Analysis of regional ischemic left ventricular dysfunction by quantitative cineangiography.

The ability of left ventricular angiography to detect regional ischemic dysfunction was assessed in 10 closed-chest dogs during the course of acute balloon occlusion of the anterior descending coronary artery. During the 2-minute period of occlusion, serial cineangiography revealed a sequence of wall motion abnormalities over the anteroapical region almost identical to that observed using directly implanted gauges. This sequence consisted of progressive reduction in regional systolic shortening with eventual replacement by systolic expansion. These changes preceded both electrocardiographic ST-segment and hemodynamic alterations, and were readily observed by gross subjective inspection of the cineangiograms, but with an intraobserver variability of 22%. Frame-by-frame motional analysis of the ventricular perimeter relative to its centroid of mass allowed more precise characterization of regional dysfunction. These data are consistent with previous studies demonstrating that regional wall motion abnormalities are both sensitive and specific markers of acute ischemia, and support the use of computerized left ventricular angiography for the quantitative assessment of clinical ischemic dysfunction.


Response of right ventricular ejection fraction to upright bicycle exercise in coronary artery disease.

The right ventricular (RV) response to exercise was assessed in 32 patients with angiographically documented coronary artery disease and in 14 normal controls without cardiopulmonary disease. The relationships between exercise RV reserve, exercise left ventricular (LV) reserve, and the presence of proximal right coronary stenosis were also evaluated. RV and LV ejection fractions were determined using first-pass radionuclide angiocardiograms. The normal response to exercise was at least a 5% absolute increase in RV and LV ejection fractions. In the group with coronary artery disease, RV ejection fraction either decreased or remained the same with exercise (abnormal exercise RV reserve) in 19 of 32 patients. LV exercise reserve was abnormal in 26 of 32 patients. All 19 patients with abnormal exercise RV reserve had abnormal exercise LV reserve, and all six patients with normal LV reserve had normal RV reserve. There was a significant linear relationship between the direction and magnitude of change from rest to exercise of LV ejection fraction and RV ejection fraction (r = 0.77). In contrast, the RV response to exercise was not primarily dependent upon the presence or absence of proximal right coronary stenosis. These data suggest that abnormal exercise RV reserve occurs frequently in coronary artery disease and that the concomitant LV response to exercise appears to be its major determinant.


Comparative value of eight M-mode echocardiographic formulas for determining left ventricular stroke volume. A correlative study with thermodilution and left ventricular single-plane cineangiography.

Sixty-six consecutive patients without left ventricular volume overload, significant arrhythmia or significant pericardial effusion were examined by M-mode echocardiography immediately before diagnostic left- and right-heart catheterization. Using various echocardiographic measurements, left ventricular stroke volume (SV) was calculated according to eight different echocardiographic formulas (SVE) that have been proposed previously. At catheterization SV was also determined by thermodilution (SVT) and by single-plane left ventricular cineangiography in the right anterior oblique projection (SVA). When comparing SVE with SVT, the four formulas developed to calculate mitral or aortic flow failed (r = 0.10 to 0.54). As expected, poor correlations (r = 0.22 to 0.47) were also found when formulas used to calculate ventricular volumes from the ventricular diameter or SV from the change in diameter (left ventricular formulas) were used in coronary patients with grossly asymmetrical ventricular contraction patterns. When the use of the left ventricular formulas was confined to patients with symmetrical or almost symmetrical contraction, two formulas yielded favorable correlations of r = 0.84, SEE = 12.7 ml and r = 0.86, SEE = 12.2 ml, respectively. These correlations were comparable to the correlation between our two invasive reference techniques (r = 0.81; SEE = 12.2 ml). The comparison between SVE and SVA confirmed the results of the thermodilution study, though the correlations were generally weaker. We conclude that the formula of Teichholz et al., which was the best of all tested formulas, may be used to obtain a clinically useful estimate of SV in patients in whom symmetrical or almost symmetrical left ventricular contraction can be anticipated.


Angiographic study of univentricular heart of right ventricular type.

An angiographic analysis of 10 cases of univentricular heart of the right ventricular type is reported. This congenital malformation is characterized by a large chamber with right ventricular morphology that receives both atrioventricular valves, and a second, smaller chamber, a trabecular pouch, with left ventricular morphology. These chambers are separated by a posterior septum but are connected by an inlet septal defect. The angiographic studies were done using the angled angiographic techniques in three patients and the standard frontal and lateral angiographic views in seven cases. The atrial situs in seven patients was solitus, in one inversus, and in two it was ambiguus with left isomerism. In seven patients the usually large right ventricular chamber received two atrioventricular valves and in four patients, one atrioventricular valve was straddling. Three patients had atresia of one atrioventricular valve. The trabecular pouch was small in seven patients but relatively large in three. In six patients the trabecular pouch was located posterior and to the left of the right ventricular chamber and in four anterior and to the right. Double outlet right ventricle was present in all cases. The aorta arose anteriorly to the pulmonary artery in nine patients and posteriorly in one. An autopsy was performed in one case and its correlation with the angiographic findings was remarkable. The angiographic demonstration of the anatomicaly details of this entity and its associated anomalies was facilitated by angled angiography.


Performance of conventional orthogonal and multiple-dipole electrocardiograms in estimating left ventricular muscle mass.

For estimating left ventricular mass (LVM), ECG criteria for left ventricular hypertrophy (LVH) were selected from conventional 12-lead ECGs, orthogonal three-lead ECGs, and multiple-dipole ECGs (MDECG). The three cardiograms were recorded in 139 patients for whom the degree of LVH was independently determined from biplane ventriculograms. Tested ECG criteria included Sokolow-Lyon measurements for the 12-lead ECG; for the orthogonal ECG, maximal QRS magnitude in the horizontal plane, R duration in the z-lead and Jxyz (spatial magnitude of point J); and for the 126 leads of the MDECG, the dipole activity (DA) of the septum and the free left ventricular wall. Correlation coefficients between LVM and the 12-lead ECG, three-lead ECG and MDECG were 0.61, 0.78 and 0.89, respectively, with corresponding errors of estimated LVM of 103, 82 and 60 g. More complex recording and analytic methods clearly led to increased accuracy in LVM estimates. However, the large error of estimate may limit practical applicability of such correlations. For classification of subjects into normal and above-normal categories, a likelihood ratio was also used and led to a maximum performance index of 86% with MDECG measurements.


Distinguising features of left anterior fascicular block and inferior myocardial infarction as presented by body surface potential mapping.

Total body surface maps obtained from 19 patients with previous inferior myocardial infarction (IMI) were compared with maps obtained from 19 patients with left anterior fascicular block (LAFB) and six more patients in whom electrocardiographic changes were indistinguishable between IMI and LAFB. Three distinguishing features were detected: 1) abnormal high anterior positivity developed both in IMI and LAFB, but its onset was earlier in LAFB; 2) a broad rim of abnormal right lower negativity was seen in both groups, but in IMI it was within the first 40 msec, whereas in LAFB it was found in the middle and later parts of depolarization; 3) abnormal left lower negativity was seen in all the patients with LAFB, but was absent in IMI. Thus, despite similarities in the abnormalities detected, we found definite temporal and topographical differences that should aid in differentiating between IMI and LAFB in ambiguous cases.


The natural history of conduction system disease in myotonic muscular dystrophy as determined by serial electrophysiologic studies.

To evaluate the progression of conduction system disease in myotonic muscular dystrophy, nine patients underwent serial electrophysiologic studies at a mean of 35 months apart. At the initial study, seven patients had first-degree atrioventricular block and three of these seven had disease in the His-Purkinje system (HV greater than 55 msec). At the second study, seven patients had prolonged HV intervals, and during the almost 3-year period, HV intervals increased by at least 5 msec in all seven patients. No electrophysiologic or electrocardiographic measures could be found that correlated with progression of conduction disease in these patients. Because of the failure of electrophysiologic measures to predict progression of conduction disease in these patients, electrophysiologic studies are recommended only for symptomatic patients. If significant disease is found in either impulse formation or conduction, permanent pacemaker therapy is warranted.


Atrioventricular block and supraventricular arrhythmias with X-linked muscular dystrophy.

This report describes a family showing muscular dystrophy and atrioventricular block with an x-linked hereditary transmission. Among a known pedigree of 101 family members, 12 males were found to have skeletal muscle involvement and six needed pacemakers around age 30 years. Unlike the x-linked muscular dystrophies of Duchenne and of Becker, the predominant skeletal involvement was in humeral muscles, was usually very mild, and did not produce incapacitation. Cardiac involvement consisted of various atrial arrhythmias and atrioventricular block. The few sporadic reports of other families that describe the same disease under different names are briefly reviewed. Recognition of this subtle muscular dystrophy is important for early detection of incipient complete atrioventricular block to prevent fatal complications by pacemaker insertion.


Dual atrioventricular nodal pathways: a common electrophysiologic response in children.

Electrophysiologic investigation was performed on 61 children and young adults during evaluation of either cardiac dysrhythmia or pre- or postoperative congenital heart disease. The results of these studies were reviewed retrospectively to determine if longitudinal dissociation of the atrioventricular node (AVN) was present. Dual AVN pathways were detected by the atrial extrastimulus technique, using His bundle electrograms. A discontinuous H1H2 response curve indicated the presence of dual AVN pathways. There was a higher incidence of dual AVN pathways in patients with clinically evident paroxysmal supraventricular tachycardia (PSVT) than in those without PSVT. Dual AVN pathways were equally prevalent in children with corrected and uncorrected congenital cardiac defects.


Epicardial mapping of the onset of ventricular tachycardia initiated by programmed stimulation in the canine heart with chronic infarction.

The initial beats of ventricular tachycardia (VT) induced by programmed stimulation (PS) of the heart have frequently been observed to differ in QRS configuration from the subsequent uniform QRS complexes of tachycardia. The transient nature of these initial beats has made their study difficult during epicardial mapping with conventional, hand-held recording electrodes. Twenty-four dogs were studied with PS 1-10 months after coronary ligation. Twenty-six epicardial electrograms were recorded simultaneously during PS. The data were digitized for computer generation of isochronic maps for any desired beat. Three patterns of initiation were observed in episodes of tachycardia in which the initial beats differed from the subsequent beats of VT (11 of 18 runs of VT). Most frequently, the initial beats of VT originated near the pacing electrode before moving to a stable infarction zone location. Less frequently, the initial beats were due to transient reentry in the bundle branches or a transient shifting of early breakthrough sites in the infarction zone.


Endocardial excision: a new surgical technique for the treatment of recurrent ventricular tachycardia.

Twelve patients with medically refractory ventricular tachycardia secondary to ischemic heart disease underwent surgery for cure of their arrhythmia. Preoperatively, the tachycardia could be reproducibly initiated and terminated in each patient by programmed stimulation. In all instances, intraoperative mapping localized the tachycardia to the border of the aneurysm, a site not routinely resected during aneurysmectomy. In nine instances, the area of origin involved the septum. During bypass the tachycardia could still be induced after standard aneurysmectomy or ventriculotomy in 11 of 12 patients. On the basis of intraoperative mapping, resection of endocardium in the area of origin (25--40% the circumference of the aneurysmectomy) up to normal muscle was performed. In one patient without a discrete aneurysm, endocardial excision alone through a ventriculotomy was performed. There was one operative death due to cardiogenic shock (preoperative ejection fraction 5%) and one late death due to rupture of a mycotic aneurysm in the pulmonary artery. Before discharge, all patients underwent a repeat relectrophysiologic study off antiarrhythmic agents and in none could ventricular tachycardia be initiated. Hemodynamic and angiographic catheterization showed improved hemodynamics and ejection fractions in all. The 10 survivors remained free of sustained ventricular tachycardia for 9--20 months, with one late nonarrhythmic death.


Significance of block distal to the His bundle induced by atrial pacing in patients with chronic bifascicular block.

Twenty-one of 496 (4%) patients with chronic bifascicular block, studied and followed prospectively, had block distal to the His bundle (BDH) induced by atrial pacing during initial electrophysiologic studies. In six, BDH was noted during pacing-induced atrioventricular (AV) nodal Wenckebach periods (at paced rates of 150--190 beats/min), with BDH in the short HH cycles after the AV nodal blocked P (lond cycle). The AH interval was normal in all six patients and HV was normal in four. None of the six patients has developed AV block during a mean follow-up of 5.33 +/- 0.48 years. In 15 patients, pacing-induced BDH was noted during intact AV nodal conduction (paced rate of 80--200 beats/min). The AH interval was prolonged in one, and HV was prolonged in 10 of the 15 patients. During a mean follow-up of 3.4 +/- 0.59 years, seven of these patients developed AV block, one had treadmill-provoked AV block, and two died suddenly (major morbid event in 10 of 15 patients). In conclusion, BDH induced by atrial pacing is an infrequent finding in patients with bifascicular block, and can be a functional as well as a pathologic response. The latter is associated with a high risk of major morbid events (AV block and sudden death).


Atypical patterns of retrograde conduction over accessory atrioventricular pathways in the Wolff-Parkinson-White syndrome.

Patterns of ventriculoatrial conduction have been used to distinguish retrograde conduction over an accessory atrioventricular pathway from that over the normal atrioventricular conduction system. Ventriculoatrial conduction at a constant interval during incremental ventricular pacing and during progressive prematurity of ventricular extrastimuli has been considered characteristic of conduction over an accessory pathway. We describe three patients with the Wolff-Parkinson-White syndrome who had progressive or sudden increments in ventriculoatrial conduction over an accessory pathway during fixed-rate ventricular pacing or during introduction of ventricular extrastimuli. Such properties have been considered characteristic of conduction over the normal atrioventricular conduction system. We conclude that retrograde conduction over accessory pathways may resemble conduction over the normal atrioventricular conduction system.


Wolff-Parkinson-White syndrome in children: electrophysiologic and pharmacologic characteristics.

Intracardiac electrophysiologic studies were performed on 28 infants and children, ages 1 month to 18 years, with the Wolff-Parkinson-White syndrome to try to determine 1) the electrophysiologic characteristics of the accessory connection and 2) the mechanisms of associated supraventricular dysrhythmias. Although the antegrade refractory periods of the normal conduction system were shorter than those found in adults, those of the accessory connection were slightly longer. Reciprocating supraventricular tachycardia (SVT), which had been a clinical problem in 26 of 28, could be induced in the laboratory in all 26 subjects. The mechanism involved reentry with antegrade conduction through the atrioventricular (AV) node and retrograde through the accessory connection in 22. Eleven of these 22 had a wide QRS during tachycardia due to a bundle branch block. Three other subjects had wide QRS tachycardia, but the mechanism involved antegrade conduction through the accessory connection and retrograde through the AV node. The other patient had AV node reentry tachycardia. Two patients did not have clinical SVT, and in these two, SVT could not be induced. Neither patient had retrograde conduction through the accessory connection. The site of the accessory connection could be identified in 26 subjects by the sequence of retrograde activation of the atrium during SVT or ventricular pacing. Digitalis shortened the refractory period of the accessory connection in five of the eight patients studied.


Prospective diagnosis of d-transposition of the great arteries in neonates by subxiphoid, two-dimensional echocardiography.

Subxiphoid, two-dimensional echocardiograms (S2DE) were performed and interpreted before diagnostic cardiac catheterization on 59 neonates who weighed 1.3--6.0 kg (median 3.3 kg) and were 1--35 days old (median 4.5 days). The echocardiographic studies were successfully performed on 58 of 59 infants. Using appropriate longitudinal and transverse projections, S2DE permitted simultaneous visualization of the branch pulmonary arteries, proximal thoracic aorta and ventriculoarterial attachments. D-transposition of the great arteries was correctly predicted in all 16 infants with levocardia, situs solitus and atrioventricular concordance. In these patients, the standard left ventricular longitudinal projection demonstrated the bifurcating main pulmonary artery attached to the posterior ventricle; the transverse projection displayed the relationship of the proximal thoracic aorta to the anterior ventricle. The broad acoustical window using the subxiphoid approach in conjunction with a high-frequency focused transducer and a large active-element diameter permitted detailed imaging of intra- and supracardiac structures.


Increased circulating bradykinin during hypothermia and cardiopulmonary bypass in children.

To determine whether cold could activate the kallikrein-kinin system in vivo as it does in vitro, the circulating systemic concentrations of bradykinin were serially measured in 10 cyildren with congenital diseases of the heart undergoing corrective cardiac surgery. Bradykinin was measured by radioimmunoassay in blood samples obtained before, during and after profound hypothermia (to 18 degrees C) and cardiopulmonary bypass. The circulating concentrations of bradykinin increased significantly as body temperature decreased during surface cooling. The increase in circulating bradykinin was associated with a decrease in the circulating level of bradykininogen, the precursor of bradykinin. With the onset of cardiopulmonary bypass and hence, removal of the lung and pulmonary converting enzyme from the circulation, there was a further rise in the already elevated concentrations of bradykinin. This is the first in vivo demonstration that hypothermia leads to an increase in the circulating concentrations of bradykinin.


Exercise can promote coronary collateral development without improving perfusion of ischemic myocardium.

We studied the effect of exercise training on the coronary collaterals that developed in response to gradual coronary occlusion in dogs. After their proximal left circumflex coronary artery occlusion, 33 dogs were randomly assigned to exercise or sedentary groups. Coronary collateral function was evaluted 5 weeks or 8 weeks later. The exercised dogs developed better epicardial collateral connections to the occluded left circumflex as judged by higher retrograde blood flow from the distal left circumflex and lower pressure drop across the collaterals. No difference in collaterals was apparent angiographically. Microsphere data indicated that exercise dogs were not better protected against tachycardia provoked subendocardial ischenia in the myocardium supplied by the collaterals.


Diagnosis and management of postoperative pulmonary hypertensive crisis.

In this paper we discuss two infants and one child who experienced a previously unreported complication after complete correction of a large, unrestrictive ventricular septal defect. Two patients had documented pulmonary hypertensive crises and severe right-heart failure secondary to hypoxia and pulmonary vasoconstriction. These crises were associated with significantly increased right ventricular (RV) peak systolic and end-diastolic pressures and right-to-left shunting via a foramen ovale which, in turn, exaggerated the hypoxis. The crises were treated successfully with tolazoline in the second and third patients. RV pressure returned to normal values and have remained normal up to 12 months postoperatively in the second patient. Although the RV pressures decreased with tolazoline in the third patient, they never reached normal values. Postoperative monitoring of pulmonary artery and RV pressures in infants with large ventricular septal defects is essential when unexplained complications are encountered. Tolazoline proved to be very effective in the treatment of two patients with pulmonary vasoconstriction secondary to hypoxia.


Two-dimensional echocardiography and B-mode ultrasonography for the diagnosis of loculated pericardial effusion.

Two cases of loculated pericardial effusion resulting in cardiac tamponade are presented. The loculated nature and extent of the effusion was best defined by two-dimensional echocardiography or B- mode ultrasonography. Cross-sectional images should probably be obtained in all cases of suspected loculated pericardial effusion and in patients in whom the interpretation of the M-mode echocardiogram is equivocal as to the presence or absence of pericardial effusion.


HLA haplotypes and hayfever: a possible protective role.

The HLA haplotype frequencies of European asthmatic children and their immediate families were studied, and a disassociation between haplotype A1-B8 and skin sensitivity to grass pollens was found, suggesting that within this allergic population, possession of the haplotype A1-B8 conferred possible protection against grass pollinosis. There was no association between A1-B8 and clinical asthma or between it and skin sensitivity to the house dust mite.


Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure.

A 58-year-old pharmaceutical worker regularly developed asthma and rhinitis when handling bromelain, a purified protease of pineapple (Ananas comosus), at her work-place, where she had been employed for about 10 years. RAST and prick test showed strong positive reactions to bromelain. Both inhalation test with 0.03 mg bromelain and peroral challenge by ingestion of 190 g pineapple resulted in asthmatic reactions; the latter challenge was accompanied by gastrointestinal symptoms. Five of six workers sensitized to papain, showed positive RAST and skin test results to bromelain, two of them also showed immediate asthmatic reactions after bronchial challenge with bromelain. Out of sixty asthmatics not exposed to airborne proteases but probably to these as constituents of foods, two had positive skin test results and eight had positive RAST results to bromelain; but in no case was there clear evidence for clinical sensitization. The presented data prove conclusively that bromelain is capable of inducing IgE mediated respiratory and gastrointestinal allergic reactions. Furthermore, there is evidence for immunological cross-reaction between the two plant proteases bromelain and papain in human subjects.


Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain.

The sera of seven patients clinically hypersensitive to papain--in one case also to baromelain--and the sera of sixty asthmatic patients with allergies to other inhalant and food allergens were investigated for IgE antibody activity to the plant proteases papain and bromelain and to common allergens by RAST, confirmed in some sera by RAST inhibition. There seems to be a relation between the antibody reactions to papain and bromelain, in several cases also between the reactions to these proteases and to grass pollen and flour. Studies by RAST inhibition showed that papain, bromelain, wheat flour, rye flour, grass pollen and birch pollen mutually inhibit IgE antibody to each antigen; but the degree of inhibition varies among the different sera and allergens. Our results suggest that these allergens from various plants, besides having specific antigenic determinants, also possess similar or even identical antigenically active regions, leading to immunological cross-reactivity.


Intradermal skin tests with Dermatophagoides pteronyssinus in asthmatic children: correlation with specific IgE and bronchial provocation tests.

The purpose of the present study was to compare the results of the skin tests, the specific IgE levels and bronchial provocation tests in a group of sensitive asthmatic children with a Dermatophagoides pteronyssinus extract standardized by the RAST inhibition method. Skin tests showed a positive 'end point' in twelve children of 0.5 U/ml antigen; in eleven 5 U/ml; seven of 50 U/ml; six of 500 U/ml. Specific IgE was present in thirty-three children (92%). A close relationship between positive skin tests and serum IgE levels was found. Bronchial provocation tests were positive in twenty-eight children (78%): eight children with both positive RAST and positive skin tests had negative bronchial provocation tests.


Species specific grass pollen sensitivity: diagnosis and treatment with single grass species Allpyral vaccines.

Skin test titrations and nasal provocation tests in sixty patients with hay fever showed specific reactions to extracts of individual grass species. There was, however, no correlation between skin and nasal sensitivity. Repeat testing after treatment with Allpyral vaccines consisting of only the grass species to which the nasal reaction was most severe, or only one of several pollens to which reactions were equally severe, showed marked diminution of skin and nasal sensitivity not only to the single pollen used for immuno-therapy but to all five common pollens used in the Allpyral grass mix. Clinical results seemed much improved as compared with results in the same year for Allpyral five grass mix vaccines, especially in the case of patients treated with Timothy, rye, or cocksfoot. It was concluded that these three grassees were to be preferred for treatment in England, and that these grasses contain common allergens.


Failure to detect circulating immune complexes in allergic patients on injection therapy.

Injection therapy for allergic diseases may create an environment conducive to circulating immune complex formation. Therefore, we examined the sera of eleven patients receiving injection therapy for the presence of circulating immune complexes. A sensitive Raji cell radioimmune assay was used to examine the sera prior to and 4, 8 and 24 hours after allergenic injection. Levels measured in these sera were compared to values obtained from forty-two healthy controls. Ten of eleven allergic patients receiving injection therapy had values within the normal range prior to maintenance injection. These ten patients also had normal values for circulating immune complexes at each interval after maintenance injection. The data suggest that circulating immune complexes are not a routine consequence of injection therapy for allergic disease.


Airflow obstruction in asthma induced by inhalation of small minimum doses of allergen.

In order to define allergen-induced bronchial responses, sixteen asthmatics, assessed as mild (twelve cases) and moderate (four cases) were tested by inhalation of small doses of house dust allergen. The minimum dose was first determined in each patient. It caused no abnormal respiratory sensation, while a fall of Vmax50 air with no change or slight decrease of Vmax50 He-O2 and a rise of density dependence ratio were observed. Inhalation tests with multiples of the minimum dose were made and showed that the minimum dose was dependent on the individual, his condition and induced airflow obstruction in a dose-related fashion.


Asthma in Asian immigrants.

Adult Asian immigrants to the United Kingdom attending an asthma clinic have been compared with a control group of non-immigrant Caucasian asthmatic patients of similar age distribution. The Asian immigrants had a later age of onset of asthma than their non-immigrant controls. Comparison with studies of asthmatic patients in India suggests that this may be an intrinsic ethnic difference but an effect of migration in early adult life is not excluded. Despite a later age of onset, the frequency of positive skin prick tests to common allergens was similar in the immigrant and control groups and 71% of the Asians had positive reactions to the house dust mite. Most other clinical features, the variability of airways obstruction and the requirements for treatment showed no significant differences between the two groups.


Hereditary angio-oedema and C3 nephritic factor--HL-A study.

In one family of twenty-four members hereditary angio-oedema was present in the family for six generations. The protein C1 esterase inactivator found in nine patients proved to be non-active in a functional test. Another anomaly found in the complementary system was labelled C3 nephritic factor without any renal, or other clinical symptoms. Study of HL-A haplotypes did not show any linkage with the loci A, B and C. Hereditary angio-oedema is a disease arising from a specific defect in the inactivator of the C1 esterase (C1 INA) which is a regulating component of the complement system (Donaldson & Evans, 1963). This system is of current interest because of its interaction with other mechanisms of inflammation. Moreover, some links have been discovered recently between HL-A and hereditary defects of complement. This paper reports new findings in a family with hereditary angio-oedema.


IgE antibodies to bee venom, phospholipase A, melittin and wasp venom.

Specific IgE antibodies against bee venom, phospholipase A, melittin and wasp venom have been examined in fifty patients with an unusually severe reaction after bee or wasp sting. Two thirds of the bee venom-sensitive patients also have detectable IgE antibodies to wasp venom. More than 50% of the wasp venom-sensitive patients are also allergic to bee venom. Phospholipase A and melittin IgE antibodies were found, respectively, in two thirds and one third of the bee venom-sensitive cases. Specific IgE antibody determinations by the Radioallergosorbent test play an essential role in the diagnostic work. After a reaction to hymenoptera stings both bee and wasp venom tests are necessary due to the high incidence of a false or incomplete identification of the stinging insect. Melittin, known for its potent pharmacological activity and possibly responsible for most of the side effects in bee venom immunotherapy, can probably not be excluded from therapeutic venom preparations since IgE antibodies to the melittin preparation were detected in one third of the cases.


Muscle protein analysis. I. High-resolution two-dimensional electrophoresis of skeletal muscle proteins for analysis of small biopsy samples.

We have been developing a clinically useful method for high-resolution two-dimensional electrophoretic analysis of small (5--10 mg) human muscle biopsy samples with sufficient resolution to resolve the major contractile proteins and enzymes. Using rabbit psoas muscle as a model, we describe methods for sample preparation and two-dimensional electrophoresis. Basic proteins, which appear as streaks when conventional isoelectric focusing is used in the first dimension, are resolved through a modification of the nonequilibrium pH gradient electrophoresis method [Cell 12, 1133 (1977)]. In the two-dimensional patterns obtained from rabbit muscle, we identify the components of 10 enzymes and of myosin, actin, tropomyosin, and troponin. These patterns indicate charge heterogeneity in a large fraction of the proteins. Comparison of rabbit and normal human muscle patterns shows many similarities, but much additional work is required to confirm identifications. We conclude that analysis of small biopsy samples is feasible, but that all aspects of human sample acquisition, storage (when necessary), and preparation require thorough study before the method becomes routine in human muscle research and, ultimately, in the diagnosis of some muscle diseases.


Abrnomal lipoprotein patterns in human serum as determined by agarose gel electrophoresis.

Two groups of abnormal electrophoretic patterns of serum lipoproteins are reported here. One demonstrates a deficiency or absence of lipoprotein fractions, which is characteristic of patients with abeta-lipoproteinemia, hypo-beta-lipoproteinemia, or Tangier disease. The other shows the presence of extra lipoprotein fractions, as found in cholestasis and multiple myeloma. These patterns, together with those of hyperlipoproteinemia phenotypes previously reported (Clin. Chem. 24:227, 1978), form a reference record and a basis for the detection and evaluation of lipoprotein abnormalities in normal and dyslipoproteinemic subjects, as determined by a sensitive, accurate, rapid, and inexpensive electrophoretic technique.


Determination of ammonia and urea in urine and of urea in blood by use of an ammonia-selective electrode.

I propose a single, quick method for measuring ammonia in urine and urea in plasma and urine. An ammonia-selective electrodie is used, set up on a microcell, which allows use of small sample volumes. Ammonia is measured directly after partial conversion of ammonium ions to NH3. Urea is measured after its hydrolysis by urease. With urine, the two procedures can be carried out successively in the same cell and on the same sample without changing the procedural conditions. Linear electrode response and accuracy have been checked for concentrations in the expected (normal) range.


Disopyramide determination by gas chromatography, liquid chromatography, and gas chromatography--mass spectrometry.

Disopyramide is determined in serum by gas chromatography with a nitrogen-selective detector, by liquid chromatography, and by gas chromatography--mass spectrometry. Comparable results are obtained with the three techniques, with a within-run and between-run precision of 5 to 10% (coefficient of variation). Least-squares analysis of data on patients' sera, analyzed first by gas chromatography (y) and then liquid chromatography (x), gave a slope of 1.12; y-intercept, -0.31; standard error of estimate, 0.46; and correlation coefficient, 0.94. Comparison of patients' sera by gas chromatography (y) and then by gas chromatography--mass spectrometry (x) gave a slope of 0.94; y-intercept, 0.42; standard error of estimate, 0.38; and correlation coefficient, 0.97. Interferences observed when using one technique--for example, gas chromatography--can be eliminated by analyzing the sample extract with one of the other techniques.


Rate nephelometric measurement of rheumatoid factor in serum.

We describe the measurement of rheumatoid factor in human sera with a rate nephelometer. The National Reference Preparation for Rheumatoid Factors is used to calibrate the assay in International Units. We used Hyland Positive Control, Level I, as a secondary standard. The standard curve is exponential, but is linear when plotted on log-log graph paper. Aggregated immune globulin (IgG) is the antigen used to detect rheumatoid factor (IgM-class antibody to IgG). The rate reaction measures the rate of increase in light-scatter by the antigen-antibody complexes; the reaction takes place in 17 to 20 s. Precision, linearity, and accuracy are excellent. Results agree well with those for a commonly used latex precipitation test. The advantages of speed, quantification in International Units, and superior discrimination of concentration as compared to serological titration provide a more reliable test for use in the diagnosis and treatment of rheumatoid arthritis.


Determination of manganese in whole blood and serum.

We describe methods for determination of manganese in whole blood and serum with Zeeman-effect flameless atomic absorption spectroscopy. These analyses are performed on a twofold or fourfold dilution of the specimen in Triton X-100, 1 g/L. No predigestion or extraction procedures are required. The method of standard additions was used for quantitation. Within-run coefficients of variation for whole-blood manganese were 7.0 and 5.5% for 2.29 and 5.67 micrograms/L, respectively. For determination of serum manganese, coefficients of variation were 10.3 and 5.3% for 0.97 and 3.01 micrograms/L, respectively. Manganese detection limits for the assays were 3.0 pg. Whole-blood manganese concentrations, determined for 60 subjects, yielded a mean (+/- SD) of 9.03 (+/- 2.25) micrograms/L. Mean serum manganese concentration, determined for 20 subjects, was 1.82 (+/- 0.64) microgram/L. No correlation was found between blood manganese concentrations and age, sex, or smoking status.


Quantitative gel-electrophoretic determination of serum amylase isoenzyme distributions.

I report a direct, sensitive, quantitative method for determining serum amylase isoenzyme activity with commercially available reagents. Day-to-day reproducibility (CV) was 3--4% for the isoenzymes in normal serum; within-run precision was 8, 3, and 2% for low, normal and high isoenzyme activities. Amylase isoenzymes, separated into the pancreatic and salivary types by electrophoresis in polyacrylamide gel, are then quantified by directly incubating the gels in soluble-starch solution, staining with iodine, and densitometry. The proportion of pancreatic isoenzyme (47 normal sera) was 43 +/- 8% (mean +/- SD). Isoenzyme activities as low as 2% of normal can be measured accurately in 10 micro L of serum. The reproducibility, precision, and sensitivity indicate that the method is applicable to differential diagnosis of hyperamylasemia or hypoamylasemia, and is suited for monitoring the subtle changes in serum amylase isoenzyme distribution that may accompany disease progression or therapy.


Liquid-chromatographic measurement of endogenous and exogenous glucocorticoids in plasma.

The therapeutic response to and side effects of glucocorticoids will be better recognized and the recovery of the adrenals during the tapering of therapy with steroids better evaluated if endogenous and exogenous glucocorticoids are separately assessed. We describe a specific method for simultaneously measuring the concentrations of cortisone, cortisol, prednisone, and prednisolone in plasma by "high-pressure" liquid chromatography. The steroids, together with an internal standard, dexamethasone, are extracted from 1 mL of plasma with methylene chloride-ether, washed with acid and base, and separated isocratically on a normal-phase silica column with a mobile phase consisting of methylene chloride/tetrahydrofuran/methanol/glacial acetic acid (96.85/1/2.1/0.05 by vol) at a flow rate of 1.3 mL/min. The steroids are detected at 254 nm and quantitated by peak-height measurements; their retention times range from 6 to 20 min. The lower limits for routine detection of all four compounds is 10 microgram/L. The analytical recoveries are about 75%; the intra-day variability (CV) is 1 to 9%, and the inter-day variability 2 to 11%. Of 26 drugs and 20 steroids tested, only theophylline presents an interference problem.


Direct determination of lead and cadmium in blood and urine by flameless atomic absorption spectrophotometry.

We describe procedures for direct determination of lead and cadmium in blood and urine by flameless atomic absorption spectrophotometry. Before analysis, the samples are pre-ashed in microboats in an ordinary laboratory oven. In this way, many samples can be prepared and pre-ashed simultaneously. We find the procedures presented in this work to be rapid, accurate, and precise.


Response-surface co-optimization of reaction conditions in clinical chemical methods.

We describe the theory and applications of the response-surface approach to simultaneous optimization (co-optimization of multiple interdependent variables. The co-optimization experiments are designed according to a selected response-surface model. Computer-assisted analysis includes fitting the data to the model, testing the resulting fit for statistical validity, and plotting contour maps of the model for simple interpretation. Co-optimizations of the reaction parameters of three methods--creatine kinase, lipase, and aspartate aminotransfrease--are discussed to illustrate the application of the approach. In contrast to the commonly used optimization strategies in which each factor is varied in turn while the others are kept constant, the response-surface approach allows study of several responses (reaction rates, sensitivities) and effects (linear, curvature, interaction) at the same time. It also allows determination of accurate optima, which is necessary for the formulation of analytically reliable clinical methods.


Quantitation of hemoglobin A1a+b and hemoglobin A1c by automated "high-performance" liquid chromatography.

The glycosylated hemoglobins A1a+b and A1c have been rapidly and precisely quantitated in 5-micro L samples of human blood hemolysate (approximately 240 micrograms of hemoglobin) by cation-exchange column chromatography. Total chromatographic is 22.0 min. Proportions of Hb A1c range from 3.85 to 6.71% in normal individuals and from 4.23 to 19.90% in diabetic subjects. Within-day variation was 1.58 and 1.10% for mean Hb A1c proportions of 4.92 and 10.32%, respectively. Hb A1c and Hb A1 are stable in hemolysates stored at 4 degrees C for as long as seven days, and indefinitely under liquid nitrogen.


Cryoactivation of renin in plasma from pregnant and nonpregnant subjects, and its control.

Plasma renin activity increased by a mean of 7% from baseline values when blood from nonpregnant persons was kept at 0 degrees C for 5 h before incubation. Freezing chilled plasma and thawing it before incubation resulted in a mean increase of 11%. The same procedures used on plasma from normal pregnant women produced mean increases in plasma renin activity of 44 and 89%, respectively. If blood from pregnant women was kept at 0 degrees C for 5 h, and the plasma then separated, frozen, and thawed before incubation, the resulting mean increase in plasma renin activity from baseline values was 160%. We conclude that plasma from pregnant women should be handled at room temperature, or, if samples must be stored, they must be rapidly frozen, then thawed as rapidly as possible before incubation and assay if results are to be reproducible.


Effects of contaminant radioactivity on results of 125I-radioligand assay.

Diagnostic radionuclide imaging procedures are often used in patients whose sera are later assayed by use of 125I-labeled radioligands; thus, it is important to identify those assays that potentially may be affected by contaminating radioactivity. Results obtained with assays in which specific separation methods (solid-phase primary antibody, second antibody) or small (10--25 micdo L) sample volumes are used are little affected by the presence of such contaminating radioactivity. Less-specific techniques (polyethylene glycol, charcoal, ion-exchange resin) segregate some of the contaminant activity into the bound fraction. The degree to which such activity is protein bound and the concentration of endogenous ligand then contribute to the resulting error in dose estimation. Samples for these assays should be screened for radioactivity before the assay is begun. Inclusion of nonspecific binding tubes for patients' samples when contamination is present permits the contaminating radioactivity to be evaluated and the patient's dose concentration to be more accurately estimated.


Pre-renal azotemia mimicking chronic renal failure in a hypotensive patient.

A 56-year-old Samoan man with a documented history of hypertension, who presented with atrial fibrillation and hypotension, quickly developed renal failure with a serum urea nitrogen of 1.370 g/L and a serum creatinine of 92 mg/L. After hydration of the patient, the creatinine value became normal in two days, the urea nitrogen in four days. The urinary creatinine output during the first 24 h of hospitalization was 3.7 g. This case illustrates the rapidity with which unusually large amounts of creatinine (more commonly seen in chronic renal failure) can accumulate and be excreted in pre-renal failure. It also reaffirms the usefulness of the urea nitrogen/creatnine ratio in evaluating the causes of azotemia.


Mass spectrometry of a volatile Mg chelate in the measurement of stable 26Mg when used as a tracer.

A method for the detection of 26Mg enrichment of natural Mg was developed based on mass spectrometry (MS) of a Mg chelate made by complexing Mg to 2,2',6,6'-tetramethylheptanedione (THD). The chelate [Mg(THD)2] was extracted at pH greater than 9 from dilute aqueous solutions into ethyl ether, recovered by sublimation at room temperature, and introduced by solid probe into a Finnigan 3300 mass spectrometer. The chelate was ionized by electron impact. Samples were heated to a maximum temperature of 200 degrees C at a rate of 700 degrees C/h. Each analysis required 1--5 micrograms Mg(THD)2. Enrichment levels as low as 5% above natural abundance could be detected satisfactorily. Precision was best at 26Mg enrichment levels of 8--40% above natural abundance, the levels most likely to be encountered in analysis of plasma, urine and fecal samples from experimental subjects who had received 26Mg as a tracer. The method was compared to neutron activation (NA) analysis and judged superior.


Comparison between immunofixation and crossed immunoelectrophoresis for the detection of C3 activation products.

C3 breakdown products were measured in 51 fresh and stored sera and/or EDTA plasma samples from 18 healthy subjects, 8 patients affected by essential mixed cryoglobulinaemia, and 15 patients with miscellaneous glomerulonephritis, by simultaneous crossed immunoelectrophoresis and immunofixation. C3 splitting products, as determined by both methods compared well, and showed a highly significant correlation. The advantages and reliability of these two methods are discussed. Immunofixation seems to be the most suitable for routine use in clinical practice, being less expensive and more rapid to perform.


Prediction of infarct size from serial CK determinations: evaluation by clinical studies and computer simulation.

To assess reduction of infarct size by therapeutic intervention, a high predictive accuracy is mandatory. The CK release in the circulation (CKr) was studied in 12 consecutive patients after uncomplicated myocardial infarction, admitted within 5 h after onset of symptoms. Despite improvement of existing methods, such as a more frequent sampling, CK-MB determination instead of total CK determination and use of a gamma-exponential instead of a log-normal curve-fitting technique, the correlation between CKr predicted from measurements within 7 h after the start of CK rise and CKr calculated after completion of the CK curve remained poor. Computer simulations were done to investigate measurement errors as a cause of this failure. Normally distributed noise, with standard deviations ranging from 0.2% to 8.0% of peak CK-MB, was added to the first points of an ideal gamma-exponential CK-MB curve and predictions were made from these "noisy" points. A small noise already produced a great variation in prediction: 0.8% noise resulted in a deviation of predicted CKr from calculated CKr ranging from --20 to +6%. It is concluded that adequate prediction of infarct size from serial CK determinations in the first 7 h after onset of the CK rise must fail if the precision of the biochemical determination is not less than 0.4%.


Gross errors made by routine blood sampling from two sites using a tourniquet applied at different positions.

Tourniquet application in routine blood sampling procedures may induce considerable haemoconcentration and thereby augment the concentration of serum protein and protein-bound substances. To evaluate this effect serum protein, calcium and magnesium were measured in 31 healthy persons before and after 3-min venous stasis induced by a standardized tourniquet. Four sites of tourniquet and two sampling sites on the arm were compared. The concentration of measured serum constituents rose after the stasis period (5--13% rise in serum protein), the changes being similar at all tourniquet positions. However, blood sampled from a cubital arm vein showed significantly larger haemoconcentration than samples obtained simultaneously more distally on the arm. Taking three samples in a series, the serum concentration of protein, calcium and magnesium rose from tube to tube (5--10% change). The study demonstrates that neither use of a standardized tourniquet nor release of the tourniquet before blood sampling eliminates the errors inherent in routine venepuncture. Adjustment to a constant serum protein level minimizes these errors.


Human erythrocyte fraction in "Percoll" density gradients.

A new rapid method for the age fractionation of human erythrocytes by centrifugation through a "Percoll" density gradient is described. The fractionation is demonstrated by density-related changes in the volume, haemoglobin concentration, pyruvate kinase and acetylcholine esterase activities and potassium contents of the erythrocytes, and the distribution of reticulocytes on the gradients.


Excretion of alpha-keto-delta-guanidinovaleric acid and its cyclic form in patients with hyperargininemia.

alpha-Keto-delta-guanidinovaleric acid, in equilibrium with its cyclic form, has been identified in the urines of three sisters affected with hyperargininemia. Identification was achieved on the basis of its similarity with the enzymatically synthesized compounds.


Separation and assay of iron proteins in needle biopsy specimens of human liver.

A micro method has been developed for the separation of the principal classes of iron proteins in needle biopsy specimens of human liver. The iron content of the fractions was determined by automated flameless atomic absorption spectrophotometry in a one step procedure. The levels of total iron, transferrin-, ferritin-, haemprotein- and haemosiderin-iron are reported for control tissue.


The combined radioimmunoassay of triiodothyronine and thyroxine.

An RIA method for the concurrent determination of serum triiodothyronine (T3) and thyroxine (T4) is described. The extraction of the hormones from serum and competitive binding reactions using specific T3 and T4 antisera were conducted in sequence in a single Sephadex column. Precision studies resulted in average interassay relative standard deviations for T3 and T4 of 17 and 9.5%, respectively. The assay also exhibited satisfactory recovery and correlation with reference procedures (T3: y = 0.84x -- 36, r = 0.98; T4: y = 0.96x + 0.06, r = 0.98, where y is the value obtained by the combined method and x is the value obtained by the reference method.


A semi-automated method for the determination of glycosylated haemoglobin.

A new routine, automated method for the determination of glycosylated haemoglobin is presented. The method offers improvements in analytical capacity, and precision, together with reduced running costs over existing methods, which should assist in making the determination of glycosylated haemoglobin more readily available to the clinician treating diabetes.


Influence of zinc ions addition to different lots of 2-amino-2-methyl-1-propanol (AMP) buffer on the alkaline phosphatase activities.

The influence of Zn2+ on the inactivation of alkaline phosphatase [orthophosphoric monoester phosphohydrolase (alkaline optimum), EC 3.1 3.1] in serum during preincubation with 2-amino-2-methyl-1-propanol (AMP) buffers was investigated. Addition of Zn2+ to the buffer before preincubation increases the enzyme activity. An optimum Zn2+ concentration different for each lot of AMP buffer can be found, at which the enzyme activities are restored to a level equal to activities measured without preincubation. There is a relation between the inactivating properties of the different AMP buffers and the amount of Zn2+ needed to prevent this inactivation. Since Zn2+ chelating substituted diamines are held responsible for the inactivation by removing Zn2+ from the enzyme, we assume that the addition of Zn2+ to the buffer prevents this removal. As Zn2+ itself is an inhibitor of the enzyme, the addition of both too much or too little Zn2+ results in lower enzyme activities after preincubation with AMP buffer.


Rapid development of immunoprecipitins in agarose gel.

A procedure for the rapid development of immunoprecipitins in agarose gels has been developed using polyanion precipitation after immunoelectrophoretical separations. Excellent results are obtained for serum apolipoproteins, immunoglobulins and other proteins. It is shown that quantitative determination of apolipoprotein B in hyperlipemic serum and isolated lipoproteins is affected by immunoprecipitated complexes when rocket immunoelectrophoresis is used. This effect can be avoided by addition of polyvinylpyrrolidone.


Gas chromatographic chemical ionization-mass fragmentometric assay of catecholamines in the brain.

A method for gas chromatographic chemical ionization-mass fragmentometric assay of tissue catecholamines is described. Catecholamines were extracted by HClO4, absorbed to aluminum oxide and eluted by acetic acid. Pentafluoropropionic derivatives were made and injected into a gas chromatograph-mass spectrometer equipped with a chemical ionization device. The method was found to be very sensitive and results were reproducible. Epinephrine and norepinephrine could be assayed without interference from each other because of the differences of m/e numbers. Results of dopamine and norepinephrine analyses on human autopsy brain specimens were consistent with those reported in the literature using different methods. Epinephrine in small amounts could be detected in most of the cases analyzed, being highest in amount in the hypothalamus. The results suggest that epinephrine may be acting as a neurotransmitter in certain areas of the human brain.


Investigation of pregnancy-related changes in red cell 2,3-diphosphoglycerate.

Significant gestational changes in red cell 2,3-DPG were found. No significant correlation was found between these pregnancy-related changes and alterations in the parameters of iron metabolism or red cell enzymes during the same gestational period. Possible reasons for the high concentration found at 21--24 weeks gestation are discussed.


The application of high pressure liquid chromatography to the analysis of bile salts in human bile.

Two high pressure liquid chromatography (HPLC) systems have been evaluated for the separation of conjugated bile salts from human bile. Partisil-10 ODS with mobile phase of methanol/water pH 2 (55 : 45) at 200 nm, 0.1 AUF UV detection gave only partial separation of bile salts. However, a mu Bondapak fatty acid analysis column using isopropanol/8.8 mmol/l potassium phosphate pH 2.5 (32 : 68) as the mobile phase and 193 nm, 0.1 AUF UV detection separated all the six conjugated bile salts in bile. The limit of detection ranged from 0.1 microgram for sodium taurocholate to 0.2 microgram for sodium glycodeoxycholate. The reproducibility and the application of the method to the analysis of conjugated bile salts was demonstrated using bile from five patients. Its application to the studies of hepato-biliary disease is discussed.


An ion-exchange assay for high molecular weight alkaline phosphatase.

An ion-exchange method for the measurement of a high molecular weight form of alkaline phosphatase in serum is described. The method is simple, rapid, precise and suitable for processing small batches of samples. Other forms of alkaline phosphatase commonly encountered in serum do not interfere. The correlation between results obtained by this method and those obtained by Sephadex 6B chromatography is discussed. Electrophoretic methods of measurement were also investigated but were found to be both imprecise and inaccurate.


Is immunochemical determination of haptoglobin phenotype dependent?

Immunochemical methods have been used to determine the concentration of haptoglobins. The dependence on the phenotype was tested with highly purified Hp 2-1, Hp 2-2 and Hp 1-1, by immunonephelometry and radial immunodiffusion (RID). Measurements with three different instruments: automated immunonephelometer (AIP, Technicon), laser nephelometer (LN, Behring) and immunochemistry system (ICS, Beckman) were performed. For each type of apparatus antisera against a pool of haptoglobins were provided by the respective manufacturers. Some experiments were done with an antiserum to the haptoglobin heavy chain prepared in the laboratory. This study shows that haptoglobin determination depends neither on the physical geometry of the instruments or on the type of antiserum used in this work. In contrast, the data display a dependence on haptoglobin phenotype. When Hp 2-1, the most common phenotype, is taken as a standard, thd values obtained for Hp 2-2 are in good agreement with those obtained for Hp 2-1. However, the values obtained for Hp 1-1 are overestimated unless they are corrected by an experimental factor which has been determined in this study.


Trace metal determinations in blood obtained in evacuated collection tubes.

Using atomic absorption spectrophotometry, we determined levels of iron, copper and zinc in serum or plasma samples collected in acid-washed containers and in commercially available evacuated tubes including one model equipped with rubber stoppers prepared by a process which reduces zinc contamination of the rubber. Serum or plasma from all evacuated tubes yielded iron and copper values which were comparable to those from serum obtained in acid-washed glass. Zinc values were higher from all evacuated tubes than from acid-washed glassware. Values obtained from samples collected in the specially-prepared tubes were 10% higher than values obtained from samples collected in acid-washed glassware. Thus, the specially-prepared evacuated tubes may only be useful in large-scale clinical screening studies. Traditional blood collection methods for zinc determination should be used when accuracy is required.


Effects of sample-diluent interactions on surface tension and pressures in continuous flow manifolds.

When a plasma sample is aspirated into a continuous flow analyser the internal pressure of the manifold increases. The pressure change is the result of insufficient detergent present to bind all the protein in the sample, and is a potential source of inaccuracy and imprecision in the assay. It is recommended that Brij 35 be used at a concentration 10 times above the binding capacity of the albumin in the sample, to minimise changes in pressure between samples.


Electrophoretic separation of A gamma and G gamma human globin chains in Nonidet P-40.

Electrophoresis in cellulose acetate in the presence of 3% Nonidet P-40 can resolve two neutral genetic variants, A gamma and G gamma human fetal globin chains. The ratio of these two chains, determined by densitometry of the electrophoretic strips, is in excellent agreement with the Gly-Ala ratio obtained by chemical analysis of the cyanogen bromide fragment gamma CB3. It is suggested that the detergent binds preferentially to the hydrophobic amino acid segment 133-141 in the A gamma chain, thus masking either a Lys or an Arg residue at the two extremes.


Pattern of aliphatic dicarboxylic acids in uremic serum including a new organic acid, 2,4-dimethyladipic acid.

(1) 2,4-Dimethyladipic acid was first identified in normal human urine using gas chromatography-mass spectrometry. Urinary excretion of 2,4-dimethyladipic acid in 7 healthy adults ranged from 4.9 mumol to 14 mumol per 24 h. (2) Succinic acid, adipic acid, 3-methyladipic acid, 2,4-dimethyladipic acid, pimelic acid and azelaic acid were identified in the ultrafiltrate of the blood obtained from a chronic uremic patient using a hemodialyzer. (3) Levels of succinic acid, adipic acid, 3-methyladipic acid, 2,4-dimethyladipic acid, pimelic acid and azelaic acid in uremic serum were determined using a mass fragmentographic technique. Concentration of succinic acid in uremic serum was comparable to that in normal serum, whereas concentrations of adipic acid, 3-methyladipic acid, 2,4-dimethyladipic acid, pimelic acid and azelaic acid were highly elevated in uremic serum.


Micro determination of plasma renin activity in normal infants and children of capillary and venous blood.

Plasma renin activity (PRA) has been measured by microassay on capillary and venous blood sampled simultaneously in 21 subjects; there is no significant difference between these two groups of PRA values. PRA values in normal infants, children and adults have been measured with this microassay and the results are similar to those previously published by authors using different radioimmunological assays.


Electroencephalographic correlates of compulsive eating.

Fifty-nine compulsive eaters were interviewed, had a complete waking and sleep EEG tracing, and were offered a trial with phenytoin. Forty-seven patients had an adequate pharmacological intervention. Analyses of the EEGs showed a disproportionately higher percentage of abnormal EEGs and of paroxysmal EEGs in particular among compulsive eaters as contrasted with unselected psychiatric patients and normal controls. Patients with abnormal EEGs responded to phenytoin treatment statistically more frequently than those with normal EEGs--even after conservatively classifying "uncertain" patients as non-responders. Patients with 14 & 6/sec. positive spikes alone showed a phenytoin improvement significantly greater than that seen with either normal EEG subjects or other EEG abnormalities. There are suggestions of a weight by EEG interaction in that the combination of weight deviance (viz: emaciated or obese) plus abnormal EEG seems especially highly predictive of good phenytoin response. The EEG results combined with phenytoin response suggest that neurophysiological etiological hypotheses may have merit for some compulsive eating disorders. Suggestions for additional research are made and the need for controlled replication of these data results is stressed.


Prognostic value of EEG in acute vascular aphasia: a long term clinical-EEG study of 53 patients.

A group of 53 patients rendered acutely aphasic by occlusive cerebrovascular disease were studied by serial EEG's, repeated neurologic examinations and speech evaluations (Porch Index of Communicative Ability) over a period of eight to twenty-four months, in order to correlate EEG findings with the degree of language disorder and prognosis for language recovery. Normal and mildly abnormal EEG's, posterior slow foci, focal slowing of semirhythmic type and higher alpha frequencies over the intact hemisphere correlated with good language recovery. In the majority of the patients, the curves of "EEG Improvement" and "Language Recovery" closely paralleled each other. These data indicate that the EEG is of prognostic value as to recovery from aphasia in patients suffering from acute occlusive cerebrovascular disease. Despite the advent of newer diagnostic tests, such as CAT scan, which has established its value in evaluation of the anatomy of aphasia, (9) EEG remains to be useful as a tool that could predict the outcome of aphasia in stroke patients.


Patterns resembling tracé alternant in quiet sleep of an adult.

An 18-year-old man with lymphoma and Listeria meningitis developed a pattern similar to tracé alternant during quiet sleep. This is a pattern normally seen in the neonate during quiet sleep and probably represents diffuse brain disturbance of both cortical and deep gray matter if occurring in the adult, as with other discontinuous or burst-suppression patterns.


Equivocation in EEG reporting: the clinician's response.

Evidence is presented that about 29% of the time that an electroencephalographer feels he needs to equivocate about the findings in an EEG, the clinician interprets, or at least recalls, the EEG without this equivocation. When there is a lack of recall of an equivocal report, the clinician's error is usually in the direction of considering that the record has been interpreted by the electroencephalographer as being abnormal.


LM-Ag and LSP--two different target antigens involved in the immunopathogenesis of chronic active hepatitis?

Two different types of immune reactions against liver membrane antigens have been described: firstly, cell-mediated immunity and autoantibodies against the liver-specific protein (LSP) in HBsAg-negative and HBsAg-positive chronic active hepatitis (CAH), and secondly, a liver membrane autoantibody (LMA) in HBsAg-negative CAH. Using 100,000 g supernatants of human and rabbit liver homogenates, the corresponding antigen of LMA could be separated by affinity chromatography on insolubilized LMA-positive sera from patients with HBsAg-negative CAH. A further characterization by crossed immunoelectrophoresis showed that LMA is directed against a soluble liver membrane antigen (LM-Ag) that is not a constituent of the purified LSP. LM-Ag seems to be species-unspecific and moves faster than LSP and serum albumin in crossed immunoelectrophoresis. While LSP is believed to be involved in the pathogenesis of HBsAg-negative and HBsAg-positive chronic active hepatitis, LM-Ag may be a target antigen only in cases of HBsAg-negative autoimmune CAH.


Autoimmune implications of immune complexes in clinical variants of hepatitis B.

Immune complexes (IC) were investigated in sera from 208 individuals with various clinical types of viral hepatitis diagnosed by clinical and laboratory criteria, including liver biopsy. Immune complexes were assessed by platelet aggregation (PI A) and by radioimmunoassay (RIA). The data were related to autoimmune phenomena (especially rheumatoid factors) and to the role that the IgM class of hepatitis B (HB) antibody might have in IC formation. Although the highest frequency of P1 A was in the few sera from patients with cirrhosis or hepatoma, the next highest was in sera from acute hepatitis patients (71%), and the lowest in sera from chronic active (57%) and chronic persistent (46%) hepatitis patients. A proportional number of patients with IC's were positive for hepatitis B surface antigen (HBs). A parallel prevalence was noted between P1 A and autoantibodies, with anti-Ig's being found more frequently in sera from acute hepatitis and chronic active hepatitis patients. The relationship between RIA results for complexes and RIA results for anti-IgG was inverse, as though anti-IgG interfered with IC reactivity by RIA. Anti-IgM pre-incubated with sera increased the amount of P1 A in sera from patients with acute hepatitis as well as in those from patients with chronic persistent hepatitis, suggesting a more frequent IgM involvement in IC's in these diseases than in chronic active hepatitis. Whereas liver cell damage in acute and active hepatitis may reflect elevated autoantibodies, the IgM class of HBs antibody may be involved in acute as well as chronic persistent hepatitis.


Circulating immune complexes in acute schistosomiasis.

The sera of patients with acute and chronic schistosomasis were tested for the presence of circulating immune complexes with the 125I-Clq binding assay. Fourteen out of fifteen (93%) patients with acute schistosomiasis had elevated 125I-Clq binding activity, while only two out of eleven (18%) patients with chronic disease had C1q binding complexes. This difference was significant (P less than 0.001) and paralleled the degree of clinical didsease activity between the two groups of patients. IgG and IgM were readily detected in all of these circulating complexes but the specific parasite antigens initiating their formation could not be defined. The level of circulating immune complexes was inversely correlated with the absolute eosinophil counts for individuals in the acutely infected group, an observation compatible wiht the hypothesis that a functional role for the eosinophil is the destruction and elimination of immune complexes.


Predominance of immunoglobulin G sub-class 3 among the complement-fixing antibodies to streptococcal M-associated protein.

During investigation of the absorption of group-A streptococcal antibodies from human sera by a protein A-positive Staphylococcus aureus strain, we found that the complement-fixing antibodies to M-associated protein (MAP) were only partially absorbed from the majority of sera tested, although they were shown to belong to the immunoglobulin G (IgG) class by density gradient centrifugation. In contrast, other streptococcal antibodies: anti-streptolysin O (ASO), anti-deoxyribonuclease B (anti-DNAase B), 'bactericidal' M antibody and anti-opacity factor (anti-OF), were completely absorbed from all but a minority of sera. We suggest that the complement-fixing antibodies to MAP may be of restricted heterogeneity and have an abnormal IgG sub-class distribution, with a marked predominance of IgG3 (the only sub-class that does not interact with protein A) over the IgG1 and IgG2 sub-class; IgG4 does not participate in complement fixation. The concentration and relative porportions of IgG sub-classes are believed to be genetically influenced, so our findings may have some bearing on the immune responsiveness of different individuals to streptococcal infection, and possibly have important implications in the development of the secondary sequelae.


Lack of immunoglobulin E response to longstanding strongyloidiasis.

Patients harbouring worm infections usually have very marked elevations of serum immunoglobulin E (IgE) concentration. However, in a group of twenty ex-Far East prisoners of war with strongyloidiasis only two (10%) had raised levels due to the worm, and these were only moderately elevated. This poor IgE response may be related to the very longstanding nature of the infection (at least 30 years). The patients may have a form of immunological incompetence, or may have become immunologically tolerant to the parasite.


Purification of soluble immune complexes from serum using polymethylmetacrylate beads coated with conglutinin or C1q. Application to the analysis of the components of in vitro formed immune complexes and of immune complexes occurring in vivo during leishmaniasis.

A procedure for the isolation of immune complexes from human sera has been developed. Two steps are involved: (1) lipid-free serum is precipitated by polyethylene glycol; (2) the solubilized precipitate is absorbed on a column of polymethylmethacrylate beads coated with conglutinin (K) or C1q; the column is washed, the complexes are then eluted, using 0.02 M EDTA (for K column) or 0.5 M NaCl (for C1q column). This procedure permitted the purification and the characterization of soluble 125I-BSA-anti-BSA, 125 I-tetanus toxoid-anti-tetanus toxoid, and 125-I-HBsAg-anti-HBsAg complexes made in vitro in the presence of fresh human serum. The isolated complexes were shown to contain antigen, antibody, C1q, C1r, C1s and C3. When normal human serum was submitted to such a procedure, no detectable amount of protein was present in the final eluted fraction. Immune complexes formed in vivo were also purified by conglutinin column from the serum of a patient with disseminated leishmaniasis. The isolated material was found to contain IgM, IgG, C1q, C1r, C1s, C3c and C3d. The purified complexes dissociated at acid pH were found to contain anti-IgG and anti-leishmania antibodies.


Lymphocyte transformation to phytohaemagglutinin and delayed hypersensitivity related to age and previous cancer history.

Declining immunosurveillance in old age has been considered one possible explanation for the increased incidence of cancer in the elderly. This study was set up to search for evidence of persistent immunodeficiency in patients with a past history of cancer. Lymphocyte responses to phytohaemagglutinin and cutaneous delayed hypersensivity were assessed in fifty-seven elderly subjects who had successfully completed treatment for cancer more than 18 months previously and compared with those of forty-three healthy controls matched for age and sex. Although a significant difference between mean tritiated thymidine uptake was observed in the lymphocyte response to phytohaemagglutinin (cancer patients 1859 cpm, control 2502 cpm), this could be explained by an unexpectedly prolonged effect of radiotherapy. Mean counts for those twenty-six cancer patients receiving radiotherapy within the period 18 months to 4 years were low (1257 cpm), but were normal (2366 cpm) for the remainder. A significant negative correlation of lymphocyte transformation with age was confirmed in both groups. There was no significant difference in cutaneous delayed hypersensitivity response to commonly encountered antigens. Whilst recognising that these tests do not comprehensively assess immune function, the present results provide no support for the theory that an age-related decline in immune function contributes to the heightened incidence of cancer in the elderly.


Extracellular fluid distribution in rats with chronic one- and two-kidney Goldblatt hypertension.

1. The influence of the intact kidney on blood pressure, extracellular fluid volume (ECF, ferrocyanide space) and ECF volume distribution was studied in rats 60 days after constriction of the contralateral renal artery. 2. Renal artery constriction increased both blood pressure and ECF levels. The rise of both variables was more pronounced in rats with the contralateral kidney removed (one-kidney rats) than with the contralateral kidney intact (two-kidney rats). 3. The interstitial fluid volume increased similarly in both experimental groups, the more pronounced ECF increase in the more severly hypertensive one-kidney rats being due to increased plasma volume. In the less hypertensive two-kidney group the plasma volume was not increased significantly but correlated positively with the blood pressure levels. 4. The plasma volume/interstitial fluid volume ratio was decreased in the two-kidney group but did not differ from control values in the one-kidney group thus resembling the ECF partition reported in the hypo-and hypervolaemic type of essential hypertension, respectively. 5. It is suggested that the antihypertensive influence of the intact kidney may be partly due to its ability to escape from the sodium-retaining mechanism activated by renal artery stenosis, which determines the degree of plasma volume expansion and, in connection with this, also the degree of blood pressure elevation.


Comparison of the bronchodilator and vasodilator activity of sodium azide and sodium nitroprusside in the guinea-pig.

1. Sodium azide and sodium nitroprusside are potent dilators of the intact guinea-pig tracheal preparation in vitro. 2. Both substances are bronchodilators in the anaesthetized guinea-pig in vivo when administered intravenously or by aerosol inhalation. 3. Sodium azide and sodium nitroprusside are also potent vasodilators in the guinea pig. 4. At all doses and by route of administration, including aerosol inhalation, the hypotensive effect predominates over bronchodilatation.


The interaction of cigarette smoking and chronic drug ingestion on human drug metabolism.

1. Drug metabolism was assessed by the disappearance rate of antipyrine as measured in saliva. Results were expressed in terms of both clearance and half life. 2. Basal measurements of antipyrine disappearance rate were performed in seven non-smokers and six smokers. After administration of glutethimide 250 mg daily for 7 days a second measurement of antipyrine disappearance rate was made. 3. Glutethimide enhanced antipyrine metabolism in both smokers and non-smokers. The degree of change in both groups was similar. 4. A similar study was carried out with a smaller dose (125 mg) of glutethimide. There was no significant difference between smokers and non-smokers.5. The data are consistent with smoking and chronic drug ingestion having additive effects on enhancement of hepatic drug metabolism.


Hepatic microvascular effects of terbutaline in experimental cardiogenic shock in rats.

1. Experimental myocardial infarction was produced in rats by direct electrical cauterization of the myocardium of left ventricle. This produced cardiogenic shock with the accompanying haemodynamic changes of low cardiac output, low mean arterial pressure, raised central venous pressure and an absence of cardiac arrhythmias. 2. The liver microcirculation was observed using in vivo television microscope method. The diameter and erythrocyte flow velocity in the liver sinusoids were measured quantitatively. 3. During experimental cardiogenic shock 80% of the liver sinusoids were constricted; the remaining 20% showed dilatation. In all these liver sinusoids the erythrocyte flow velocity was only 50% of the pre-shock level. 4. Intravenous injection of the selective beta 2-adrenoceptor agonist terbutaline (0.15 mg/kg) restored the systemic arterial pressure to pre-shcok levels and partially raised the cardiac output. In the liver microcirculation terbutaline restored both constricted and dilated liver sinusoids to pre-shock calibres, but only partially raised erythrocyte flow velocity. 5. It is proposed that during experimental cardiogenic shock, terbutaline produces dilatation in the terminal liver microcirculation by opening sphincters of liver sinusoids and restores sinusoid diameters to pre-shock calibres. Therefore, terbutaline has the capacity to decrease peripheral resistance and unload the circulation during cardiogenic shock.


The effect of (-)-trans-delta 9-tetrahydrocannabinol on regional brain levels and subcellular distribution of monoamines in the rat.

1. The effect of intravenously injected delta 9-tetrahydrocannabinol (delta 9-THC, 2 mg/kg) on subcellular distribution in the whole brain and the regional brain levels of noradrenaline, dopamine, serotonin and 5-hydroxyindoleacetic acid were determined in the rat. 2. The levels of noradrenaline and dopamine were not altered by delta 9-THC in the hypothalamic, medullary and rest of brain areas, whereas those of serotonin and 5-hydroxyindoleacetic acid were elevated in the medullary and hypothalalmic areas, respectively. 3. delta 9-THC did not alter the levels of these monoamines and the metabolite 10 min after injection; however, there was a shift of dopamine from the bound to the free fraction. On the other hand, there was a shift of 5-hydroxyindoleacetic acid from the free to the bound fraction. 4. After 1 h, there was no difference in the subcellular ratios of noradrenaline, dopamine, serotonin and 5-hydroxyindoleacetic acid were increased. 5. It is suggested that the effects of delta 9-THC may be mediated by modification of the subcellular distribution of dopamine and serotonin.


The inhibitory innervation of the guinea-pig trachea: a study of its adrenergic and non-adrenergic components.

(1) Inhibitory responses to field stimulation have been determined in strip preparations from the thoracic, middle and cervical regions of the trachea and in the tracheal tube preparation. (2) The adrenergic neurone blocking drug guanethidine was found to cause a partial reduction of the amplitudes of the responses in all preparations. (3) The guanethidine-resistant inhibitory responses were resistant to pentolinium but were abolished by tetrodotoxin. The data favours the existence of non-adrenergic inhibitory intramural nerves in the guinea-pig trachea. (4) Inhibitory responses have been determined in the presence and absence of guanethidine at frequencies ranging from 2 to 60 Hz. This has enabled the combined responses to stimulation of both adrenergic and non-adrenergic nerves to be compared with the response to stimulation of non-adrenergic nerves alone at each frequency and in each preparation. (5) The contribution of each innervation to the combined inhibitory response was frequency dependent. The adrenergic innervation was more effective at lower frequencies and the non-adrenaration is discussed. Its origin is considered.


Chronotropic incompetence in exercise testing.

Patients with chronotropic incompetence, defined as a failure of the heart rate response to exercise to rise to within two standard deviations of the expected increase with exercise, where studied and compared to patients with known coronary disease by angiogram with and without ST segment depression. 72% of the patients with chronotropic incompetence but without ST depression had significant coronary heart disease. The demonstration of chronotropic incompetence in exercise testing has important predictive implications and should be looked upon as carefully as ST segment changes. There was no evidence of SA node ischemia in these patients. Intrinsic heart rate measurements done in this study suggest autonomic dysfunction as a possible pathophysiologic mechanism for chronotropic incompetence. The heart rate response to exercise may be a useful predictor of the presence and severity of coronary disease. Therefore, a predicted heart rate response with standard deviation for age and sex should be included as part of the stress test protocol.


Angina, aortic stenosis and coronary heart disease.

The pre-operative clinical and haemodynamic findings of 139 consecutive patients with aortic stenosis were analysed in an attempt to determine the incidence and influence of coronary heart disease on the mode of presentation of patients with aortic stenosis. The overall incidence of coronary heart disease was 32%. 105 patients (76%) presented with angina and of these, 41 patients (39%) had significant coronary heart disease as compared to 4 (13%) of the remaining 34 patients who did not present with angina. Clinical parameters including age, sex, severity of angina together with the presence of associated symptoms and precipitating factors were unhelpful in distinguishing those patients with coronary heart disease. Evidence of previous transmural myocardial infarction or the presence of ST-T abnormalities in the absence of digitalis and the changes of left ventricular hypertrophy were reliable electrocardiographic signs of coronary heart disease. Although peak systolic aortic valve gradient tended to decrease with increasing severity of coronary heart disease, the severity of aortic stenosis was not a reliable indicator of the presence of coronary disease. Patients with coronary heart disease in the absence of angina all had a combination of moderate aortic stenosis and single vessel disease. It is concluded that coronary heart disease cannot be predicted in patients with angina and, in the absence of angina occurs with an incidence sufficiently high to advocate the use of coronary angiography as part of the investigation of all patients with aortic stenosis being considered for valve replacement.


Indication and clinical significance of exercise surface mapping.

A technique of recording electrocardiographic maps after exercise is described. This technique allows a measurement to be made of the area of ST segment changes that are projected onto the front of the chest after exercise. A comparison of the sensitivity and specificity of this technique with the orthogonal lead system and a single chest lead showed that praecordial exercise mapping was significantly superior to the other two lead systems in the diagnosis of ischaemic heart disease and may help in identifying patients with extensive disease. In addition information obtained from praecordial exercise mapping can be used to increase the data that are obtained from Holter monitoring of ST segments. The place of the technique in the management of medical and surgical treatment remains to be evaluated.


Electrophysiological and haemodynamic effects of a new inotropic agent (UK14275) in the dog.

1. Electrophysiological and haemodynamic effects after intravenous administration of a new inotropic agent (UK14275) have been examined in open-chest dogs under pentobarbitone anaesthesia. 2. UK14275 produced slight shortening of QT interval, ventricular functional refractory period and atrio-ventricular conduction time but did not affect action potential duration or endocardial-epicardial conduction time. 3. Cardiac output and left ventricular dP/dt increased, and systemic vascular resistance fell. 4. An end-systolic pressure gradient developed between left ventricle and aorta attributable to left ventricular cavity obliteration.


Reversibility of the toxicity of methotrexate by dihydrofolate in mice.

1. Dihydrofolate in mice can reverse the toxicity of a lethal dose of methotrexate. 2. The 'rescue' of mice after a lethal dose of methotrexate suggests that dihydrofolate could have a clinical use as an antidote in treating methotrexate-induced toxicity.


Structure-activity relationships of met5- and leu5-enkephalin analogues.

1. The effect of various analogues of met5- and leu5-enkephalin were determined on the reduction in twitch height of the electrically-stimulated longitudinal muscle preparation of the guinea-pig ileum and of the isolated mouse vas deferens. 2. In the guinea-pig ileum, D-alanine2-met5-enkephalin was the most potent whereas leu5-enkephalin was the most potent in the mouse vas deferens. 3. The met5-enkephalin analogues were more effective in reducing the twitch height of the ileum than they were in depressing that of the vas deferens preparation. The leu5-enkephalin analogues were more potent in their effects on the mouse vas deferens than they were on the guinea-pig ileum. 4. When a peptide bond is replaced by a glycol bond as in glycol2-3-leu5-enkephalin there is a marked reduction in opiate-like activity. 5. Substitution of a D-alanine residue for the glycine2 residue, as in D-alanine2-met5-enkephalin, increases the duration and potency of opiate-like activity. 6. These results confirm that modification of either met5- or leu5-enkephalin can alter the opiate-like potency of the resulting analogues. It appears that an intact tyrosyl residue of leu5-enkephalin is essential for such activity and that substitution of a D-alanine2 residue for the glycine2 residue confers resistance to enzymatic degradation on the met5-enkephalin peptide. In addition, the glycine2-3 peptide bond is essential for opiate-like activity.


Prodromal characteristics as indicators of cardiac events in patients hospitalized for chest pain.

In an effort to determine the usefulness of prodromata for predicting a myocardial infarction, a prospective analysis was made of 211 consecutive patients with chest pain who were admitted to the Stanford University Medical Center Coronary Care Unit. In their subsequent course, 91 patients had a myocardial infarction, 102 had a myocardial infarction ruled-out, and 18 had a noncardiac etiology for their chest pain. Prodromal chest pain in the previous six months had occurred in 65% of patients and unstable angina in 61%. Infarction versus noninfarction patient groups could not be identified on the basis of prodromal ill health, chest pain, unstable angina, typical versus atypical nature of the chest pain, or activity at the onset of pain. Complaints of preceding fatigue and increased perceived stress were common in both groups. Activity at the onset of the admission chest pain was strenuous in 15% of the infarction patients and 12% of the noninfarction patients. We conclude that prodromal symptoms are common in both infarction and noninfarction patients. Although chest pain probably remains the single most frequent identifier of a new cardiac event, it is common in noninfarction patients and cannot be used alone to predict infarction or death.


A previously unrecognized drug interaction between quinidine and digoxin.

Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.


Coronary ostial embolus and mitral vegetation simulating a left atrial myxoma: a case of probable cryptococcal valvulitis.

A 56 year old man died with disseminated cryptococcosis after immunosuppressive therapy for a hematologic disorder of unknown etiology. The immediate cause of death was cardiogenic shock, probably resulting from a large right coronary ostial embolus and subsequent ischemic myocardial injury. The embolus originated from a bulky mitral vegetation (possibly cryptococcal) demonstrated ante mortem by echocardiography and cardiac angiography, and at autopsy. The differential diagnosis of such an echocardiographic pattern is discussed.


Aneurysm of the left atrial appendage.

A 2-year old asymptomatic girl is presented in whom the chest x-ray film led to the discovery of a grossly distorted cardiac shadow. Angiocardiography showed a giant aneurysm originating from the left atrium. At operation an intrapericardial aneurysm of the left atrial appendage, measuring 12 X 4 X 4 cm, was found. It communicated with the left atrium through an orifice measuring 3 cm. The aneurysm was excised.


Systolic honk in heart failure: its origin and mechanism of production.

Systolic honks have so far been synonymous with prolapse of the mitral valve leaflet. Evidence of tricuspid valve involvement in two cases is presented. These patients developed systolic honk during the deterioration of their congestive heart failure. Simultaneous recordings of echocardiograms and phonocardiograms showed fluttering of the tricuspid valve, coinciding with the systolic honk. This fluttering was not seen when honk was absent. The mechanism of production of this honk is discussed.


Anatomy of the forefoot, normal and pathologic.

The metatarsophalangeal joints divide the forefoot as a lever for the push-off into two segments. The proximal segment is used for the first antigravitational phase, and the distal is added when the foot has gained speed. The ligaments of the ball of the foot are tied to the distal segment and are in their function dependent on free mobility of this segment. Thus, for the kinematics of the foot, for the stability of the arches, and for the ability of the skin to withstand shear forces, it is important to select a shoe that does not compress the toes, restrict their movements unnecessarily or expose the metatarsal heads to uneven pressure.


Transcutaneous Doppler ultrasound in the prediction of healing and the selection of surgical level for dysvascular lesions of the toes and forefoot.

Dysvascular lesions of the toes and forefoot are divided into 5 grades and matched with appropriate treatment programs. Patients with diabetes mellitus and arterosclerosis obliterans make up the greatest number presenting with such problems. Transcutaneous Doppler ultrasound has been added to clinical criteria as an aid in the prediction of healing. Systolic blood pressures are taken at the thigh, knee, calf, ankle, foot and toes using transcutaneous Doppler ultrasound as a sensitive stethoscope. Systolic blood pressure taken at the antecubital fossa is divided into the lower extremity pressures to obtain an ischemic index. Healing can be predicted with 90% or better accuracy where the ischemic index is above 0.35 in the arteriosclerotic foot and above 0.45 in the diabetic foot.


Ipsilateral fracture of the femur and tibia treated in a quadrilateral cast brace.

In 15 patients traction followed by cast brace was an acceptable method of treatment for ipsilateral fractures of the tibia and femur. Prolonged healing times and limited range of motion of the knee were not significant problems. This method of treatment is especially indicated in patients with severe open injuries or comminution of femoral shaft fractures which do not safely lend themselves to rigid internal fixation. The hospitalization time, 5 weeks, is considerably less than for spica cast treatment of femoral shaft fractures and is comparable to that reported for open reduction and rigid fixation of femoral shaft fractures.


Chronic anteromedial instability of the knee.

This is a review of 26 patients with 2 or more years of knee pain or giving way or both in whom the most striking clinical finding was moderate or marked anteromedial instability. Of 27 knees, more than 15 responded favorably to a thigh-muscle-strengthening program. The Lenox Hill brace proved to be a useful adjunct in 9 patients.


Bilateral traumatic rupture of the infrapatellar tendon.

This is a case report and discussion of the traumatic lesion of bilateral rupture of the infrapatellar tendon in a 52-year-old man. This injury is very rare and seems not to have been previously documented. The treatment consists of surgical repair and cast immobilization. Bilateral rupture of the infrapatellar tendon should be suspected when after injury a patient is unable to actively extend his knee.


The Synovial shelf syndrome.

A syndrome complex mimicking a tear of the anterior horn of the medial meniscus consists of absence of effusion with negative arthrographic and arthroscopic examinations. Because of a thickened band of the medial synovial shelf this entity is termed the "medial synovial shelf syndrome."


Paget's disease of the patella.

Isolated Paget's disease of the patella occurred in a 44-year-old man, and included previously unreported complications of this disorder such as patellofemoral arthritis and elevated serum alkaline phosphatase.


An artificial ankle joint.

Ankle fusion has been the time-honored treatment for painful debilitating conditions of the ankle due to osteoarthritis and rheumatoid arthritis. It is not a uniformly successful operation and has a high complication rate. If there is pre-existing disease in the knee or midtarsal joints, the pain is frequently made worse by ankle fusion. If there is no pre-existing disease, then painful degenerative changes frequently occur in the midtarsal joints subsequently. An artificial ankle joint has been used successfully since 1973 in patients who otherwise would require ankle fusion. The design of the prosthesis allows unrestricted motion in all planes. It also allows imperfect placement of the device without compromising results. The dome of the talus is not resected during insertion of the prosthesis. Only 1 cm of distal tibia is resected, thus allowing fusion without difficulty should it later become necessary. The superior position of the polyethylene device decreases wear from particulate matter which might settle by gravity. Study of 50 total ankle arthroplasty cases shows that predictably good results can be obtained in ankles with good stability, reasonably normal anatomy, and rheumatoids who are not on long-term steroid therapy.


Surgery of the wrist in rheumatoid arthritis.

One hundred four patients with rheumatoid arthritis of the wrist were evaluated a minimum of 12 months post-operatively (average of 34 months). Seventy patients had 87 arthroplasties and 34 patients had 41 arthrodeses performed on the Arthritis Service of Rancho Los Amigos Hospital (Downey, California), from 1962 to 1975. Seventy-eight per cent of the arthrodeses fused, yet only 69% were painfree. Of the 22% that did not fuse, 67% were pain-free. Carpal and/or intercarpal synovitis recurred in 16% of the fused group and 33% of the nonfused group. Eighty-three per cent of the arthroplasties were pain-free, 91% were stable, and all lost motion which averaged 40 degrees (55%). Spontaneous fusion occurred in 16%). Synovitis recurred in 8.0%.


Wrist arthrodesis.

Arthrodesis of the wrist is an excellent procedure indicated only in carefully selected and evaluated cases. Eleven patients with various pathological lesions were treated by a modification of standard surgical techniques. Good stability and bone graft placement was secured by an easily removed internal fixation device. External immobilization was required for minimal periods of time. The end results were satisfactory.