a mean follow-up period of 2 years, sudden death occurred in two patients, death from heart failure in two, and death from subarachnoid hemorrhage in one patient; 15 (75%) patients are alive and free of arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of propranolol (0.1 mg/kg intravenously followed by 320 mg given over 27 hour orally) on serum levels of creatine kinase enzyme was studied in a randomized trial involving 95 patients seen within 12 hours of onset of symptoms of uncomplicated myocardial infarction. In 15 patients who were treated with propranolol within 4 hours of onset, and who eventually developed pathological Q waves, peak measured enzyme levels were 27% (P less than 0.0125) lower than in 19 control patients who were also seen within 4 hours of the onset but had no specific treatment. Total calculated enzyme appearance was also lower in the treated patients (reduced 25%, P less than 0.05) as was the calculated rate of the appearance (33%, P less than 0.005). No significant difference was found for treated compared with control patients entering the trial more than 4 hours after the onset of chest pain. This evidence suggests that propranolol may reduce the size of uncomplicated infarctions if it is given intravenously within 4 hours of the onset.

The effects of atenolol on ventricular arrhythmias were evaluated in 25 men with significant ventricular ectopy. The patients received 2 weeks each of placebo, 50, 100, and 200 mg of oral atenolol. Efficacy was determined by weekly 24-hour Holter monitors. In 20 patients who completed the protocol, the frequency of total ventricular ectopic beats, ectopic couplets, and ventricular tachycardia was significantly decreased after treatment. The complexity of ventricular ectopy was also decreased as measured by the Lown grade and the proportion of hours in which multiform ectopic beats were present. A therapeutic response, defined as the minimum percentage reduction in ventricular arrhythmias to demonstrate an effect due to atenolol rather than spontaneous variation, was achieved in up to 70% of patients for total number of ectopic beats, 75% for ectopic couplets, and 73% for ventricular tachycardia beats. The results show that oral atenolol is an effective agent for the treatment for ventricular arrhythmias.

The relationship between early and late epicardial electrocardiographic changes as well as those in regional myocardial blood flow (MBF) and the severity of myocardial damage was determined in 12 anesthetized dogs with left anterior descending coronary artery ligation. Radioactive microspheres (15 mum) were used to measure regional MBF at 15 min (early) and 24 h (late) after coronary occlusion. Severity of myocardial damage was assessed by the extent of myocardial creatine phosphokinase depletion 24 h after coronary ligation. There was a close linear correlation between myocardial creatine phosphokinase activity and regional MBF both early (r=0.93, 2P less than 0.001) and late (r=0.88, 2P less than 0.001). An inverse but less precise relationship existed between acute epicardial ST-segment elevation and early (r=-0.41, 2P less than 0.001), or late (r=0.35, 2P less than 0.05) regional MBF. Similarly, a weak correlation was found between myocardial creatine phosphokinase (IU/mg protein) at 24 h and early epicardial ST (millivolt) elevation (r=-0.36, 2P less than 0.02). In the center zones of the infarct with MBF 1/10 of normal, about 35% of the areas with normal QRS width had no epicardial ST-segment elevation 15 min after coronary occlusion. About 44% of the areas which developed pathological Q-waves in the electrocardiogram at 24 h had no ST elevation 15 min after coronary ligation. Late evolution of abnormal Q-waves occurred almost invariably in areas in which the early MBF was reduced to less than 50% of normal and in areas which subsequently had myocardial creatine phosphokinase levels reduced to less than 60% of normal. After coronary occlusion, the severity of the ultimate myocardial damage, which was directly proportional to the degree of reduction in MBF, was therefore not reliably predicted by the early epicardial ST-segment elevation. The data obtained in these studies suggest the need for caution in the use of acute ST-segment elevation as a predictive index of the extent or severity of myocardial ischemic damage.

The results of valve replacement with a stent-mounted antibiotic-treated aortic allograft valve are reported in 129 patients with isolated mitral valve disease. Of these patients, 70 per cent were in N.Y.H.A. Class IV. The hospital mortality rate was 3.9 percent. The cumulative complication-free rate at 5 years was only 37 percent as 21 percent died late, a further 15 percent were alive following reoperation, 4 percent had an embolic episode, 4 percent were alive with important incompetence, and 20 percent had unimportant incompetence. Proved valve failure was due mainly to detachment of the aortic wall remnant of the valve from the pillar of the rigid metal stent (16 percent incidence at 5 years) and methods for preventing this complication are discussed. Because of these complications the use of this device in the mitral position has been discontinued.

Changes in left ventricular (LV) meridional and circumferential end-systolic wall stress during isometric and isotonic exercises were determined noninvasively in 12 healthy subjects using echocardiography and cuff blood pressure measurements. Isometric exercise was performed at 20 and 40% of maximal voluntary contraction using a handgrip dynamometer, and isotonic exercise was done on a cycle ergometer at 150 kpm/min increments every 3 minutes to a maximum of 600 kpm/min. Although the increase in systolic blood pressure was similar in both forms of exercise, LV systolic stress in the circumferential and meridional planes increased markedly during isometric exercise but decreased slightly during higher intensity isotonic exercise. Isometric exercise also produced a significant decrease in fractional shortening, whereas isotonic exercise significantly increased fractional shortening. Wall stress and fractional shortening were linearly and inversely related, but isometric and isotonic exercise produced divergent and significantly different linear regressions. In normal subjects isometric exercise produces a significant increase in LV afterload that leads to a decrease in LV global function. In contrast, isotonic exercise causes an increase in LV global function, most likely from an unchanged or slight decrease in afterload associated with increased LV contractility from greater catecholamine release.

Myocardial creatine phosphokinase (CPK) activity and myocardial blood flow (MFB, 15 +/- mu microspheres) were measured at 24 hours after ligation of the left anterior descending coronary artery in nine untreated anesthetized dogs, in eight dogs pretreated with intravenous propranolol 5 mg/kg and in eight which had both pretreatment as well as infusion of propranolol (1.25 mg/kg/hour) after occlusion. Loss of CPK activity from the border and center zones of the myocardial infarct was similar in extent in dogs which had pretreatment but no infusion of propranolol as it was in the control group. Loss of CPK from the center zone was greater (P less than 0.005) in dogs receiving pretreatment followed by constant infusion of the drug. Propranolol had no significant effect on collateral blood flow to the border or center zone of the infarct. In separate experiments, there was no important difference in hemodynamic measurements, except a slower heart rate (P less than 0.01), when pretreated dogs were compared with control dogs up to 2 hours after coronary ligation. We conclude that propranolol given in this dose does not influence nyocardial damage, on the basis of regional myocardial blood flow or tissue CPK depletion values at 24 hr after coronary occlusion.

Praecordial ST segment elevation was measured at 35 electrode positions in each of 40 patients admitted to a coronary care unit after acute transmural anterior myocardial infarction. Serial praecordial electrocardiographic maps were recorded to determine (a) the time course as well as reproducibility of measurements of ST segment alterations, and (b) the degree of correlation between the magnitude of ST segment elevation and the severity of infarction, as assessed clinically or by sequential estimations of serum creatine kinase activity. Large variations in ST segment elevation were found in different patients with a comparable degree of myocardial damage, and at intervals of as little as four hours in the same patient. These variations were greater than could be explained by technical factors, and were not related to apparent changes in the patients' clinical status. The patterns of release of myocardial creatine kinase showed that the time course of ST segment elevation was longer than the period of myocardial necrosis. No correlation was found between the myocardial infarct size as determined by enzyme release and the highest levels of ST segment elevation recorded. The findings suggest that ST segment elevation as measured by praecordial electrocardiographic mapping does not constitute a reliable index of the size or severity of myocardial infarcts in man.

A system of exercise stress echocardiography was developed in which, during exercise on a bicycle ergometer in a semirecumbent position, the echocardiographic transducer is held by a special device which maintains a relatively constant position between the transducer and the heart. The system was evaluated in 21 healthy subjects and technically satisfactory studies were obtained in 20. In these, the resolution and relative position of the cardiac image remained stable throughout exercise. Blood pressure and heart rate increased appropriately with our protocol with supine exercise; 95% of the subjects reached 90% of their predicted maximum heart rate for age. Ejection fraction measured by echocardiography increased from 54 +/- 1% to 70 +/- 1%. It is concluded that the use of our transducer-holding device in subjects performing exercise in the supine position significantly improves ultrasonic image quality and should enhance the clinical usefulness of exercise stress echocardiography.

Although normalization of previously inverted T waves in the ECG is not uncommon during exercise treadmill testing, the clinical significance of this finding is still unclear. This was investigated in 45 patients during thallium-201 exercise testing. Patients with secondary T wave abnormalities on the resting ECG and ischemic exercise ST segment depression were excluded. On the thallium-201 scans, the left ventricle was divided into anterior-septal and inferior-posterior segments; these were considered equivalent to T wave changes in leads V1 and V5, and aVF, respectively. A positive thallium-201 scan was found in 43 of 45 (95%) patients and in 49 of 52 (94%) cardiac segments that showed T wave normalization. When thallium scans and T wave changes were matched to sites of involvement, 76% of T wave normalization in lead aV, was associated with positive thallium scans in the inferior-posterior segments, and 77% of T wave normalization in V1 and V5 was associated with positive thallium scans in the anterior-septal segments. These site correlations were similar for reversible and fixed thallium defects, and for patients not on digoxin therapy. Similar correlations were noted for the sites of T wave changes and coronary artery lesions in 12 patients who had angiography. In patients with a high prevalence for coronary artery disease, exercise T wave normalization is highly specific for the presence of the disease. In addition, it represents predominantly either previous injury or exercise-induced ischemic changes over the site of ECG involvement, rather than reciprocal changes of the opposite ventricular wall.

A retrospective study was made of 158 patients with unstable angina admitted to a coronary care unit over a 4-year period. Twenty patients (13 per cent) had myocardial infarcts while in hospital, and of these 3 died; three others died without preceding evidence of myocardial infarction. There was thus an acute mortality rate of 4 per cent. Patients with persisting angina after the first 24 hours and those without a previous history of myocardial ischaemia were more likely to develop a myocardial infarct or to die in hospital. Follow-up information, ranging from 3 to 7 years, was available in 144 of 152 hospital survivors. Patients older than 60 years (P less than 0-05), with cardiomegaly (P less than 0-01) and with pulmonary venous congestion (P less than 0-05) were found to have significantly increased long-term mortality. Long-term mortality was also found to rise with increasing coronary prognostic index. The average mortality rate for the whole group of hospital survivors was about 5 per cent per annum. Of the 111 patients who were alive at follow-up, 19 (17%) had had a myocardial infarct after leaving hospital, and a similar number had moderate or severe angina.

Cross-sectional echocardiography was utilized for quantification of volume in 19 formalin-fixed left ventricles in the presence or absence of ventricular symmetry, defined by the ratio of septal-lateral to anterior-posterior diameter. In 10 symmetric ventricles this ratio was 1.23 +/- 0.06 (mean +/- SEM), whereas in nine asymmetric ventricles the ratio was 1.80 +/- 0.07. Area, diameter, and length measurements were obtained from short- and long-axis cross-sectional images of the left ventricle and volume was calculated by five mathematical models previously described. To evaluate the reliability of each model, echocardiographic left ventricular volume was compared by linear regression and percent error analyses to directly measured fluid volume. In symmetric ventricles, excellent correlations (r = 0.996 to 0.967) and reasonable mean percent errors (6% to 31%) were observed for all models. In asymmetric ventricles, models utilizing short-axis area or two short-axis diameters retained high correlation coefficients (r = 0.985 to 0.956) and similar mean percent errors, but standard formulas previously used with M-mode echo and angiography showed lower correlations (r = 0.886 to 0.873) and higher mean percent errors (52% to 54%). Thus, in the presence of ventricular asymmetry, analysis of short-axis areas or diameters with cross-sectional echocardiography is well suited for quantification of left ventricular volumes.

Antinuclear antibodies are present in most patients receiving procainamide. To ascertain whether IgG antiguanosine antibodies are associated with the development of the symptoms of systemic lupus erythematosus, we compared the levels of these antibodies in the sera of 65 patients receiving procainamide: 18 with procainamide-induced symptoms and 47 asymptomatic patients. Antinuclear antibodies measured by immunofluorescence were present in the 18 patients with drug-induced symptoms but also in 24 asymptomatic patients. Similarly, elevated serum levels of antibodies to single-stranded DNA were found in 15 patients with symptoms and in 20 asymptomatic patients. In contrast, levels of IgG antiguanosine antibodies were elevated in 15 patients with drug-induced symptoms, but in only 3 asymptomatic patients. Antiguanosine antibodies binding to single-stranded DNA were found primarily in patients with arthritis, pleuritis, and pericarditis. These results suggest a strong association between IgG antiguanosine antibodies and major manifestations of procainamide-induced systemic lupus erythematosus.

Ambulatory cardiac (Holter) monitoring is often recommended in the routine evaluation of patients who fall; however, the prevalence of arrhythmias in old people is high, and the usefulness of such monitoring is unproven. As part of a large study of institutionalized elderly fallers, we compared Holter findings of fallers (N = 51) with a group of nonfallers (N = 27) having similar medical and demographic characteristics. Prevalence of ventricular arrhythmias was 82% in each group, and all patients had supraventricular arrhythmias. The mean number of ventricular and supraventricular couplets and runs did not differ between groups. There was no difference in severity of arrhythmias between fallers and nonfallers; in fact, fallers had slightly fewer Lown 4B arrhythmias than nonfallers (10% vs 18%, NS). Prevalence of heart disease was 78% in both groups and was associated with increased ventricular ectopy in the form of runs and couplets (P less than .05). No symptoms were reported during the Holter monitoring. We conclude that Holter monitoring should not be a routine part of the work-up of the patient who falls.

Lacate concentrations were measured in blood from (a) coronary veins within ischaemic myocardium and (b) veins nearer to the coronary vein, for periods of up to 2 1/2 hours after ligation of the left anterior descending artery in dogs. Concentrations at (a) were three to four times higher than at (b), while blood sampled simultaneously from two veins at (a) yielded similar concentrations of lactate. At 2 1/2 hours after ligation the veno-arterial difference of lactate concentration in blood from (a) was about one half of the difference at 15 minutes. Lactate concentration at (a) was approximately twice as great when the area of ischaemic myocardium drained by the vein was large (18 not equal to 1% of heart weight) than when it was small (6 not equal to 1% of heart weight). No close correlation was apparent between the height of epicardial ST-segment elevation and the level of lactate release. These experiments extend previous observations that changes in lactate concentration at a given site may reflect changes in venous dilution, rather than in the rate of production of lactate, and emphasize that caution is necessary in interpretation of changes in concentrations of metabolites in coronary sinus blood after acute myocardial infarction in man.

Cross-sectional echocardiography was used to quantify volume in 21 canine left ventricles that were fixed in formalin and immersed in mineral oil. Area, length and diameter measurements were obtained from short- and long-axis cross-sectional images of the left ventricle and volume was calculated by seven mathematic models. Calculated volume was then compared, by linear regression and percent error analyses, with fluid volume of the left ventricle, obtained by filling the chamber with a known amount of fluid. Volumes ranged from 13-146 ml. Mathematic models using short-axis area and long-axis length gave higher correlation coefficients (r = 0.982 and r = 0.969) and lower mean errors (10-20%) than standard formulas previously used for M-mode echo and angiography. Thus, short-axis area analysis with cross-sectional echocardiography is well-suited for quantifying left ventricular volumes in dogs.

Hemodynamic effects of sustained-action oral isosorbide dinitrate (40 or 80 mg) were studied in 10 patients with stable angina for a period of 16 hours. Control hemodynamic parameters monitored for eight hours prior to the administration of isosorbide dinitrate showed no significant change. However significant reduction in mean arterial pressure, cardiac index, pulmonary artery wedge pressure, mean pulmonary artery pressure, double product (systolic pressure multiplied by heart rate), stroke volume index, and stroke work index occurred in the first two hours and persisted for 12 hours following the administration of isosorbide dinitrate. Heart rate did not change significantly for 12 hours. It can be concluded that the hemodynamic effects of sustained-action oral isosorbide dinitrate occur in the first two hours and last up to 12 hours. The predominant hemodynamic effect appears to be on the myocardial preload. The antianginal effect of the drug could be attributed to the reduction of myocardial oxygen demand reflected by a decrease in the double product and stroke work. The duration of the hemodynamic changes observed in this study indicates that high-dose oral isosorbide dinitrate could be administered conveniently two or three times daily.

The incidence of ST segment depression during tooth extraction was significantly higher in patients with cardiac disease than it was in patients without cardiac disease, indicating that the cardiac patients experienced myocardial ischemia. The almost equivalent incidence of ST segment depression during anesthetic administration and surgery suggests that the administration of local anesthetic is as stressful as tooth extraction for cardiac patients. Medical consultation before dental treatment and use of stress-reduction techniques may be indicated for patients with or suspected to have cardiac disease.

Regional uptake of 99mTechnetium diphosphonate was compared with regional myocardial blood flow 6, 12 and 24 h after the onset of myocardial infarction in dogs, and with regional creatine kinase depletion 24 h after the onset. Uptake of the imaging agent increased from 6 to 24 h, but no consistent relationship could be demonstrated between regional myocardial blood flow and regional uptake of the diphosphonate nor between uptake and regional creatine kinase depletion at the centre or border of the infarct. In addition, inappropriately high levels of 99m Technetium uptake could be demonstrated in the epicardial layer of the normal tissue surrounding the infarct. We conclude that diphosphonate uptake is not quantitatively related to the severity of ischaemia, and that use of this substance for imaging may over-estimate myocardial infarct size.

Although asymmetric septal hypertrophy is noted in a wide variety of cardiac disorders, its cause remains unclear. One possible mechanism is that the septum is subjected to greater systolic stress because of its flatter (more eccentric) contour. This was investigated noninvasively in nine subjects by estimation of regional myocardial stress from measurements of blood pressure by cuff sphygmomanometry and by echocardiographic examinations of left ventricular shape and dimensions. Analysis of left ventricular cavity shape showed that both the free and septal walls were elliptical, but the septum was more eccentric than the free wall. Using a conceptual model to determine changes in regional systolic stress, the theoretical rate of increase in regional stress relative to pressure (delta S/delta P) was significantly greater in the septum compared to the free wall. Increased hypertrophy of the septum to normalize this increased delta S/delta P may be the cause of asymmetric septal hypertrophy in many disorders associated with elevated left ventricular pressure.

The effects of intravenous verapamil on the electrocardiogram in 15 patients with heart disease in sinus rhythm and in 44 patients with supraventricular and ventricular tachyarrhythmias were evaluated. Verapamil prolonged the P-R interval without effect on the QRS duration or the Q-Tc interval. In patients with atrial flutter and fibrillation, A-V block was increased, with slowing of the ventricular rate, in almost all cases but sinus rhythm was restored in only 1 of 12 patients in atrial fibrillation and in 2 of the 11 patients with flutter. Verapamil had no effect in 3 patients with atrial fibrillation complicating WPW syndrome; in 1 of 5 patients with ventricular tachycardia it caused reversion to sinus rhythm. Sinus rhythm was restored promptly by verapamil in 13 of 17 patients with paroxysmal supraventricular tachycardias; in 2 others, sinus rhythm became established 1 to 2 hours after administration of the drug. Transient hypotension, not requiring treatment, was the only side effect noted but not in the patients with supraventricular tachycardias, in whom blood pressure generally increased after reversion to sinus rhythm by verapamil.

To improve ultrasound images during exercise 2-dimensional echocardiography (2-D echo), a device was developed to hold the transducer and maintain its orientation relative to the heart. The value of this technique in detecting wall motion abnormalities and changes in ejection fraction was evaluated in 54 men undergoing stress test for angina. Thallium-201 scanning, electrocardiography and exercise 2-D echo were recorded concurrently. Technically satisfactory echo studies were obtained in 47 patients (87%). The sensitivity and specificity of exercise echo in the detection of myocardial ischemia as judged by wall motion abnormalities were 100% and 93%, respectively. Sixteen patients with normal thallium scans increased their ejection fraction (EF) estimated by echo (from 52 +/- 1% at rest to 67 +/- 1% at maximal exercise, p less than 0.001); all showed an increase of 5% or more. In contrast, 11 patients who had reversible thallium scan defects showed a consistent decrease in EF (from 53 +/- 2% at rest to 43 +/- 2% during exercise, p less than 0.001); 20 patients with irreversible thallium scan defects showed no specific trend in the EF (48 +/- 2% at rest and 50 +/- 2% during exercise, difference not significant). Changes in heart rate and blood pressure did not distinguish the 3 groups of patients. Our technique of exercise 2-D echo may be useful for detecting wall motion abnormalities and EF changes during exercise and possibly enhance the sensitivity of thallium scanning in the noninvasive diagnosis of coronary artery disease.

To determine alterations in myocardial metabolism and and hemodynamics that occur within the first 30 minutes after coronary arterial occlusion, before the onset of ventricular fibrillation, measurements were compared in two series of dogs. Series A, 90 dogs that did not manifest ventricular fibrillation after coronary occlusion, were considered a control group. Series B consisted of 28 dogs that had ventricular fibrillation within 30 minutes after occlusion. All had similar comprehensive measurements completed preceding the onset of ventricular fibrillation. The animals in series B (subseuqnt fibrillation) had significantly higher heart rates before and after coronary occlusion. In this series cardiac metabolism of the occluded segment judged by transmyocardial lactate extraction, potassium balance, sodium/potassium ratio and blood pH because grossly more abnormal after coronary occlusion than in series A. In 5 animals whose measurements were obtained within 5 minutes of the onset of ventricular fibrillation, a sudden massive lactate production, potassium loss and increased acidosis of the occluded portion supervened minutes before the onset of the fatal arrhythmia. Animals with ventricular fibrillation had higher intracoronary S-T segment elevation that persisted until the onset of ventricular fibrillation. Measurements of abnormal hemodynamic function (left ventricular end-diastolic pressure, peak systolic pressure and first derivative of left ventricular pressure [DP/dt]) were not associated with an increased incidence of ventricular fibrillation. The study indicates that animals that manifest ventricular fibrillation within 30 minutes after coronary occlusion have higher preocclusion heart rates, a more severe metabolic disorder of the coronary occluded segment and more persistent intracoronary S-T segment elevation compared with animals that do not manifest ventricular fibrillation.

Necrobiosis lipoidica in diabetics has been considered to be a cutaneous manifestation of diabetic microangiopathy. Seven diabetic patients with necrobiotic ulcers of recent onset that healed after administration of acetylsalicylic acid and dipyridamole had elevated thromboxane levels. Healing was associated with depression of the elevated thromboxane levels in all seven patients.

Cross-sectional echocardiography was used to quantify left ventricular mass noninvasively in 21 dogs. Short- and long-axis cross-sectional images of the left ventricle were reproducibly traced at endocardial and epicardial borders during stop-motion video-tape replay. We used area, length and diameter measurements to calculate left ventricular mass by seven mathematic models, including the standard formulas used with M-mode echocardiography and cineangiography. Calculated mass was compared with excised weight of the left ventricle by regression and percent error analyses. Formulas using short-axis areas and long-axis length resulted in higher correlation coefficients (0.94--0.95) and lower mean errors (6--7%) than for standard formulas. Since short-axis areas account for regional left ventricular irregularities, noninvasive quantification of left ventricular mass by cross-sectional echocardiography in dogs is most accurate with formulas using short-axis areas.

Serial measurements on serum creatine phosphokinase (CPK) and alpha-hydroxybutyrate dehydrogenase (HBD) activity were made in 17 patients with acute myocardial infarction. Activities of both enzymes were measured 4-hourly from less than 12 h after the onset of chest pain until CPK activity had returned to near-normal levels. Blood was then sampled twice daily for a further 4--6 days in order to follow the decline in HBD activity. Degradation rates (KD) were calculated for both enzymes, and individual figures for KD were used in order to estimate the total cumulative release of each enzyme. We found a significant correlation between the duration (r = 0.66, P less than 0.01) and magnitude (r = 0.67, P less than 0.01) of release of the 2 enzymes, comparing different patients with one another. Duration od HBD release was 11 h greater than the duration of CPK release in 9 of the 17 patients who were suffering from cardiac failure (t = 0.01, P less than 0.02). Degradation rate (KD) for HBD was on average about one quarter of that for CPK, but there was no significant correlation between KD for the 2 enzymes. KD did not appear to be reduced in patients with cardiac failure. We conclude that the release patterns of CPK and HBD after myocardial infarction are similar, and this strengthens the case for acceptance of total enzyme release as a valid index of myocardial infarct size.

The extent of left ventricular (LV) dyssynergy was assessed noninvasively in 19 dogs with two-dimensional echocardiographic short-axis sections during myocardial ischemia and infarction. After coronary occlusion, two-dimensional echocardiography uniformly indicated an increase in LV end-diastolic volume and a decrease in LV ejection fraction. Two-dimensional echocardiographic measurements of dyssynergy were evaluated and compared in three subgroups against (1) the extent of LV dyssynergy determined by force-gauge mapping during 10 coronary occlusions of 30-60 minutes' duration in eight open-chest dogs, (2) infarct size delineated by nitroblue tetrazolium (NBT) staining of left ventricular slabs after 48 hours of left anterior descending coronary artery (LAD) occlusion in five closed-chest dogs, and (3) NBT infarct size after 3-hour LAD occlusion followed by 45 hours of reperfusion in six closed-chest dogs. Linear regression analysis of results from these three comparisons gave good correlations (r = 0.89) for groups 1 and 2; in group 2, the extent of dyssynergy by two-dimensional echocardiography was consistently greater than infarct size by NBT. In group 3, the correlation was poor (r = 0.39). These results suggest that an adequate estimate for the extent of LV dyssynergy or infarct size may be obtained with two-dimensional echocardiography during myocardial ischemia or infarction, but not in the presence of coronary reflow, which causes an acute discrepancy between myocardial viability and function.

The effect of glucose-insulin-potassium (GIK) infusions was studied in 45 dogs after left anterior descending coronary artery ligation. GIK caused a modest increase in lactate concentration in small veins draining the infarct but did not affect glucose uptake. No effect on creatine kinase activity in the infarct was seen from GIK, although there was a slight increase in blood flow to the centre of the infarct. We concluded that GIK did not reduce infarct size in this experimental model.

A number of beta-adrenoceptor blocking drugs have been reported to induce a papulosquamous eruption which resembles psoriasis. We report distinctive clinical, histopathologic, immunocytochemical, and electron microscopic features in beta-blocker-induced psoriasiform eruptions that differentiate this syndrome from psoriasis. Preliminary data suggest that biopsy specimens from eruptions caused by beta 1-selective adrenoceptor blocking agents (metoprolol and atenolol) were characterized by excessive degranulation of the neutrophils in the dermis, while the nonselective beta blockers (propranolol, nadolol, and sotalol) were marked by excessive release of proteolytic enzymes from macrophages, which are thought to possess beta 2-adrenergic receptors. Surprisingly, excessive release of enzymes by lymphocytes were noted in both the beta 1-selective and in the nonselective induced syndromes. It is believed that excessive lysosomal enzyme release by neutrophils, lymphocytes, and macrophages is responsible for the presence of basal keratinocyte herniations, which have previously been shown to correlate with hyperproliferation and psoriasiform changes, as well as with the presence of excessive proteolytic enzymes in the skin. It is postulated that the beta-blocker-induced syndrome may result from enhanced proliferation, motility, and activity of lymphocytes, neutrophils, and cells of the macrophage-Langerhans cell series, stemming from depressed intracellular cyclic adenosine monophosphate levels caused by the beta blockade.

The cardiac helical fiber concept was introduced in 1969 and was shown mathematically to provide better approximations of normal ejection fractions compared with the conventional circumferential fiber model. The clinical applicability of this concept was evaluated noninvasively by M-mode and two-dimensional echocardiography in 55 subjects: 10 with aortic insufficiency, 10 with congestive cardiomyopathy, eight with hypertension, eight who were long-distance runners, 12 who were active and seven who were sedentary normals. Comparison of myocardial shortening by the circumferential and helical fiber models showed that the former discriminated only two groups of subjects, while endocardial and epicardial helical shortening discriminated three and four groups, respectively. Regression analyses suggest that more than 90% (r2 = 0.92) of variation in ejection fraction may be accounted for by variation in endocardial shortening, and that more than 75% (r2 = 0.77) of variation in observed endocardial shortening may be accounted for by variation in epicardial contraction. The study demonstrates that the helical fiber length concept may be useful for the noninvasive evaluation of left ventricular function in man.