Long-term survival after aortic valve replacement using Smeloff-Cutter prosthesis.

The long-term prognosis of 187 consecutive patients who received single aortic valve replacement using Smeloff-Cutter prosthesis was studied. Of the 163 patients who survived the operation, a long-term follow-up (up to eight years) was obtained in 153 patients (95%). A total of 34 patients (22%) died during the follow-up period. Including the hospital mortality, the actuarial survival rate of our patients with Smeloff-Cutter prosthesis was 0.69 after the fifth year and 0.611 after the eighth year of follow-up. This is similar to the actuarial survival rate of patients with Starr-Edwards prosthesis but it appears significantly better than the expected survival rate of symptomatic patients with aortic stenosis treated without surgery. Thus, this result supports the contention that aortic valve surgery in properly selected patients can prolong life expectancy in addition to relieving symptoms in patients with aortic valve disease. The majority of surviving patients reported to have improved (88%) since the operation and to be symptom free (82%).


De subitaneis mortibus. XV. Hereditary stenosis of the His bundle in Pug dogs.

Syncope and sudden death occurs in certain purebred Pug dogs which have been found to have intermittent sinus pauses and paroxysmal second degree heart block on electrocardiographic (ECG) study. We have established a colony of such dogs to study this problem and here report the results of histological examination of the cardiac conduction system in twenty-one of them. These include a dam which may be considered the proband, three of her offspring (two littermates) and three fetal pups in an unborn litter of one of these; three of the four adult dogs died suddenly and unexpectedly. Two groups of puppies descendants of these lines were also studied after they all died within three days of birth. The first group of puppies (8) did not have suitable ECG studies but the second group (6) did and showed ECG changes similar to those in the adult dogs. In all 21 dogs the sinus node was anatomically normal, but in every one there was significant stenosis of the midportion of the His bundle. There was no abnormality of the atrioventricular (A-V) node or of the bundle branches, and the cardiac valves and coronary arteries were normal. Two pups had ventricular septal defects and one of these had an atrial defect as well. All the dogs were of the normal fawn color, had a normal physical appearance and no visible evidence of associated extracardiac abnormalities. The adult dogs were able to hear normally but the puppies died too early to test their hearing. The paroxysmal heart block may in part be attributable to the abnormality in the His bundle, but other factors possibly leading to heart block and long sinus pauses are discussed. Stenosis of the midportion of the His bundle appears to be a heritable trait in these purebred Pug dogs.


The incidence and clinical implications of coronary artery spasm.

The total incidence of coronary artery spasm during coronary angiography has been reported to be between 0.26% and 0.93%. The rarity of this phenomenon has been invoked to minimize its clinical significance. Review of a one-year experience in our catheterization laboratory showed that coronary spasm occurred in eight of 274 coronary angiograms (2.93%). In three instances, spasm could not be ascribed to catheter tip irrigation, and was considered to be spontaneous. Since multiple factors during coronary arteriography might inhibit the occurrence of coronary spasm, it is believed that the incidence of spontaneous spasm may be higher than can be documented during angiography. Coronary spasm may have important clinical significance in various chest pain syndromes and greater methodical attention should be directed toward this phenomenon.


Electrophysiologic characteristics of Ebstein's anomaly of the tricuspid valve.

Electrophysiologic characteristics of five patients with Ebstein's anomaly of the tricuspid valve were defined with studies using luminal intracardiac electrode catheters. The diagnosis was made in each case from clinical data and confirmed at cardiac catheterization by the presence of an atrialized right ventricular chamber with atrial mechanical activity and ventricular electrical activity. In three cases intra-right atrial conduction was prolonged (P-A intervals of 50, 50, and 65 msec), a finding which reflected the presence of a characteristically large right atrium. The bundle of His electrogram was recorded in its usual anatomical location. Atrioventricular nodal conduction was prolonged in only one case. Intra-His delay was observed in two cases (bundle of His duration of 30 and 30 msec). Infranodal conduction was prolonged in four cases with H-V intervals of 60, 65, 65, and 80 msec. The anatomical abnormalities were least severe in the only patient with a normal H-V interval (50 msec). The prolonged H-V interval was thought to result from stretching of the conduction system over the atrialized right ventricle (ARV). The late depolarization during the splintered R' of the electrocardiogram found during intracardiac mapping of the ARV in three patients confirms the theory that the ARV produces the "second QRS" typically seen in this anomaly. The ARV was particularly irritable, and ventricular fibrillation was produced in two patients during catheter manipulation in this area. In one case the ARV had a shorter refractory period than the body of the right ventricle. Re-entrant supraventricular tachycardia was induced in the only patient with Wolff-Parkinson-White syndrome. In addition to the previously recognized electrophysiologic features reconfirmed here, patients with Ebstein's anomaly of the tricuspid valve usually have: normal position of the bundle of His, prolonged intra- right atrial conduction, prolonged infranodal conduction, and irritable ARV with delayed activation.


Left ventricular function in tricuspid atresia. Angiographic analysis in 28 patients.

Thirty-one left ventricular (LV) biplane angiograms were performed in 28 patients with tricuspid atresia. Measurements of left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume were obtained by the modified Simpson's rule and systolic ejection fraction (EF) calculated. Left ventricular volumes and ejection fractions were also obtained in 19 control patients with no significant heart disease. The patients with tricuspid atresia were classified according to the appearance of the pulmonary vascularity on initial radiologic examination: Group A, decreased pulmonary vascularity; Group B, increased pulmonary vascularity. In the 13 group A infants who were unoperated, LVEDV was increased and EF mildly diminished. In the group B patients LVEDV was increased and EF normal. In the 12 group A patients with surgical shunts LVEDV was elevated. The five group A patients with long-standing systemic artery to pulmonary artery anastomoses (greater than 10 years) showed the largest LVEDV and the poorest EF. The angiographic data indicate that patients with tricuspid atresia experience significant LV dysfunction as a consequence of longstanding LV volume overload. The early detection of LV dysfunction may be an indication for a right ventricular bypass procedure in these patients.


Demographic characteristics and trends in arteriosclerotic heart disease mortality: Sudden death and myocardial infarction.

The Baltimore Study of Sudden Death and Myocardial Infarction was a two-year project to investigate the epidemiological, clinical and pathological characteristics of sudden death and myocardial infarction in a defined population. The incidence of sudden death was much higher in men than women for both blacks and whites. Blacks and white women had a similar incidence of transmural myocardial infarction, but white men had a much higher incidence of transmural myocardial infarction than black men. White men who died suddenly had twice as many coronary thrombi at postmortem examination than black men and a greater extent of coronary artery stenosis than the other three race-sex groups. Black men had a higher prevalence of heart weights greater than 500 grams. Women who died suddenly were more often not married and smoked more cigarettes than neighborhood controls. Nine of 39 white women who died suddenly due to ASHD had a definite prior psychiatric history. The ASHD death rates have been declining in the 45 to 64 age groups, especially for white men. However, a comparison of the 1964 and 1970-72 sudden death studies in Baltimore reveals that the same percentage of ASHD deaths were sudden unwitnessed, occurred in a hospital or had a prior history of heart disease in both time periods.


The nervous system and cardiac arrhythmias.

The nervous system has marked influence on the electrophysiological state of the heart and in certain circumstances may lead to serious cardiac arrhythmias. Electrocardiographic waveform abnormalities that occur in association with central nervous system disease suggest disturbances of ventricular repolarization. Disorders of ventricular depolarization have been implicated in vulnerability to and occurrence of ventricular arrhythmias, including fibrillation. Experimental studies have demonstrated localized influences of cardiac sympathetic nerves and have provided suggestive evidence that regional cardiac disorders due to inappropriate sympathetic influence occur in disease. Clinical observations suggest that such autonomic abnormalities occur in a variety of conditions, including the idiopathic prolonged QT interval syndromes, acute myocardial infarction, and in association with central nervous system disease.


Electrophysiological mechanisms involved in ventricular fibrillation.

This report reviews the electrophysiological mechanisms involved in the initiation, maintenance, and termination of ventricular fibrillation. Ventricular fibrillation may be defined as chaotic, random, asynchronous electrical activity of the ventricles due to repetitive re-entrant excitation and/or rapid focal discharge. The capacity to fibrillate is inherent in ventricular muscle because the electrophysiological properties of the various segments of the ventricle are not uniform. Factors that enhance electrical asynchrony facilitate, while factors that decrease electrical asynchrony hinder, the development of fibrillation. Ventricular fibrillation may result following stimulation during the vulnerable period; under certain circumstances, rapid ventricular rates produced by ventricular or supraventricular arrhythmias may provoke ventricular fibrillation. Once fibrillation is initiated, a large mass, brief refractory period, and slow conduction velocity favor perpetuation. Reducing the excitable ventricular mass to a value less than the amount necessary to support spontaneous fibrillation causes fibrillation to terminate. Depolarization of every cell in both ventricles is not necessary to terminate ventricular fibrillation in the entire heart.


Validity of myocardial infarction models.

Because of the importance of acute myocardial infarction, much effort has been made to develop a representative animal model. Clinical characteristics that have been sought in the models include sudden death, early and late tachyarrhythmias, slow cardiac rhythms and bundle blocks, and variable influence of location of infarction. Each of these characteristics has been found under some conditions and in some models, but it has not been possible to imitate the entire range of the human disease in a simple model. Each model has significant drawbacks in terms of nonhuman cardiac response to stress or drugs, different coronary artery physiology, convenience of study, or cost. In particular, the use of isolated tissue confuses the influences of hypoxia and ischemia. The models have been of great value to investigation in myocardial infarction, but more focus on physiological and biochemical mechanisms may help to avoid the errors inherent in the use of models.


Predictors of sudden cardiac death.

A search was made for predictors of sudden cardiac death (SCD) among 197 men, age 40 to 79, who had multiphasic health checkups and experienced SCD 2 days to 5 1/2 years later (mean 18.1 months). Two age-sex-race-matched control groups, one matched and one unmatched for standard coronary risk factors, have been compared to the cases. In this ambulatory population, SCD occurred largely in persons with prior diagnosed heart disease. Standard coronary risk factors were confirmed as predictors of SCD. Predictors among other laboratory and quantitative tests include chylous serum, uric acid, hemoglobin, leukocyte count, pulse rate, diminished lung volumes, and hearing loss. Some of these had predictive value independent of standard risk factors. Pain tolerance was not related to SCD or to death in, versus out of hospital. Most of these predictors were not related to terminal symptom duration; this suggests a relationship more to the underlying atherosclerotic process than to the terminal fatal mechanism.


Sudden death in patients evaluated for ischemic heart disease.

Data from 981 patients evaluated for ischemic heart disease with coronary angiography were reviewed to identify variables predictive of sudden death and duration from onset of symptoms to death. During the period of follow-up, 113 patients died. Of these deaths, 99 were classified as cardiovascular. Forty percent occurred within 1 hour of onset of symptoms, 34% within 24 hours, and 25% in greater than 24 hours. Patients prone to sudden death were characterized as having severe multiple-vessel disease in combination with left ventricular dysfunction and disturbances in intraventricular conduction and rhythm. The best five-variable model to predict sudden death in these patients included the following variables: number of vessels greater than or equal to 70% obstructed (P less than .001); therapeutic requirement of inotropic (P less than .003) and diuretic (P less than .006) drugs; premature beats (P less than .006); and ventricular conduction defects (P less than .008). Additional variables were related significantly to the duration of the terminal episode. These data are preliminary, but indicate the possibility of identifying patients prone to sudden death.


Anatomical pathology of sudden unexpected cardiac death.

Approximately one-third of patients dying suddenly exhibit occlusive coronary artery thrombi, in contrast to the high frequency (90%) associated with transmural myocardial infarction. Such a discrepancy, along with other considerations, indicates that not all cases of sudden cardiac death are simply the result of myocardial ischemia or infarction in the traditional sense, and does, we believe, justify a rigorous search for alternative pathophysiological mechanisms. Some alternative mechanisms have been discussed, including disturbances in the cardiac conducting system, and the potentially very important role of platelet microembolism or microthrombosis in the genesis of focal ischemia and the lethal arrhythmias. Additionally, not all disturbances leading to the development of lethal arrhythmias may be reflected in light microscopic changes. There is a need for more sophisticated methodological approaches to the detection of early ischemia or other changes at a subcellular level. Although existing studies have provided a useful initial approach to an understanding of the pathology of sudden cardiac death, more questions remain unanswered than answered. In particular, no definitive comparison of deaths occurring in or out of hospital is currently possible, while much more information is necessary in relationship to the clinical status of patients dying suddenly. For example, one needs to know whether there are fundamental pathological differences in patients dying instantaneously relative to those surviving minutes or hours after the onset of terminal symptoms or signs; to what extent the pathologic findings are modified by therapy; whether there are any terminal symptoms specifically associated with particular pathological findings; what differences, if any, exist between patients with myocardial injury who die suddenly and those who do not; and how one can ensure a reasonable degree of comparability between different studies. Answers to these and many other questions will not, we believe, be forthcoming if we continue to be preoccupied with the epicardial arteries and light microscopy alone, but rather from well-conceived studies employing the collective resources of clinical cardiology, epidemiology, pathology, and experimental biology.


Sudden death due to coronary artery disease. A clinical, hemodynamic, and angiographic profile.

The authors followed 536 medically managed patients with angiographically documented coronary artery disease for up to 4 years, and examined antemortem clinical, anatomical, and hemodynamic characteristics of the 29 patients who died suddenly during the follow-up period. These patients are compared in terms of hemodynamic characteristics to those who survived and those who died non-suddenly of coronary heart disease. Of the 29 patients who died suddenly, more than 80% had evidence of moderate to severe impairment of myocardial function many months prior to death. Only a single patient had the combination of relatively mild coronary artery disease and normal ventricular function. This single patient would be the ultimate target of a program designed to prevent sudden death. However, it has been necessary to follow 536 patients with angiographically documented coronary artery disease in order to find this one potential benefactor of sudden death prophylaxis. This study demonstrates that there are patients with coronary artery disease who die suddenly, despite relatively mild disease; however, these patients appear to represent only a small proportion of all sudden deaths.


Emergency care.

Prehospital ventricular fibrillation can be treated successfully by rescue (paramedic) personnel. By retrospective history, one-half of prehospital sudden death victims experienced no prior warning and collapsed either instantaneously or within one minute of symptoms. The follow-up course was analyzed. Of 301 such subjects, 199 were defibrillated successfully, but only 101 survived long enough to be hospitalized, and only 42 were discharged alive. Predictors for successful outcome were initially rapid post-defibrillation heart rates and atrial fibrillation or sinus tachycardia rhythms. In the hospitalized group, 57% suffered repeat ventricular fibrillation and/or ventricular tachycardia usually during the first 24 hours. Among those discharged from the hospital, mean survival was 13 months with 28% dying suddenly regardless of presence of antiarrhythmic therapy. Intensive antiarrhythmic therapy and monitoring of this survivor population seems indicated.


Coronary revascularization in patients surviving unexpected ventricular fibrillation.

Coronary angiography and hemodynamic studies were performed in a group of 13 patients who had been successfully resuscitated from unexpected ventricular fibrillation, had had angina pectoris prior to the cardiac arrest, and who had not had an acute myocardial infarction in the periarrest period. Eleven of the 13 had one or more coronary artery lesions which were amenable to surgical intervention, and eight of the 11 accepted surgery. Left ventricular end-diastolic pressure was elevated in most patients, while cardiac index and ejection fraction were depressed. Bypassable lesions were found in the main left coronary artery in one patient, and the proximal left anterior descending artery in two. Both of these patients had disease elsewhere. The remaining five patients had diffuse three-vessel disease. The eight patients have survived for periods ranging from 8 to 32 months (average = 24 months). This contrasts to an overall 1-year mortality of approximately 30% in survivors of hospitalization after unexpected ventricular fibrillation.


Resuscitation from out-of-hospital ventricular fibrillation: 4 years follow-up.

In 51 months, 234 patients with out-of-hospital ventricular fibrillation (VF) were successfully resuscitated, hospitalized, and discharged home. Patients surviving an episode of primary ventricular fibrillation, that is, VF not associated with acute myocardial infarction, showed a 2-year mortality rate greater than three times that of survivors from VF associated with acute transmural infarction. Recurrent out-of-hospital VF was common, and a pattern of early recurrence was noted, with a median interval of 17 weeks in 34 documented cases. Ten patients were counted as long-term survivors from second episodes of out-of-hospital VF, one of whom survived a third episode. Coronary anatomy and ventricular function were studied in 29 survivors of primary VF. Of the 29 patients, 23 had coronary disease, considered "operable" in 17. Exercise testing and left ventricular function studies were normal or minimally abnormal in approximately half of these patients. There is an obvious need to develop effective measures to prevent primary VF, which commonly presents almost instantaneously, without prodromal symptoms.


Pharmacological modification of arrhythmias after experimentally induced acute myocardial infarction. Drugs acting on the nervous system.

The adrenergic neurohumors, when present locally in the myocardium in high concentrations, can produce a variety of cardiac arrhythmias which may develop into ventricular fibrillation (VF). Of particular importance are the arrhythmias observed immediately after experimentally induced acute myocardial infarction (AMI). Fatal VF, often seen to occur after acute coronary occlusion in the canine heart, may be related to the release of endogenous catecholamines, and a similar phenomenon might be responsible for sudden coronary death (SCD) in man. If adrenergic amines play a vital role in the development of arrhythmias and VF in response to acute myocardial ischemia, then it is conceivable that pharmacological means may be undertaken in an attempt to prevent the release of the adrenergic neurotransmitter or to prevent its arrhythmogenic actions by specific blockade of cardiac beta-adrenergic receptors. Drugs that have a central site of action and are capable of producing a decrease in sympathetic outflow might also play a valuable role in the prevention of arrhythmias and SCD. While the activity of the autonomic nervous system can modify the type and severity of arrhythmias resulting from AMI, existing pharmacological agents have little to offer in preventing the potential adverse effects of adrenergic stimulation without compromising the level of consciousness or cardiovascular function through the removal of adrenergic support to the heart. It would seem more beneficial to direct drug therapy at the electrophysiological defect in the myocardium in an effort to prevent arrhythmias and fatal VF. While currently available antiarrhythmic agents fail to achieve the desired effect, the recent evidence dealing with the quaternary ammonium derivatives of propranolol, lidocaine, and bretylium provides some hope for the future development of drugs with antiarrhythmic as well as antifibrillatory properties which may provide a therapeutic approach to the prevention of SCD.


Arteriosclerosis of coronary arteries in sudden, unexpected deaths.

The authors graphically studied the topographic pattern and severity of coronary arteriosclerosis in arteriosclerotic heart disease (ASHD) sudden deaths using an improved technique involving in toto removal and decalcification of the main coronary tree. The study involved 171 cases of ASHD sudden death and 154 deaths from other causes. White males were the most severely affected group. The majority of the ASHD deaths had three or four major coronary vessels showing greater than 75% luminal stenosis; single-artery disease was a rare occurence. The intra- and interarterial pattern of coronary stenosis was equally severe and diffuse, with the exception of the arteries to SA and AV nodes. No small intramyocardial blood vessel disease was evident. Severe chronic coronary stenosis was associated with a high incidence of old myocardial infarction. The anatomical and pathological pattern of coronary stenosis in ASHD deaths appears to have ominous therapeutic implications.


The pathogenesis of coronary plaques, thromboses, and hemorrhages: an evaluative review.

The initial appearance and continuous development of a coronary plaque depends on a combination of hemodynamic trauma, deposition of excess cholesterol, and accretion and incorporation of thrombogenic elements as well as fully formed mural thrombi. Plaques become life-threatening when rupture of their intimal surface due to internal necrosis and calcification leads to acute thrombosis and/or intramural hemorrhage. Although infarcts can and do occur in the absence of acute thrombi, the latter are caused not by the occurrence of infarcts, but almost always by plaque rupture. Following the occurrence of and survival from an acute occlusive coronary thrombosis, canalization of the thrombus frequently takes place, leading to the formation of a "luminal collateral vascularization." The vessels making up such complexes are prone in turn to hemorrhage and thrombosis.


Pathology of the myocardium and the conduction system in sudden coronary death.

This review summarizes previously unpublished and recently published autopsy findings of prehospital sudden coronary death (SCD) in four different counties (Olmsted, Minnesota; Albany, New York; Dade, Florida; and San Francisco Bay Area, California), totaling 868 patients. The prevalence of cardiomegaly and significant coronary atherosclerosis, and the relative infrequency of acute coronary thrombosis in prehospital SCD, well documented in the past, have been reaffirmed in current studies. Differences in the patient populations and laboratory techniques notwithstanding, these independent autopsy studies showed that 62% to 74% of cases of SCD had either acute or old myocardial infarction (MI); the incidence of acute MI ranged from 12% to 47%, and that of old MI from 22% to 53%. The prospective autopsy study of 120 Olmsted County SCD cases showed that among those with established acute MI, subendocardial lesions outnumbered transmural lesions by the ratio of 2:1, and the infarcts ranged in histological age from less than 24 hours to 4 weeks. Evidence of acute myocardial ischemia, as determined by the histological criteria of myofibrillar degeneration, sinuous fibers, and positive HBFP staining, was present in 52% to 81% of patients. Such high incidence of myocardial ischemia is compatible with the proposed mechanism of the terminal event in SCD, namely ventricular fibrillation or asystole, and underscores the importance of presymptomatic diagnosis of coronary heart disease. The lack of specific or acute anatomical lesions in the conduction system in SCD, however, does not preclude the possibility of bradyarrhythmias occurring shortly before death.


Pathology of atherosclerotic heart disease in sudden death. I. Organizing thrombosis and acute coronary vessel lesions.

The significance of organizing thrombosis was investigated in 121 cases of sudden death with atherosclerotic heart disease. Organizing thrombosis was observed in one-third of the cases, and sites at which it was present showed a higher prevalence of acute lesions -- thrombus, plaque rupture, and hemorrhage -- than sites at which it was not present. Acute and subacute coronary lesions were almost entirely restricted to vessels with 75% or greater obstruction. Evidence was presented suggesting that the organization of thrombosis in the coronary arteries was a more extended process than that observed in peripheral arteries.


Myocardial cell necrosis and sudden death in humans.

Using morphologic criteria to distinguish between myocardial infarction and lesions that selectively involve myocardial cells, the authors found evidence of ongoing selective myocardial necrosis in 88% of 50 individuals dying suddenly. Acute coronary thrombosis was rare. Since the morphological characteristics of the cell injury differ significantly from that seen in infarction and since the lesion may occur in individuals without significant epicardial coronary disease, factors other than permanent vascular obstruction are indicated as having a role in sudden cardiac death. Some other yet-unidentified process may alter susceptible myocardial cells.


Pathology of atherosclerotic heart disease in sudden death. II. The significance of myocardial infarction.

The role of myocardial infarction was investigated in 121 cases of sudden death with atherosclerotic heart disease. In addition to supporting other reports which have demonstrated the importance of chronic occlusion of the coronary vessels in relation to the high rate of infarctions found in such cases, the authors presented evidence which showed differences in occurrence in the sites of remote and recent infarctions, a lack of concordance between the sites of recent infarctions, and acute thrombosis in coronary vessels proximal to these lesions. No relationship between patient age or prior symptoms could be associated with the occurrence of infarction. Evidence was also presented which discounted the possible role of transmural infarction in the formation of acute thrombosis. These pathological observations support the concept that sudden cardiac deaths are results of functional instability of the myocardium produced by advanced coronary atherosclerosis.


Methodological considerations for the study of sudden cardiac death: An autopsy protocol.

An autopsy protocol, devised specifically for the pathologic study of sudden cardiac death, is presented. In addition to providing guidelines for the precise clinical documentation of the patients studied, it emphasizes a number of areas of potential importance needing further and detailed exploration, including the cardiac conducting system, and the intramyocardial microvascular circulatory bed. Some of the problems and procedural approaches recommended are briefly discussed.


Possible electrophysiological mechanisms for lethal arrhythmias accompanying myocardial ischemia and infarction.

Ventricular arrhythmias are probably the cause of sudden death due to myocardial ischemia or infarction. Such arrhythmias result from alterations in the transmembrane potentials of ventricular muscle and Purkinje fibers. Most of our knowledge concerning mechanisms for these arrhythmias has been derived from experimental studies on the canine heart. In this model, the early ventricular arrhythmias which occur within minutes after coronary artery occlusion probably have different electrophysiological mechanisms than the late arrhythmias which occur several or more hours after the onset of ischemia. The early arrhythmias probably result from reentry in ventricular muscle due to slow conduction in ischemic or infarcting muscle cells. The later arrhythmias most likely arise in subendocardial Purkinje fibers which develop spontaneous diastolic depolarization and abnormally prolonged action potential duration. It is important for future investigations to determine the relevance of electrophysiological studies on the canine heart to human ischemic and infarction arrhythmias.


Vitamin C metabolism and atopic allergy.

The procedure for carrying out the Leucocyte Ascorbic Acid Uptake Direct Antigen Challenge Test (LAADACT) is described. Leucocytes from normal individuals, when incubated in a buffered medium containing ascorbic acid, increase their ascorbic acid concentration by about 80%. When leucocytes from atopic individuals are incubated in a medium containing the antigen to which they are sensitive, as shown by positive skin tests, the leucocyte uptake of ascorbic acid is significantly reduced. Addition of antigen, to which atopic or normal individuals are not sensitive, to the incubation mixture does not reduce leucocyte ascorbic acid uptake. Measurement of ascorbic acid uptake into leucocytes is a relatively simple, routine, laboratory procedure. The LAADACT, therefore, provides a quick and accurate blood test for diagnosing sensitivity to specific antigens, and measuring relative antigenic sensitivities. The underlying mechanism of the LAADACT is discussed.


IgE, IgG and patient-self tests during slow hyposensitization to grass pollen.

Twenty-two patients with severe hay fever unrelieved by antihistamines in previous years were slowly hyposensitized with alum-precipitated pyridine grass pollen extracts. Their responses were objectively assessed as very good (55%), good (18%) or improved (23%). Two mechanisms were detected: (i) an increase in serum blocking activity in 59% and (ii) the prevention in 59% of the serum IgE elevation expected in the pollen season.


More sensitive automated detection of polyamines in physiological fluids and tissue extracts with omicron-phthalaldehyde.

Omicron-Phthalaldehyde reacts with primary amines to form an intensely blue-fluorescing product. Replacing ninhydrin with this compound in our automated high-pressure liquid-chromatographic technique for determination of polyamines, we achieved a 6- to 10-fold increase in sensitivity. Linearity and reproducibility are excellent, and the method is shown to be applicable to analysis of physiological fluids and of tissue extracts.


Evaluation of kinetic light scattering as an approach to the measurement of specific proteins with the centrifugal analyzer. I. Methodology.

A laser-modified centrifugal analyzer was used to develop kinetic light scattering methods for the measurement of human immunoglobulins IgG, IgA, and IgM. Comparison of equilibrium light scattering methods with kinetic procedures for IgG and IgA demonstrate equivalent precision and relative accuracy. However, quantitative results obtained by equilibrium and kinetics methods for IgM were found to differ significantly. Recovery studies performed with purified IgM have shown that both methods can yield quantitative results in the normal range. Our observations demonstrate that the technique offers a viable and in some respects a superior alternative to other methods currently used in the clinical laboratory.


Evaluation of kinetic light scattering as an approach to the measurement of specific proteins with the centrifugal analyzer. II. Theoretical considerations.

Development of centrifugal analyzers capable of making light-scattering measurements has prompted the investigation of the application of this type of instrumentation to the measurement of specific proteins. Investigation of antigen/antibody complex dimension and the kinetics of the IgG/anti-IgG reaction as followed by light scattering are examined in relation to improved analytical methodology. The effect of nonspecific protein on the reaction rate has been investigated for IgM, and data are presented that provide insight into the mechanism of the effect of periodic mixing.


Enzymatic immunoassay vs. gas/liquid chromatography for determination of phenobarbital and diphenylhydantoin in serum.

The antiepileptic drugs diphenylhydantoin and phenobarbital were measured in serum by a new commercially available enzyme immunoassay procedure ("EMIT," Syva Corp.). The procedure requires less than 5 min and no more than 50 mul of serum per determination. It is simple; only four steps (pipetting and diluting with an automatic pipettor-dilutor) are required before spectrophotometry. Twenty replicate analyses of a serum containing phenobarbital and diphenylhydantoin gave results with a CV of 6.8% and 9.1%, respectively. Results attained in a large series of patients were compared with results by a gas/liquid chromatographic procedure. For phenobarbital r = 0.97, and for diphenylhydantoin r = 0.98. No false negatives or false positives were encountered.


Scatchard plot and heterogeneity in binding affinity of labeled and unlabeled ligand.

In saturation analysis the Scatchard plot is a generally accepted method for calculation of the affinity constant, K, and the molar concentration, q, of the binder. However, in a system where the K's for the labeled and unlabeled ligand are unequal, a nonlinear plot can be obtained from which incorrect values for K and q may be calculated. This paper mathematically explains how the plot may deviate and under which conditions there will be a maximum in the curve. When the binding sites are homogeneous, the coordinates of this maximum can be used to calculate K and q. A general mathematical expression is derived on the basis of which a linear curve can be constructed for calculation of q and K, which is valid even when affinity for the labeled and unlabeled ligand is not identical.


Plasma theophylline concentrations measured by high-pressure liquid chromatography.

We present a specific, sensitive high-pressure liquid-chromatographic assay for theophylline in plasma. Only 0.5 ml of plasma is required for each determination, and the lower limit of detection by this method is 0.1 mg/liter. Other xanthines and their metabolites do not interfere. This method is suitable for use in studying the pharmacokinetics of this drug in infants and children, from whom only small volumes of blood are available.


Fluorometric determination of delta-aminolaevulinate dehydratase activity in human erythrocytes as an index to lead exposure.

We describe a fluorometric method for determining delta-aminolaevulinate dehydratase (EC 4.2.1.24) activity in human erythrocytes and compare it with the existing colorimetric method. Incubation conditions are identical. In the proposed method, the porphobilinogen formed during incubation is converted to a stable and highly fluorescent uroporphyrin by heating for 20 min at 93 degrees C in an acidic medium in the presence of air. The correlation between results by the two methods was good (r = 0.89). We found a good negative correlation between the activity of the enzyme and the concentration of circulating lead with both methods (r = -0.61 for present method and -0.59 for colorimetric method) for groups of persons subjected to various degrees of lead exposure. Our method is more sensitive and accurate, requires less sample, and the fluorescence is more stable than is the color in the colorimetric method.


Fluorometric assay of serum acid or alkaline phosphatase, either in solution or on a semisolid surface.

We describe enzymatic fluorometric methods for determining activities of serum alkaline phosphatase and of serum acid phosphatase in solution and on silicone rubber pads. 4-Methylumbelliferone phosphate is used as substrate, in either tris(hydroxymethyl)aminomethane or citrate buffer. In solution, the reaction is measured at 37 degrees C in a 3-ml Pyrex cuvette. Measurements on the pads are also made at 37 degrees C, after establishing a stable substrate film by lyophilizing all reagents on the surface of the pads. Only 20 to 30 mul of substrate solution, 50 mul of buffer solution, and 1 to 10 mul of blood are necessary, making a total volume of 51 to 60 mul for each assay. The rate of appearance of the fluorescent 4-methylumbelliferone liberated from 4-methylumbelliferone phosphate by the enzymatic action is measured and equated to enzyme activity. Calibration plots of the change in fluorescence per minute vs. enzyme activity for measurements in solution and on pads show a good proportionality in the range of 30.8 to 633 U/liter for alkaline phosphatase and in the range of 0.265 to 5.3 King-Armstrong units for acid phosphatase, indicating the usefulness of these methods in the clinical laboratory.


Screening for albuminuria: a case for estimation of albumin in urine.

The usefulness of bromcresol green for estimating albumin in urine was evaluated by comparison with the Laurell "rocket" technique. In contrast to the bromcresol green method applied for urinary albumin, rather doubtful results were obtained with conventional (Microzone) electrophoresis for albumin and with precipitation techniques for total protein estimation. Albumin estimation with bromcresol green is recommended as a more reliable substitute for total-protein estimations in urine. Limitations of bromcresol green are also pointed out.


Semi-solid surface fluorometric analysis of glucose.

We describe an enzymatic fluorometric method for determining glucose concentrations in blood samples by analysis on a semi-solid surface (silicone-rubber pads). The method is an adaptation of existing spectrophotometric procedures based on the sequential coupling reactions with glucose-6-phosphate dehydrogenase and NADP+. The rate of appearance of NADPH fluorescence at 460 nm (excitation wavelength, 340 nm) is monitored and related to the glucose concentration in plasma or serum. The calibration curve is linear to 2.50 g/liter. The chief advantages of this method over the spectrophotometric procedure are low cost and rapid response. The results obtained correlate well with those of the o-toluidine method (correlation coefficient, 0.986).


Negligible interference by spironolactone and prednisone in digoxin radioimmunoassay.

Spironolactone and prednisone reportedly cause measurable values for apparent digoxin, even when none is present. Effects of these medications were evaluated with 125I-labeled digoxin kits from five different manufacturers. Values obtained for apparent digoxin were either negligible or not sufficiently great to be clinically significant, regardless of kit methodology or manufacturer.


Screening for drug abuse: use of NaCl to increase drug recovery from papers coated with ion-exchange resin.

Use of papers loaded with ion-exchange resins to adsorb drugs from urine specimens resulted in large losses during the procedure. The first step, removal of drugs from urine specimens, was 25-85% efficient. The second step, elution of drugs from paper for further processing, was approximately 40-70% complete. The efficiency of the first step was decreased and the efficiency of the second step was increased by addition of NaCl, except in the case of barbiturates. Presence of salt during elution increased the yield of dihydromorphine by 20%, of methadone by 16%, of amphetamine by 34%, and of chlorpromazine by 40%, but did not enhance the yield of pentobarbital. Overall recovery rates were: 51% for the opiates, 57% for methadone, 72% for a phenothiazine tranquillizer, but only 35% for amphetamine and 15% for a barbiturate.


Direct radioimmunoassay for unconjugated estriol in pregnancy serum, with use of a radioiodinated derivative of estriol.

We describe a rapid and direct 125I-based radioimmunoassay for quantification of unconjugated (free) estriol in pregnancy serum. Estriol in serum is adsorbed onto a small column of Sephadex, thereby allowing its separation from proteins and interfering materials. A radioiodinated derivative of estriol (6-ketoestriol-6(o-carboxymethyl)oxime-[125I]tyrosine methyl ester) is added to the column, followed by a limiting amount of antiserum. After incubation, the antibody-bound hormone is separated by a buffer wash. The assay exhibits satisfactory recovery and parallelism, and the intra- and inter-assay coefficients of variation are less than 10%. The values obtained by using the assay correlate well (r = 0.97) with those from a comparison method in which solvent extraction and chromatographic purification are used.


Sodium iodoacetate as an antiglycolytic agent in blood samples.

We evaluated the effect of sodium iodoacetate on glycolysis in a series of randomly selected blood samples from patients. Glucose values for serum and for serum with added sodium fluoride (2.5 g/liter) or sodium iodoacetate (2 g and 0.5 g/liter) were compared at room temperature. Respective declines in glucose values averaged 170, 40, 30, and 30 mg/liter after 24 h. Iodoacetate-preserved (0.5 g/liter) samples showed no visible hemolysis. Results of determinations of urea with urease and of other tests on SMA 12/60 (Technicon) panels were unaffected.


An example of lyophilized protein-based materials not simulating patient sera.

Use of reconstituted lyophilized protein-based materials in the clinical laboratory is partly based on the assumption that these materials adequately simulate patients' sera. We examined several of these materials and found that certain ones do not have the same adsorbancies at 340 and 380 nm as do most sera. The implication of this is examined with respect to glucose determination by the hexokinase method on a dual-wave-length blank-subtraction instrument.


Automatic treatment of radioimmunoassay data: an experimental validation of the results.

A computational method for the automatic treatment of radioimmunoassay data has been developed and a computer program has been written in accordance. The main features of the approach used are the following: (a) a constant ratio between the bound fraction and its variance is assumed and estimated in each assay; (b) the points of the dose-response curve are fitted using the three-parameter function y' equals b1/(1 plus b2x(-b)3) where y' equals bound - nonspecific counts and x is the amount of hormone; the fitting is performed using the nonlinear, least-squares technique; (c) the values of the unknown samples are evaluated from the fitted standard curve; their confidence limits are computed taking into account both the variance of the bound replicates and the variance of the parameters of the dose-response curve. Experimental data that support the validity of the assumption on the variance of bound measurement and the suitability of the chosen function to fit the points of the standard curve are presented. A comparison between the confidence limits of the unknowns experimentally obtained and those computed by the program is reported and discussed.


An improved semi-automated method for the colorimetric determination of triglycerides in serum.

A semi-automated colorimetric determination for triglycerides in serum is described. The extraction is performed in sample cups and a part of the upper layer is sampled automatically. The use of modified reagents leads to greater stability and results in only one phase in the continuous flow system. The method is simple and inexpensive and therefore convenient for most laboratories with increasing requests for triglyceride determinations in serum. The method also shows good reproducibility and excellent correlation with the enzymatic method (Eggstein, M. and Kreuz, F.H. (1966) Klin. Wochenschr., 267-273).


Serum-selenium concentrations in patients with maple-syrup-urine disease and phenylketonuria under dieto-therapy.

Serum-selenium concentrations were measured in 2 dietetically treated patients with maple-syrup-urine disease, in 11 dietetically treated patients with phenylketonuria, in 37 healthy children of different ages and in 183 healthy adults. The estimations were performed by instrumental neutron activation analysis. The values of the dietetically treated patients were much lower than those of healthy children of the same age group. Within 8 to 12 weeks the serum-selenium concentrations decreased from normal values before therapy to very low values under dieto-therapy. During infancy the serum-selenium concentrations of healthy individuals show an increase to the adult range of values.


Determination of serum bile acids by glass capillary gas-liquid chromatography.

Bile acids were extracted from serum samples by chromatography on Amberlite XAD-2 and, after alkaline or enzymic hydrolysis, purified by chromatography on aluminium oxide. The quantitation was carried out by gas-liquid chromatography with an OV-101 glass capillary column using their methyl ester trimethylsilyl derivatives. The mean total amount of cholic, chenodeoxycholic and deoxycholic acids in a group of healthy fasting women was 2.14 mumol/l, in a group of fasting pregnant women at 8-12 weeks of gestation 1.13 mumol/l and at 38-41 weeks of gestation 2.10 mumol/l. In patients with cholestasis of pregnancy the total bile acid levels varied from 6 to 86 mumol/l.


Plasma pyridoxal phosphate levels and tryptophan metabolism in children with burns and scalds.

Depression of the pyridoxal phosphate concentration in the plasma was observed in eight children after burning or scalding. The concentrations remained low for several weeks with the usual dietary supplements but could be restored rapidly with large doses of pyridoxine; this does not seem to alter the excretion of xanthurenic acid but causes an increased loss of kynurenic acid and kynurenine.


Practical aspects on the determination of serum alkaline phosphatase isoenzymes using L-phenylalanine and urea.

Simple methods for estimation of the most frequently occurring alkaline phosphatase isoenzymes in serum are evaluated. Methods based on inhibition by L-phenylalanine or denaturation by heat or urea have been adopted for a reaction-rate instrument (LKB 8600) using conditions recommended by the Scandinavian Enzyme Committee, when applicable. The analytical results are directly evaluated for various groups of patients and also used in a mathematical "three-isoenzyme" model. These calculations did not improve the clinical value of the primarily obtained data. Thus, it was concluded that under certain precautions the results obtained in the presence of L-phenylalanine or urea should be used separately.


Lactate dehydrogenase (LDH)-IgG3 immunoglobulin complexes in human serum.

Sera of fifteen patients containing complexes of LDH and IgG were analysed. The LDH-IgG complexes of fourteen of these patients were investigated for their subclass specificity. They appeared to consist of LDH and IgG3, except for one of the patients. The serum of the latter patient also contained complexes of LDH and IgG1. In this serum both types of the immunoglobulin light chains were involved in the formation of the complexes, whereas in the serum of the patients with LDH-IgG3 complexes alone, they only contained one of the two immunoglobulin light chain types; it mainly concerned kappa type. The results of the present study were compared to those of a previous study on LDH-IgA complexes, in which the IgA fraction always contained light chains of kappa type. The mean LDH activity and the heat stability of the LDH activity in the sera with LDH-IgA complexes appeared to be higher than in the sera with LDH-IgG3 complexes. In contrast to complexes of LDH and IgA which occurred in all age groups LDH-IgG3 complexes were mainly found in elderly persons. Although auto-antibodies to different tissue antigens were present in the majority of the sera containing LDH IgG3 complexes, antibodies to LDH could not be demonstrated. A relationship between the presence of the complexes in the serum and a particular disease could not be established.


Applications of statistics in clinical chemistry. A critical evaluation of regression lines.

When two chemical determination methods are compared, a regression line is commonly used to elucidate constant and proportional errors. The classical procedure for the calculation of such a line is compared to the fairly unknown procedures described by Deming and by Bartlett. It is shown that the reliability of the classical procedure is restricted to only some cases. Deming's procedure is more generally applicable and also has the advantage, that estimates are obtained for the random errors in both chemical determination methods. Bartlett's procedure is not recommended.


The influence of drugs and disease activity on biochemical and haematological data in rheumatoid arthritis.

Biochemical and haematological data from 218 patients with rheumatoid arthritis were analysed and compared with data from a reference hospital population. The comparison demonstrated significant differences in several biochemical and haematological tests and that the patterns of change are different between males and females. The data were also analysed by conventional statistical methods and discriminant analysis using a computer to establish which tests were most influenced by the activity of the disease and drug therapy. The results obtained demonstrate marked difference between groups of patients with different disease activity or receiving different drugs. The discriminant analysis also identified those tests which differentiate these groups most effectively.


Presence of serum and tissue forms of N-acetyl-beta-glucosaminidase in urine from patients with renal disease.

1. The A, B, I1 and I2 forms of N-acetyl-beta-glucosaminidase present in urine, serum, kidney, liver and cerebral spinal fluid were separated on DEAE-cellulose and their presence confirmed by cellogel electrophoresis. The relative activities of each enzyme were determined by integrating the area under the elution peaks. 2. Serum A-form was eluted at a lower molarity of chloride than liver A-form and this was designated the As-form to distinguish it from the A-form of N-acetyl-beta-glucosaminidase found in liver and kidney. 3. The P-form of N-acetyl-beta-glucosaminidase present in the serum of a group of pregnant women was not detectable in urine samples from the same women. 4. Urinary NAG activities were found to be abnormally high in patients with impaired renal function. 5. The activity of both N-acetyl-beta-glucosaminidases A and B increased in pathological urines. The higher the total N-acetyl-beta-glucosaminidase activity excreted the higher the % of activity of the B-form present. 6. In a number of patients with haematuria an A-form similar to the serum As-form was present in the urine.


Biliary lipid composition in early childhood.

The biliary lipid composition was studied in 11 children without hepatic or gastrointestinal disease who ranged in age from 15 to 54 months. The molar percentages of cholesterol, bile acids and phospholipids in the biliary lipid mixture averaged 5.0 +/- 1.1; 80 +/- 6.1 and 15 +/- 6.2%, respectively. Cholic, chenodeoxycholic, deoxycholic and ursodeoxycholic acid comprised 48; 45; 4 and 3% of total bile acids, respectively. A comparison of the lipid composition with data reported in the literature for the adult reveals that the molar percentage of cholesterol is relatively low in early childhood. This could be one of the factors which is responsible for the low incidence of cholesterol gallstones in this age group.


Evaluation of quantitative methods for determination of protein in urine.

The automated immunoprecipitin reaction (A.I.P.) and the Laurell electroimmuno assay (rocket electrophoresis) are applied to unconcentrated overnight urines from patients hospitalised for various diseases, including both Albustix-positive and Albustix-negative samples. The results of both methods and the results of a quantitative determination of total protein are compared. The correlation coefficients between the two immunochemical methods are good, with a significance level of p less than 0.01 for all r-values. The correlation coefficient between the immunochemical methods and the quantitative determination of total protein is dependent on the amount of protein excreted in the urine. If urines should be examined for proteins we recommend a quantitative screening method or an immunochemical determination of albumin. For the latter we find that the A.I.P.-reaction is the method of choice, because it is fast, precise, sensitive, and specific.


Urinary excretion of indolyl-3-acryloylglycine in some skin affections.

1. Urinary excretion of indolyl-3-acryloylglycine (chromogen of the so-called Kimmig's light band) in 15 normal subjects was highly significantly increased in June-September ("summer") against the November-April ("winter") collection in the same subjects. Possible explanation of this phenomenon is discussed. 2. In the "winter" period, the mean of 23 patients with chronic polymorphous light eruption was significantly higher than the mean of the 29 controls. In the "summer" period, though an increaes of the average against "winter" was also noted, this difference against the control group (29) disappeared. 3. In 24 patients with skin tuberculosis the mean excretion in "winter" was significantly higher than in controls. This increase cannot be simply attributed to heliotherapy. 4. In "winter", there was no significant difference between the normal subjects and 12 patients with lupus erythematosus and 10 patients with porphyria cutanea tarda. In both these groups there was marked "summer" increase in excretion, though in the case of porphyria cutanea tarda, the "summer" mean was significantly lower than that of the controls. 5. All results were expressed on creatinine basis. In part of the subjects it was possible to calculate the excretion per unit time. Identical conclusions could be drawn.


[Determination of bismuth in blood urine and cerebrospinal fluid by flameless atomic absorption spectrophotometry (author's transl)].

A method for the determination of bismuth in blood, urine and cerebrospinal fluid is described. Using ammonium pyrrolidine dithiocarbamate as chelating agent, bismuth is extracted in hexane and determined by flameless atomic absorption spectrophotometry with a graphite furnace. A sample of 0.5 ml is sufficient for the determination of bismuth at concentrations ranging from a few mug/l to 2000 mug/l. In subjects not receiving bismuth, the concentration in blood is below 10 mug/l and in subjects intoxicated with bismuth prescribed for digestive diseases the concentration can reach 2000 mug/l and more.


Studies on the interaction of dopamine beta-hydroxylase from various sources with phytohaemagglutinins.

1. Bovine adrenal medulla dopamine beta-hydroxylase, a glycoprotein with terminal mannose residues in carbohydrate moiety, did not precipitate with any lectins tested except concanavalin A. After digestion with neuraminidase, the enzyme was shown to interact with ricin, and a good correlation was found between the amount of liberated sialic acids and the extent of agglutination. This finding show either that more than one type of carbohydrate unit occurs on the protein or that three are multibranched chains in the carbohydrate moiety. 2. Dopamine beta-hydroxylase from human serum, pheochromocytoma and normal adrenal were incubated with concanavalin A, ricin, wheat germ agglutinin and lectins from Dilochos biflorus and Robinia pseudoacacia. 83% of dopamine beta-hydroxylase from pheochromocytoma was precipitated by ricin, whereas the enzyme from human serum precipitated to a lesser extent (5-15%). Neuraminidase digestion of human serum dopamine beta-hydroxylase led to an increase of precipitation with ricin. The low extent of native human serum dopamine beta-hydroxylase precipitation with ricin can be explained by the attack of plasma membrane sialidases of liver cells, whereas the greater ricin precipitation of pheochromocytoma and normal adrenal dopamine beta-hydroxylases could be due to post-mortem effects. The clinical implications of possibility of difference concerning the carbohydrate moiety structures of pheochromocytoma and normal enzymes is discussed.


Sialic acid containing abnormal amylases in human sera.

The properties of abnormal amylases with unusually fast electrophortetic mobility from five patients were studied. These abnormal amulases showed markedly reduced electrophoretic migration to the cathodic side by digestion with neuraminidase. It was suggested that these five abnormal amylases contained sialic acid in their molecules, and the increased electrophorectic mobility resulted from sialic acid, which is not present in normal human amylases.


Immunological determination of muscle-type enolase in the serum as a diagnostic test for myocardial infarction.

An antiserum raised in the chicken against purified rat skeletal muscle enolase neutralized 86% of the enolase activity of human heart muscle and 8.7% +/- 4.8% (mean +/- S.D.) of the enolase activity in normal human serum. The fraction of enolase inhibited by the antiserum, designated as 'immunologically reacting muscle enolase', promptly rose after myocardial infarction in the serum of affected subjects, reaching peak values in excess of 40% in all but one of 23 subjects. Only one subject with ischaemic heart disease, but without infarction, and 2 with miscellaneous conditions, among 117 such patients tested, yielded comparable values. The test appears to be highly specific for myocardial infarction when muscle disease can be excluded and would not be difficult to introduce as a laboratory routine.


Comparison of an all-aqueous automated urine pregnancy oestrogen method with one using organic solvent extraction.

A comparative study between an all-aqueous automated urine pregnancy oestrogen method and a well established one requiring organic solvent extraction showed good agreement (r = 0.992). Advantages offered by the all-aqueous method include a faster rate of sample analysis and elimination of the difficulties of phase separation. The storage of urine for 5 days did not affect the oestrogen concentration measured by the all-aqueous method. Glucose, which reduced the apparent oestrogen concentration, was readily removed by treatment of the urine with borohydride, and treated urines showed good recoveries. The recovery of oestrogen was inadequate when glucose was removed from urine by incubation with yeast, possibly due to the formation of acetaldehyde.


An improved method for the determination of 5-phosphoribosyl 1-pyrophosphate.

A spectrophotometric method for the determination of 5-phosphoribosyl 1-pyrophosphate (PRPP) is presented which shows several advantages in comparison to the radiochemical techniques, such as a relatively simple, rapid and less expensive procedure. This technique has been used to evaluate PRPP content in erythrocytes, leukocytes and lymphocytes of normal subjects and individuals with partial hypoxanthine guanine phosphoribosyltransferase (EC 2.4.2.8) deficiency. The results obtained proved to be completely reliable in both groups of subjects examined, with values of PRPP similar to those observed by radiochemical techniques.


Permanent chemical phenylketonuria and a normal phenylalanine tolerance in two sisters with a normal mental development.

A positive ferric chloride reaction was found at routine examination of the urine of a 14 year old mentally normal girl, admitted for complaints of headache and other meningitis-like symptoms. It turned out that she excreted permanently increased amounts of phenylpyruvic, phenyllactic and o-hydroxyphenylacetic acids, but phenylacetic acid (free plus conjugated) was normal. Fasting serum phenylalanine was not increased nor was urinary phenylalanine. On loading with L-phenylalanine (100 mg/kg) a normal serum phenylalanine response followed, but urinary phenylpyruvic, phenyllactic and o-hydroxyphenylacetic acids increased further. Phenylacetic acid responded too, but remained in the normal range. In addition to the above-mentioned abnormalities the urine contained a still unidentified abnormal acid, which also increased after loading with phenylalanine. Her 12 year old healthy sister showed the same chemical abnormality. Two older brothers and the parents had normal excretions. The enzyme defect has not been identified. As a possibility the defective decarboxylation of phenylpyruvic acid is proposed.


False rise of starch-iodine determined amylase values caused by heparin treatment during haemodialysis.

A false rise in the levels of serum amylase as determined by a starch-iodine method was observed in patients undergoing haemodialysis and after treatment with heparin. In in vitro experiments, neither dialysis of serum nor addition of heparin produced a corresponding increase. The results showed that lipoproteins, altered by heparin-induced lipoprotein lipase, may have a considerable influence by interacting with starch and thereby partly preventing the formation of starch-iodine complexes. Amyloclastic methods that employ the starch-iodine reaction for determining amylase are therefore not to be used on patients treated with heparin.


The use of preparative continuous flow electrophoresis to study low molecular weight proteins in urine.

The authors propose a convenient method for the separation of low molecular weight proteins, present in tubular urines. In particular, the method is used for the purification of beta2 microglobulin, after one recycling, and also for the isolation of the various post-gamma globulins which can later be separated on DEAE Sephadex.


Dynamics of the rectum and anus.

The anorectum is a continuously active area with integration of smooth and striated muscle sphincters. Their responses to the entry of material from the colon into the rectum are usually at a subconscious level but voluntary control can be exerted. In the accommodation response the rectum adapts to the presence of faeces and the rise in rectal pressure caused by their entry into the rectum passes off in a few minutes. The sampling response consists of transient relaxation of the upper part of the internal anal sphincter which allows the rectal content to come in contact with the somatic sensory area in the anal canal to assess the nature of the content. Defaecation is the most complex response. Controlled defaecation occurs when a moderate stimulus from the full rectum reaches consciousness by release of cortical inhibition. When the rectal stimulus is greater and combined with stimulation of the anal canal urgent defaecation takes place.


Treatment of rectal prolapse.

There are two schools of thought concerning the aetiology of rectal prolapse. On the one hand it was conceived to be a sliding hernia through a defect in the pelvic fascia, while on the other hand radiological studies have demonstrated prolapse to be represented by an intussusception of the rectum. Various operative procedures have been proposed for the treatment of rectal prolapse based on the belief in one or the other of these concepts. The anatomic defects which have been described with prolapse include a defect in the pelvic floor with diastasis of the levatores ani, loss of the normal horizontal position of the rectum, an abnormally deep cul-de-sac of Douglas, a redundant rectosigmoid, and a patulous anal sphincter. The popularly used procedure in Great Britain is that in which a sheet of Ivalon sponge is sutured to the sacrum and wrapped around the rectum thus anchoring it in place. Various authors have reported good results using this technique. The mortality and morbidity rate appear to be acceptable. In the U.S.A. a popular procedure is the Ripstein technique where a sheet of Teflon is wrapped around the rectum anteriorly anchoring the rectum to the sacrum. This technique also has its proponents who rport satisfactory results. Abdominal proctopexy and sigmoid resection, although not in common general use, has been found to be effective with an acceptable morbidity and mortality rate. These three procedures have some drawbacks but the one problem common to all the repairs so far developed for prolapse is their inability to guarantee to restore continence. Probably half the patients operated upon continue to be incontinent. Faradic stimulation of the sphincter has not proved to be as helpful as initially hoped.


The solitary ulcer syndrome of the rectum.

The solitary ulcer syndrome of the rectum is not rare but often remains unrecognised. A greater awareness of the condition will lead to more frequent diagnosis. The aetiology remains unproven but the evidence would suggest that a combination of prolapse, trauma and ischaemia, caused by excessive straining at stool may be important factors. The reasons for straining at stool are also obscure but in some cases a failure in the normal behaviour of the puborectalis may be involved. The history and clinical features of the condition are described, and the pathogenesis discussed.


Malignant tumours of the rectum. Part I: radiotherapy.

We have confined our discussion to two modalities of treatment by means of x-ray therapy which are now being used in order to improve not only the survival rate but the quality of survival in carcinoma of the rectum. Endocavity irradiation should be established as a recognised method of therapy for selected patients with carcinoma of the rectum and it should be universally available. A number of trials are now in progress which we believe will definitely demonstrate preoperative radiation therapy as an established treatment for cancer of the rectum. It is our belief that preoperative external irradiation by means of supervoltage therapy will contribute considerably to improvement in the five-year survival figures. It may be postulated that in view of the fact that external radiation reduces the number of lymph nodes found at surgery it seems reasonable to offer patients receiving endocavity irradiation a simultaneous course of external irradiation. This may further increase the survival rate for patients with localized tumours.


Conservative management of haemorrhoids. Part I: injection, freezing and ligation.

Of 111 consecutive patients treated by partial internal sphincterotomy for a haemorrhoidal disease in the course of a prospective study, 101 could be re-examined between 24 and 36 months after operation. There were no major complications but 11 patients had some significant complaints at some time after operation. There were six recurrences, five of which could be attributed to inadequate sphincterotomy. One patient had an excessive sphincterotomy which led to difficulties with continence of fluid stools. One patient developed a peri-anal abscess two years after partial sphincterotomy and four patients with marked soiling will require surgical correction of the posterior gutter. The gutter is due to secondary epithelialisation after open sphincterotomy in the posterior midline. The recommended technique entails the division of the internal sphincter up to a few millimeters above the dentate line and reconstruction of the anal mucosa with a continuous absorbable suture. 'Landscaping' by partial resections of the prolapsed haemorrhoids is recommended to avoid sclerotic tags. Submucosal sphincterotomy should be considered by the very experienced only and then provided that the anal mucosa shows little scarring.


Fissure-in-ano and anal stenosis. Part I: conservative management.

Acute superficial fissure-in-ano responds readily to conservative non-surgical treatment. For chronic deep fissures we recommend manual anal dilatation and the post-dilatation regimen but recognise that equally good results follow the simple procedure of subcutaneous lateral internal sphincterotomy. The recurrence rate following these minor procedures is less than 10 per cent and the incidence of poor flatus control and mucus leakage is even lower. It is never necessary to excise fissures nor sentinel piles although it may be desirable to excise large redundant skin tags to facilitate anal hygiene. Painless or atypically sited fissures should suggest the diagnosis of Crohn's disease. Treatment is rarely required for fissure-in-ano in this condition, although severe anal stenosis may need extremely gentle anal dilatation. Postoperative anal stenosis can also be managed successfully by manual dilatation under anaesthesia with a prolonged regimen of self dilatation until healing is complete. Radical or complicated plastic operations are rarely indicated for any patient with fissure-in-ano or stenosis and are strongly contraindicated in Crohn's disease.


A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities.

Data from a chromosome examination of 14,069 consecutive newborn infants is presented. Successful karyotypes were obtained on 13,939 babies using short-term blood cultures and conventional staining methods. Of those, 13,645 babies had normal chromosomes; 64 (0.46%) had a major chromosome abnormality; and 230 (1.65%) had a marker chromosome; giving a total of 294 (2.11%) babies with a major chromosome abnormality or distinctive marker chromosomes. Six male babies with sex chromosome abnormalities had a 47,XXY and four a 47,XYY karyotype, and three were mixoploids. Five female babies had a 47,XXX karytotype and two were mixoploids. There were three babies with ambiguous external genitalia, all with normal karyotypes. Fourteen babies had 21-trisomy; there were three 18-trisomics and one 13-trisomic. The mother of one 18-trisomy baby had a balanced (18;21) translocation. Twenty-four infants had a balanced chromosome rearrangement. Eleven of these were reciprocal and thirteen were Robertsonian translocations. One baby had an unbalanced derivative chromosome resulting from an 18;11 insertion. Two infants with additional unidentified fragments were detected. Two hundred and thirty babies (1:60) carying distinctive chromosome variants were detected. The commonest variant was the Yq+ among males (0.89%). Other common variants involved the short arms of the D and G groups (0.32% and 0.57%, respectively) 16q+ (0.09%), and 1q+ (0.04%). The results of the present study when combined with five other comparable studies, thus comprising a total of 46,150 newborn infants, indicates that the frequency of major chromosome abnormalities is between 1:150 and 1:200 live-born babies. This represents a small proportion of all conceptuses with chromosome abnormalities, which has been estimated as being approximately 1:20. It is thus clear that chromosome abnormalities form a major part of the genetic load carried by the human population. The development of chromosome banding techniques already has increased, and with further increase, the complexities of human cytogenetics and may reveal many additional rearrangements undetectable by conventional methods.


Prenatal diagnosis and family studies in a case of propionicacidaemia.

In a family with a history of two neonatal deaths, propionicacidaemia was diagnosed retrospectively from stored plasma as the cause of the second death during the mother's next pregnancy. Amniocentesis was performed and a culture of amniotic cells was assayed for propionyl CoA carboxylase activity. The absence of any detectable propionyl CoA carboxylase activity allowed the prenatal diagnosis of propionicacidaemia to be made. Treatment with biotin and a modified aminoacid diet was started in the immediate postnatal period. Investigation of propionyl CoA carboxylase in leucocytes from the parents, siblings and other relations of the patient failed to demonstrate intermediate enzyme activities in even the parents, who were presumably heterozygotes for this condition.


Syndrome of epiphyseal dysplasia, short stature, microcephaly and nystagmus.

This report describes two brothers with short stature, congenital nystagmus and microcephaly. The radiographic findings disclosed small, irregularly shaped epiphyses, square iliac bones and flattened acetabulae. The humeri and femora were short. The parents were normal. The syndrome is possibly X-linked, or autosomal recessive in origin.


Retinoblastoma-a clinical survey and its genetic implications.

A clinical, pathological and genetic study was made of 50 patients with retinoblastoma in the Newcastle Hospital region over the period 1931-1970 inclusive. Twenty-seven patients were affected in one eye only; 23 had bilateral tumours. The incidence of the tumour was approximately 1:16,000 live births. Bilateral cases tended to present at a younger age, and were more likely to be familial. In bilateral cases the tumour in the second eye was often detected at an early stage by ophthalmoscopy. In a quarter of the cases there was a considerable interval (up to 10 years) before the second eye was found to be affected. A surprisingly large proportion of eyes with clinically advanced tumour proved to have the tumour histologically confined to the retina. This disparity between clinical and pathological severity emphasises the jusifiability of conservative treatment in the first instance in many cases. Twelve of the 50 patients developed a new tumour, local spread, or reactivation of a treated tumour, over a period ranging from 2 months to 10 years after primary treatment. This finding emphasizes the importance of frequent follow-up of all cases. Follow-up should include the patient's siblings and offspring, even in apparently "sporadic" cases. The of liability to develop retinoblastoma is suggested.


Length of Y chromosome and activity in boys.

In a cytogenetic-psychological study of 47 school boys in special classes and 48 controls in normal classes in a Danish city no significant difference was found between the mean Y length. There were, however, four boys with enlarged Y among the 47 in special classes, compared with one of the 48 in the normal classes. We found a significant correlation between length of Y and level of activity with increase of level of activity correlated with increase of length of Y when both groups were taken together (P is less than 0.005). The mean activity score was 6.5 for the boys with Y/F is less than or equal to 0.83, compared with 8.1 for those with Y/F greater than or equal to 0.95 (P is less than 0.005). If the milieu is restrictive with poor understanding and support for the needs of a boy, a comparatively large Y with associated high level of activity might intensify the problems of such a boy. If the milieu is positive, understanding, permissive and with possibilities of channeling activity, the large Y associated with a high level of activity might be a positive factor in personality and social adjustment. The present study shows certain tendencies confirming this.


The inhibition of complement-dependent lymphocyte rosette formation by the sera of children with steroid-sensitive hephrotic syndrome and other renal diseases.

Sera from patients with steroid-sensitive nephrotic syndrome (SSNS) in relapse, Henoch-Schonlein purpura with nephritis (HSP) and acute post-strptococcal glomerulonephritis inhibited EAC rosette formation by normal human lymphocytes; a similar effect was seen in some patients with focal glomerulosclerosis, but not in patients with congenital neophrotic syndrome. There was significantly less inhibition by sera of SSNS and HSP patients in remission. There were fewer EAC rosette-forming cells (EAC-RFC) in the blood of three patients with SSNS in relapse, suggesting that such blockade occurred in vivo. These findings, interpreted as evidence of circulating activated C3 in the sera, provide further indirect evidence of the immunopathogenesis of these diseases. Sera of healthy adults inhibited EAC rosette formation to a small extent which correclated inversely with the numbers of EAC-RFC in their blood. The EAC rosette inhibition test may be sensitive enough to detect normal variations of complement activation in healthy individuals.


Complement-dependent and cell-dependent antiplatelet humoral antibody in sera from multi-transfused patients.

Sera from eight multi-transfused patients, who were resistant to platelet trans-fusions from allogeneic donors, were tested for antiplatelet humoral antibody. Complement-dependent cytotoxic humoral antibody against platelets was found in sera from six of eight patients. Cell-dependent cytotoxic humoral antibody against platelets was found in sera from four of seven of these patients. Sera from two patients had cell-dependent antiplatelet activity but no detectable complement-dependent antiplatelet activity. Results of this study argue that both complement-dependent and cell-dependent humoral immunity may be important pathways for in vivo resistance to platelets.


Differences between IgA and IgE as secretory proteins.

IgA is the prototype of a secretory immunoglobulin and usually is present in external fluids in proportions greater than in serum. Previous studies have suggested that IgE also is a secretory immunoglobulin. We measured IgE, IgA and albumin levels in nasal washings (NW), parotid fluids (PF) and serum in seventeen individuals. In secretions, all of these proteins were measured by radioimmunoassay (RIA). In serum, IgE was measured by RIA, IgA by a turbidimetric method, and albumin by radial immunodiffusion. IgA was detected in NW and PF in all individuals and IgA/total protein ratios in both of these secretions exceeded the corresponding ratios in serum (P less than 0-01). In contrast, IgE was detected only in NW from atopic subjects and IgE/total protein ratios were less than those in serum (P less than 0-02). IgE was not detected in the PF in any of the seventeen subjects. When the proportion (protein/total protein) of IgA, IgE, or albumin in NW was expressed as a percentage of the proportion in serum, IgA and IgE were increased when compared to albumin (P less than 0-01 and P less than 0-03, respectively). These results support the view that IgE is a secretory immunoglobulin in that it is present in NW in proportions greater than expected if it diffused from serum. However, IgE differs from secretory IgA in that ratios of IgE to total protein are greater in serum than in NW. This difference is discussed in terms of local production of IgE and passive diffusion into serum and nasal secretions. Finally, the observation that IgE is present in one external secretion while absent from another indicates that external secretions may be subdivided into two classes on the basis of their content of IgE.


The hydroxyproline content of plasma of patients with impaired renal function.

The plasma concentration of hydroxyproline fractions were determined in 52 patients with diminished renal function. High levels were found in each case and a correlation was found between the serum creatinine concentration and the plasma concentrations of peptide-bound hydroxyproline. Bone biopsies was taken from 16 patients from renal insufficiency and the results of morphometric studies of the biopsies were correlated with the blood determinations. Free hydroxyproline levels correlated significantly both with bone formation and with bone resorption. However peptide-bound and protein-bound hydroxyproline levels did not correlate with bone histology. Hence the plasma concentration of free hydroxyproline in patients with renal insufficiency can be used as an index of bone collagen turn-over.


Stauffer's syndrome--diagnostic help in hypernephroma.

Dysfunctions of the liver known as Stauffer's syndrome have been observed in various cases of renal cell carcinoma. In a case history of renal cell carcinoma the most common clinical symptoms and laboratory findings of early presentation are displayed. During the first clinical investigations the evidence of typical laboratory values indicating unusual hepatic dysfunction, did not lead to the true diagnosis until symptoms became clearer two year later. Intensified renal diagnosis are asked for in any case of unexplained abnormalities of liver function in order to exclude a renal cell carcinoma or to force its early diagnosis.


Testosterone therapy in hemodialysis patients.

30 patients undergoing regular, three times weekly hemodialysis were treated with large doses of intramuscular testosterone with evaluation of hematopoiesis before and after treatment. A control group of 30 patients not using the drug was evaluated in similar fashion. The presence or absence of native kidneys was the most important factor determining hematocrit level and transfusion requirements in these patients, whether treated with testosterone or not. The mean hematocrit was lower and the transfusion requirements were higher in bilaterally nephrectomized patients. A significant increase in hematocrit occurred in testosterone treated nephric patients, but untreated nephric patients also had a significant rise. Important adverse side effects occurred with testosterone. Anephric patients did not increase hematocrit levels with or without testosterone.


Surgical treatment of extracranial carotid occlusive disease.

This report has reviewed the preoperative evaluation, operative technique, postoperative care, results, and representative pathological findings in 225 carotid endarterectomies. Surgery is generally indicated in patients with: 1. TIA's, and carotid stenosis (lumen diameter less than 2 mm.) or an ulcerated plaque. 2. A stable, mild to moderate neurological deficit with or without TIA's, and carotid stenosis (lumen diameter less than 2 mm.) or an ulcerated plaque. 3. An acute progressive or fluctuating neurological deficit, and carotid stenosis (lumen diameter less than 2 mm.) or carotid occlusion. Surgery should be considered in some patients with: 1. TIA's, and ipsilateral carotid occlusion. 2. An acute partial persistent neurological deficit, and carotid stenosis (lumen diameter less than 2 mm.) or occlusion. 3. No symptoms, and carotid stenosis (lumen diameter less than 2 mm.). Surgery is generally not indicated in patients with an acute severe persistent neurological deficit, and carotid stenosis or occlusion.


Clinical evaluation of the unconscious patient.

A systematic approach in the differential diagnosis of the comatose patient, based on the pathophysiological classification of the various disorders causing coma and the clinical neurological examination, is outlined. This approach appears useful in that in most instances a clinical diagnosis suggesting the pathophysiological abnormality producing coma can be made. Appropriate laboratory tests can then be selected to establish a definitive etiological diagnosis. Such a systematic approach to the evaluation of the comatose patient hastens definitive therapy in a disorder where time in which to institute therapy is often short.


Hereditary hemorrhagic telangiectasia. A case report with known cerebral involvement and cardiac catheterization data.

Numerous bleeding episodes, neurological signs and symptoms, and pulmonary arteriovenous malformations are well documented in reports of families with hereditary hemorrhagic telangiectasia. It is always assumed that these are due to the arteriovenous malformations. We are here reporting a case with positive cerebral angiographic findings of large arteriovenous communications, as well as catheterization data revealing pulmonary abnormalities secondary to the cerebral arteriovenous fistula, but no abnormalities within the pulmonary vasculature itself.


The assessment of maternal nutrition.

The assessment of maternal nutrition is a very important task that should become a more integral part of clinical obstetrical care. It is not simple but neither is it overly complex for the practical office or clinic setting or personnel. This is especially critical for the groups at nutritional risk. Normal pregnancy physiology complicates the interpretation of traditional physical and laboratory techniques and, therefore, must be thoroughly understood. The dietician and/or nutritionist should be involved where available. The physician and nursing component of maternity care must, however, be increasingly aware  of and involved with assessment techniques if maternity patients are to achieve adequate nutrition in practical clinical terms.


Hydration of the low birth-weight infant.

Factors relating to water balance in the perinatal and neonatal periods are reviewed. The major areas considered are changes in body water compartments, insensible water loss, and renal function. A most striking feature in all these areas is the wide variation in 'normal' values, both within the same infant with advancing postnatal age and also between infants of the same postnatal age but of different gestational ages. A second feature is the fluctuation caused by changes in environmental conditions, e.g., temperature, humidity, type of warming device, use of phototherapy. Much of the literature on water balance relates to term infants and experimental animals; only for insensible water loss are there studies on infants as small as less than 1000 gm. Because of the developmental changes occurring in these infants, many areas require further study. The last 5 to 10 years have seen marked changes in our approach to the hydration and nutrition of the low birth-weight infant. Despite much experience with new routes and types of fluids and formulas, no method has been shown to be ideal for all situations. In replacing the neonate's ongoing water losses, the clinician strives to maintain normal volume and tonicity of the body fluids, and to prevent clinical and biochemical signs of dehydration or over-hydration. In planning therapy, the clinician is presented with a wide range of possible water requirements, and with a choice of route and type of fluid administration. Each low birth-weight infant must be viewed individually, and once fluid requirements have been estimated, frequent assessment of hydration status is necessary, with appropriately frequent readjustment of the rate of fluid administration.


Commentary: Patient package inserts. I. Nature, notions, and needs.

A total of 137 completed questionnaires were obtained from several population samples in an attempt to assess drug knowledge, information sources, and views on drug information with particular attention to the possible role of a patient-oriented package insert. The results indicated that the study population was variably informed and could make fairly accurate assessments by this knowledge. Responders placed great importance on the doctor and pharmacist as preferred and actual drug information sources. The mass media were accorded little prominence. Great emphasis was placed on the adequate provision of information, and this appears to be a crucial function in an adequate doctor-patient relationship. The results appear to indicate a favorable climate for establishing a patient-oriented package insert that should have summarized as well as detailed information to complement the doctor and pharmacist as primary information sources.


Spuriously low plasma propranolol concentrations resulting from blood collection methods.

Spuriously low values of plasma propranolol concentrations resulted when one commercial brand of collection tube was used. The mechanism of this effect was established and was due to the presence of the stopper containing substances that reduced plasma propranolol binding and resulted in a redistribution of the drug in whole blood so that more was present in the cells and less in the plasma. A similar phenomenon was noted some years ago when a needle for intravenous infusion was used as an indwelling cannula. Th mechanism in this case could not be established as in the interim the phenomenon was no longer detectable. Although it was established that these findings do not apply to all drugs, the data suggest that collection methods should be routinely checked at intervals unless separate venipuncture and all glass collection tubes are used.


Tricyclic antidepressant overdose: clinical presentation and plasma levels.

Fifteen patients were studied at 8- to 12-hr intervals during the first 24 hr after overdosing with tricyclic antidepressants, and subsequently followed daily for up to 144 hr. The severity of the overdose was determined by measuring the plasma tricyclic antidepressant level using gas chromatography-mass fragmentography. No correlation was found between total, tertiary, or desmethyl tricyclic antidepressant plasma levels and maximum heart rate, lowest blood pressure, degree of unconsciousness, or EKG changes involving the P-R interval or ST-T wave changes. There was a weak correlation between drug plasma level and maximum pupil size (r = 0.46; p less than 0.05) and a strong correlation between the duration of the QRS complex and tricyclic antidepressant plasma levels (r = 0.75; p less than 0.01). All patients with a total tricyclic antidepressant plasma level greater than or equal to 1,000 ng/ml had a QRS interval greater than or equal to 100 msec. As the total plasma tricyclic level fell, the duration of the QRS interval returned to normal. Thus, the duration of the QRS complex on the electrocardiogram appears to be the most reliable clinical sign for evaluating the seriousness of tricyclic antidepressant overdosage.


Propranolol in hypertensive dialysis patients: efficacy and compliance.

The effect of propranolol therapy on plasma renin activity and blood pressure control was evaluated in 35 uremic patients receiving intermittent center-based outpatient hemodialysis. Patients were determined to be either compliant or noncompliant with therapy based on the steady-state predialysis plasma propranolol concentration.  Noncompliance occurred with remarkable frequency and was associated with persistent hyperreninemia and poorly controlled hypertension. Blood pressure control was significantly better in compliant patients, in whom plasma renin activity was generally, but not universally, suppressed. Propranolol can be effectively used in the management of hypertensive dialysis patients, but steady-state plasma propranolol levels should be measured to assess compliance in patients apparently refractory to treatment.


Absolute bioavailability in man of N-acetylprocainamide determined by a novel stable isotope method.

Absorption of a single oral dose of N-acetylprocainamide (NAPA) was studied in 3 normal subjects. Approximately 85% of the oral dose was absorbed and peak plasma NAPA concentrations were reached in 45 to 90 min. In 2 subjects, NAPA was absorbed at a fast initial rate, then more slowly, prolonging the apparent elimination phase half-life. Absolute bioavailability was determined by a new stable isotope method that entailed intravenous injection of NAPA 13C at the same time that an unlabeled NAPA capsule was given orally. Plasma levels and urine excretion of both compounds were determined by mass fragmentography. Bioavailability was assessed by deconvoluting the plasma level vs time curves resulting from intravenous and oral drug administration, and also by comparing the relative percentage of NAPA and NAPA-13C excreted unchanged in the 24 hr after simultaneous administration.


Electrophysiologic properties of perhexiline.

Perhexiline maleate (Pexid), a promising clinical antiarrhythmic and antianginal drug, was evaluated for its electrophysiologic effects on the entire conduction system of the intact canine heart throughout a wide range of therapeutic and potentially toxic doses. Intracardiac conduction times were measured by bipolar intramyocardial and transvenous endocardial electrodes before and following the intravenous administration of each dose of perhexiline maleate, 3 mg/kg every 30 min for a total of 4 doses in 7 open-chest anesthetized dogs. Eight animals served as controls in which similar operative technique and electrophysiologic variables were recorded after infusion of the maleate diluent. In addition, the effects of perhexiline on atrial and ventricular thresholds to electrical stimulation were recorded, as well as the QRS and QT intervals, sinus rate, and rhythm disorders. It was observed that perhexiline did not significantly (p greater than .05) alter sinus rate, QT interval, QRS duration, PR interval, intra-atrial conduction time, atrioventricular nodal conduction time, and His-Purkinje conduction velocity. The drug did not affect the cardiac threshold to electrical stimulation of less than 0.1 ma. No ectopic atrial or ventricular activity emerged during the accumulated influence of the agent. From this study, it is concluded that perhexiline does not exert deleterious actions on the conduction system of the intact canine heart. In view of the negligible toxic effects and its efficacy in treating ventricular tachyarrhythmias in patients, the drug deserves further clinical evaluation.


Measuring agency investment in community mental health.

This paper reports a study of the extent to which essential elements of community mental health are part of mental health agencies' practices. A sample of 263 social workers reported on the nature of programming and services of 19 mental health facilities ranging from city and state community mental health centers to inpatient psychiatric hospitals. All agencies were found to be engaged primarily in diagnosis and treatment, and such community mental health components as primary prevention, coordination, continuity of care, and use of community boards were virtually nonexistent. Possible explanations and implications of these findings are discussed.


Community mental health boards: a comparison of their development, functions, and powers by board members and mental health center staff.

Orientations toward citizens' board functioning in a community mental health setting were studied in an urban setting involving 18 community-based mental health centers. Four groups were interviewed: citizen board members, board chairpersons, center staff, and center directors. Groups generally agreed that the primary function of a board is to make certain that community needs are met. Board members and professionals differed in perceptions of reasons for joining boards and, more important, the degree of involvement board members should have. Board members saw their role as advisory, staff favored codecision or advisory, directors favored codecision, and charipersons wanted a stronger board role.


Power: the appropriate target of community research.

The underlying power structure of communities and of the nation as a whole deeply affect the well-being of our clients and the continuity of our programs. Systematic inquiry into this area, however, has been minimal and the black-box nature of power has contributed to the alienation of those affected by it. There are, however, good sources for finding the data. Their use revealed, in one community, an interlocking power elite of about 8 to 10 persons. The type of inquiry can be conducted at many levels. It holds the promise of making visible for our clients and ourselves the sociopolitical context in which community mental health exists.


Using rumors for therapeutic purposes.

Mental health workers and programs in small towns become the subject of rumors. A method is suggested for the investigation of such rumors and their use for therapeutic purposes. Three rumor case histories are presented to illustrate these ideas. The function of rumors in a small town is discussed.


Models of mental illness and duration of hospitalization.

Three approaches to the study of mental illness are examined: the medical, the behavioral, and the societal reaction models. Operational measures of each model are presented and used to determine the relationship between the measures and duration of institutionalization and the relative importance of the three models in predicting duration of institutionalization. Data were obtained on 36 admissions at two state hospitals, and from interviews with 142 of the patients' relatives, friends, and co-workers. The measures of the societal reaction model and behavioral model were found to be related to duration of hospitalization, with the societal reaction model being the most predictive.