Intraventricular conduction in man studied with an endocardial electrode catheter mapping technique. Patients with normal QRS and right bundle branch block. The sequence of intraventricular conduction has been studied in a total of 60 patients, 38 of whom had normal QRS morphology and 37 of whom had right bundle branch block (RBBB) either present continuously or produced as functional aberrant RBBB by the introduction of atrial premature depolarizations or by rapid atrial pacing. Activation times were measured by intracardiac electrode catheters positioned at the right ventricular inflow tract (RVIT), right ventricular apex (RVA), right ventricular outflow tract (RVOT), left ventricular apex (LVA) and left ventricular outflow tract (LVOT). The activation after beginning of QRS in milliseconds plus or minus 1 SD and the number of patients studied at each location were: RVIT--normal 23 plus or minus 13 (15 patients); RVIT-RBBB 49 plus or minus 16 (15 patients); RVA--normal 18 plus or minus 9 (28 patients); RVA-RBBB 54 plus or minus 16 (30 patients); RVOT--normal 40 plus or minus 10 (28 patients); RVOT-RBBB 78 plus or minus 21 (30 patients);LVA--normal 9 plus or minus 9 (18 patients); LVA-RBBB 6 plus or minus 10 (10 patients); LVOT--normal 45 plus or minus 13 (10 patients); LVOT-RBBB 32 plus or minus 9 (7 patients). Significant differences observed were: RVA-normal versus RVA-RBBB P smaller than 0.001; RVOT-RBBB P smaller than 0.001; RVA-normal versus LVA-normal P smaller than 0.005; LVA-normal versus LVA-RBBB NS, LVOT-normal versus LVOT-RBBB P smaller than 0.05. The LVOT change was unexpected and suggests changes in left ventricular depolarization may occur when right bundle branch block develops. In patients with RBBB the activation of the RVA (r equals 0.82) and of the RVOT (r equals 0.68) was directly related to the duration of QRS. Changes in activation time when RBBB was induced by rapid atrial pacing or by introduction of atrial premature depolarizations were: RVA (7 patients) 19 plus or minus 11 to 56 plus or minus 16 (P smaller than 0.001); RVOT (9 patients) 41 plus or minus 10 to 77 plus or minus 22 (P SMALLER THAN 0.001); LVA (5 patients) and LVOT (2 patients), small insignigicant changes. These data indicate that endocardial activation changes can be evaluated in the catheterization laboratory, that right ventricular conduction becomes slower in RBBB as a direct function of total QRS and that left ventricular conduction may be affected when RBBB develops.


Corrected sinus node recovery time. Experimental physiologic and pathologic determinants. To determine the factors affecting reproducibility of sinus node recovery time, the effects of basic pacing rate, pacing duration, milliamperage, vagal and beta-adrenergic stimulation, and sinud node injury, as well as its instantaneous and daily reproducibility, were studied in 36 anesthetized dogs. Corrected sinus node recovery time (CSNRT) showed a mean variation of 9.8 plus or minus 0.4 msec at an atrial pacing rate of 200 beats/min and 29.8 plus or minus 8 msec at an atrial pacing rate of 140 beats/min (P smaller than 0.05). CSNRT increased progressively from 55.4 plus or minus 10 msec to 103.7 plus or minus 13 msec with increase in pacing rate from 140 beats/min to 200 beats/min. It was reproducible when atrial pacing was carried out for 1-5 min, although a wide variation (10-30 msec) was seen from 7-60 minutes (P smaller than 0.05). This measurement was reproducible on two consecutive days and was unaffected by changes in milliamperage. Vagal stimulation consistently prolonged the CSNRT while beta-adrenergic stimulation decreased it from 132.9 plus or minus 34.5 msec to 50.0 plus or minus 6.5 msec. Sinus node injury consistently prolonged CSNRT at all paced rates. In summary, CSNRT is reproducible only if the same pacing rate and duration are utilized. Since vagal stimulation and sinus node injury prolong this measurement while beta-adrenergic stimulation shortens it, an "abnormal" CSNRT should be assessed in terms of the possible influence of the autonomic nervous system as well as sinus node dysfunction per se.


Extracardiac recordings of His-Purkinje activity during conduction disorders and junctional rhythms. Previous investigations have demonstrated a surface recording technique using signal averaging to detect electrical activity during the "isoelectric" P-R segment. Various physiological and pharmacological interventions suggest that the source of these potentials isthe His-Purkinje system (HPS). In order to assess the sensitivity of averaged recordings to changes in HPS activation, i.e., conduction defects in the HPS recordings were made directly from the heart surface using a bipolar, anterior-posterior epicardial lead in 15  dogs which underwent thoractomy. The signal was amplified, filtered and averaged using a digital computer for purposes of signal enhancement. The epicardial averaged lead (EAL) contained activity coincident with HPS depolarization and similar to those recorded by leads on the body surface of intact dogs from previous studies. The standard ECG and His bundle electrogram from an electrode catheter served as references in localizing and assessing several conduction disorders experimentally produced by traumatic and ischemic injury. Among the disorders produced were: 1) atrioventricular (A-V) nodal block which resulted in loss of recorded activity in the EAL following the P wave. 2) First and second degree intra-His bundle block produced by anterior septal artery ligation showed split His potentials in the HBE (1 degree) and 2:1 conduction with block in the His bundle (2 degrees). In the blocked beats the EAL showed a reproducible portion of the activity coincident with proximal His bundle activity of the split His potentials in both cases. 3) In four cases of proximal right bundle branch block produced by anterior septal artery ligation the relatively proximal portions of HPS activity in the EAL showed marked diminution. 4) Two cases of distal His bundle or bilateral bundle branch delay were seen as prolonged H-V time and a normal QRS pattern. The early and late portions of the HPS activity in the EAL were not markedly changed while the middle portion was prolonged and fractionated. 5) Junctional rhythms produced by crushing the SA node resulted in no atrial activity occurring prior to HPS depolarization in the EAL. However, the QRS was preceded by HPS activity whose onset was coincident with the H recorded in the His bundle electrogram. The EAL showed consistent and reproducible morphology and timing of HPS activity at different heart rates during normal conduction and consistent alterations of the HPS activity during abnormal conduction.


"Supernormal conduction" of a premature impulse utilizing the fast pathway in a patient with dual atrioventricular nodal pathways. Electrophysiological studies with atrial extrastimulus technique suggested the presence of dual atrioventricular (A-V) nodal pathways in a patient with hypothyroidism, as evidenced by a sudden increase of H1-H2 intervals at critical A1-A2 coupling intervals. Following the atrial extrastimulus (A2), a third impulse (A3) occurred spontaneously. During slow pathway conduction of A2, and A3, appearing at a critically timed interval allowed fast pathway conduction, resulting in an earlier than expected QRS (a form of supernormal conduction). This demonstration of fast pathway conduction during slow pathway conduction adds strong evidence for the existence of dual A-V nodal pathways.


Echocardiographic detection of tricuspid valve prolapse. The echocardiographic findings in 12 patients with tricuspid valve prolapse are presented. Eight of these patients had associated mitral valve prolapse. Only one of the above patients had the characteristic physical signs of tricuspid incompetence. Two types of abnormality were noted on the echocardiogram of the tricuspid valve. In eight patients, the systolic segment of the tricuspid valve showed an initial horizontal motion followed by a posterior motion in midsystole. Four patients exhibited posterior motion of the tricuspid valve in early systole, which reached a maximum in midsystole, and this was followed by an anterior motion, thus producing a hammock-like configuration. We conclude that echocardiography is useful in the diagnosis of tricuspid valve prolapse. Since this condition may be associated with clinically significant tricuspid incompetence or bacterial endocarditis, its recognition is of clinical importance.


Measurement of mitral orifice area in patients with mitral valve disease by real-time, two-dimensional echocardiography. A quantitative assessment of mitral valve orifice area can be achieved in patients with pure mitral stenosis by cardiac catheterization. In the presence of mitral regurgitation, however, accurate measurement often is impossible because total diastolic flow through the mitral valve frequently is unknow. Using a recently developed real-time, two-dimensional echocardiography system, we are able to obtain cross-sectional images of the mitral valve by scanning the heart perpendicular to its long axis at the level of the tip of the mitral leaflets. Twenty consecutive patients undergoing operation for mitral valve disease were studied during the week prior to operation. In 18 of 20 (90%) the mitral orifice was imaged successfully in early diastole by two-dimensional echocardiography so that mitral valve orifice area could be measured directly in square centimeters. In 14 patients (ten with associated mitral regurgitation), mitral orifice area was measured both by echocardiography and directly at time of operation. In 12 of 14 (86%) patients, mitral orifice area by two-dimensional echocardiography was within 0.3 square centimeters of that measured at operation (correlation coefficient for all 14 patients equals 0.92). We conclude that two-dimensional echocardiography is extremely useful in the evaluation of patients with mitral valve disease because it provides a noninvasive method for directly measuring the mitral valve orifice area that is accurate even in the presence of mitral regurgitation.


Echocardiography manifestations of flail aortic valve leaflets in bacterial endocarditis. This report describes the echocardiographic features seen in a case of bacterial endocarditis in which the aortic valve leaflets had been partially destroyed. The endocardiogram demonstrated unusual, disorganized echo patterns in the outflow tract of the left ventricle near the anterior leaflet of the mitral valve in diastole. These were shown to be continuous with similar disorganized echo patterns demonstrated in the aortic root in diastole. These echocardiographic abnormalities were no longer present after aortic valve replacement.


Echocardiographic demonstration of early mitral valve closure in severe aortic insufficiency. Its clinical implications. Severe aortic insufficiency may accelerate mitral valve closure. We noted this echocardiographic finding in several patients with the acute onset of severe aortic insufficiency. Accordingly, we examined our total echocardiographic series retrospectively for early closure of the mitral valve (ECMV) in the setting of aortic insufficiency and found it in 11 of 53 patients with confirmed aortic insufficiency. During our study ECMV was fortuitously found in two other patients without aortic insufficiency, ECMV occurred in late diastole following the echocardiographic "A" wave, often associated with s suppressed "A" wave (type "B" ECMV). ECMV presence and subtype, along with other clinical parameters, appeared to be useful in the serial evaluation of the patient with severe aortic insufficiency. Additionally, the analysis of ECMV type helped to clarify the mechanism and significance of the Austin Flint murmur. Analysis of 17 patients with and without ECMV, with severe aortic insufficiency judged clinically (NYHA functional class III or IV) and angiographically (3+), indicated that only ECMV patients had acute aortic insufficiency and demonstrated diminished left ventricular size following successful aortic valve replacement. Although due primarily to aortic insufficiency, ECMV could be influenced by rhythm or conducted abnormalities, co-existent cardiac lesions, and pharmacologic interventions. Exclusive of these factors, ECMV was an excellent sign of acute, torrential aortic insufficiency, and a simple noninvasive indicator of the patient requiring immediate aortic valve replacement.


Variability of echocardiographic discontinuity in double outlet right ventricle and truncus arteriosus. The widespread application of echocardiography to the field of congenital heart disease has led to the development of a concept of "echocardiographic discontinuity" for the diagnosis of some conditions. Although this is a valuable sign in differentiating such entities as tetralogy of Fallot, truncus arteriosus and double outlet right ventricle, the reported cases illustrate that the echocardiographic recognition of discontinuity may be complicated by technical factors. In addition, the differential diagnosis must include truncus arteriosus with coexistence of anterior and posterior discontinuity.


Cardiac specific creatine phosphokinase isoenzyme in the diagnosis of acute myocardial infarction. The specific and sensitivity of serum creatine phosphokinase cardiac specific isoenzyme (MB) in the diagnosis of acute myocardial infarction (AMI) was evaluated. An ion-exchange chromatographic technique was used to isolate MB. Sera layered on mini-columns of DEAE-Sephadex were eluted with Tris-buffered sodium chloride. Quantification of isolated MB was performed by creatine phosphokinase (CPK) assay (Rosalki method) of column effluents. MB was expressed as a percentage of the simultaneously determined total serum CPK; MB was determined in 100 consecutive admissions to the Coronary Care Unit. Acute myocardial infarction was diagnosed by accepted criteria. In 47 patients with proven AMI, including three with normal total CPK, peak MB was greater than 4% of total CPK. In 49 patients without AMI, including 15 with elevated total CPK (due to trauma, injections, cardioversion), peak MB was less than 2% of total CPK. MB was elevated, but did not peak in four patients without AMI but with chronic atrial fibrillation. Isolation and quantification of MB by this technique is rapidly and easily performed and provides a specific and extremely sensitive tool for the diagnosis of AMI.


Time course and zonal variations of ischemia-induced myocardial cationic electrolyte derangements. Myocardial cationic electrolytes were determined at regular time intervals up to 24 hours after coronary artery ligation in the dog. Replicate electrolyte ratios were computed for different areas of the heart at each time interval. For purposes of statistical analysis, ratios from two border areas and four areas remote from the infarct were pooled as values for ZONE B and ZONE N, respectively, and compared with those from the infarct proper, ZONE I. Ischemia-induced tissue Mg++/Ca++ changes paralleled those of K+/Na+ with respect to time course and zonal variations. In ZONE I, both K+/Na+ and Mg++/Ca++ fell precipitously during the first hour, and the falls became more gradual thereafter, approac hing those of extracellular fluid at 24 hours. Changes in ZONE B, which appeared normal histologically, followed a similar downward trend but differed in magnitude from those in ZONE I (P smaller than 0.01). Changes in ZONE N were small but did not always overlap values in sham-operated dogs. It was concluded that lowered tissue K+/Na+ and Mg++/Ca++ were sensitive, but not specific, indices of myocardial ishemia, and multiple samplings of ionic ratios were essential for proper interpretation of ischemia-induced myocardial electrolyte derangements.


Early onset of pulmonary vascular obstruction in patients with aortopulmonary transposition and intact ventricular septum. Of 29 patients with aortopulmonary transposition with intact ventricular septum who underwent cardiac catheterization as neonates, five subsequently developed increased pulmonary vascular resistance at an early age (7 months to 2 1 2 years). The resistance was high in two patients (11.0 and 12.9 units (U)/m-2), moderate in one (5.5 U/m-2) and mild in two (3.6 and 4.6 U/m-2). The two patients with the highest resistances died as a result of the pulmonary vascular obstruction and it was probably a contributing factor in the death of a third patient. The finding of pulmonary vascular obstruction at an early age in five of 29 patients with transposition of the great arteries with intact septa is noteworthy. It assumes even greater significance as the measurement methods tend to underestimate pulmonary vascular resistance. The possible errors in assessing pulmnary vascular resistance and factors possibly contributing to early development of pulmonary vascular obstruction are discussed.


Nontraumatic determination of left ventricular ejection fraction by radionuclide angiocardiography. Previous reports have suggested that left ventricular ejection fraction can be assessed by recording the passage of peripherally administered radioactive bolus through the heart. The accuracy and validity of this technique were examined in 20 patients undergoing diagnostic cardiac catheterization. 99m-Tc-human serum albumin was injected via a central venous catheter into the superior vena cava and precordial activity recorded with a gamma scintillation camera interfaced to a small digital computer. A computer program was designed to generate time-activity curves from the left ventricular blood pool and to calculate left ventricular ejection fractions from the cyclic fluctuations of the left ventricular time-activity curve which correspond to left ventricular volume changes during each cardiac cycle. The results correlated well with those obtained by biplane cineangiocardiography (r equals 0.94) and indicated that the technique should allow accurate and reproducible determination of left ventricular ejection fraction. The findings, however, demonstrated that the time-activity curve must be generated from a region-of-interest which fits the left ventricular blood pool precisely and must be corrected for contributions arising from noncardiac background structures. This nontraumatic and potentially noninvasive technique appears particularly useful for serial evaluation of the acutely ill patient and for follow-up studies in nonhospitalized patients.


Alterations in preload and ejection phase indices of left ventricular performance,. Ejection phase indices such as mean velocity of circumferential fiber shortening (V-cf), ejection fraction (EF), and mean normalized systolic ejection rate (MSER) are thought to reflect the level of left ventricular (LV) inotropic state. Although known to be influenced by changes in afterload, their response to altered preload is less certain. This question was examined in ten normal subjects studied in the supine position and after 10 min of 75 degree head-up tilt. Echo VL diameter (D) and carotid pulse recordings were used to calculate LV ejection time, V-cf, MSER, LV end-diastolic and stroke volumes (EDV and SV, by D3 formula), and ejection fraction. Systemic blood pressure (BP)was measured by cuff, and heart rate (HR) counted from the ECG. Calculated LVEDV decreased with tilt (115 plus or minus 8 to 82 plus or minus 7 ml, P smaller than 0.001), as did SV (81 plus or minus 6 to 54 plus or minus 6 ml, P smaller than 0.001), and ejection time (0.31 plus or minus 0.01 to 0.27 plus or minus 0.00 sec, P smaller than 0.001), but there was no significant change in systolic or diastolic BP or HR. V-cf, EF, and MSER were not singificantly altered by tilt (1.09 plus or minsu 0.04 to 1.12 plus or minus 0.05 circ/sec; 0.70 plus or minus 0.02 to 0.65 plus or minus 0.02; and 2.29 plus or minus 0.07 to 2.43 plus or minus 0.08 end-diastolic volumes/sec, respectively). V-cf, MSER, and EF appearrelatively unaffected by acute alterations in preload. That compensatory sympathetic responses blunted potential changes cannot be excluded, although HR was not found to have increased.


Plasma dopamine-beta-hydroxylase activity in oral contraceptive hypertension. A prospective study was undertaken to evaluate the relative contribution of changes in sympathetic nervous system activity, as reflected by changes in dopamine-beta-hydroxylase (DBH) activity, to the pathogenesis of oral contraceptive-induced hypertension. Precontraceptive and serial post contraceptive determinations of blood pressure, plasma renin activity (PRA), DBH activity, and changes in body weight were obtained in twelve control patients and forty-one oral contraceptive users. Forty-four percent of oral contraceptive users had increases in blood pressure but remained normotensive and 17% became frankly hypertensive. The precontraceptive and average post contraceptive levels of mean arterial pressure (MAP), PRA and DBH activity in each patient were compared using paired group analysis. Control patients (group I) exhibited no significant changes in these variables, while the patients with contraceptive-induced increases in MAP (groups III and IV) underwent significant, parallel increases in DBH activity. Finally, the linear regression of changes in MAP on the percent change in DBH activity was examined. The positive slopes in groups III and IV differed significantly from the negative slope of the controls (group I). The data have been interpreted to reflect an inappropriate oral contraceptive-induced stimulus to sympathetic nervous system activity, leading to increases in MAP in susceptible individuals.


Radioisotopic bolus technique as a test to detect circulatory deficit associated with cerebral death. 142 studies on 80 patients demonstrating the bedside use of an innocuous IV procedure as an adjunct in the diagnosis of cerebral death. A portable radioisotopic technique was developed to demonstrate cerebral circulatory deficit, as part of a collaborative study to define and diagnose cerebral death simply and rapidly, in comatose, apneic patients with electrocerebral silence. The method involves an intravenous injection of 2mCi of 99mTcO4, and recording time/activity curves over the cranial cavity and a femoral artery simultaneously, using twin probe radioisotope detector equipment. Eight comatose, apneic patients had 142 studies in conjunction with clinical electroencephalographic and other laboratory evaluations. The results indicate that the absence of a bolus tracing from the head, as contrasted to the usual bolus seen is indicative of significant circulatory deficit to the cerebrum. This test may be used as an adjunct in confirming the diagnosis of cerebral death. A normal bolus tracing should be simultaneously observed over a femoral artery and this is used as a control. The method is safe and simple and offers significant information about the irreversibility of cerebral blood flow. Although further studies are indicated, the method appears to be most promising as a fundamental bedside laboratory test in the diagnosis of cerebral death in conjunction with other clinical and laboratory criteria.


Prosthetic aortic valvular endocarditis. Infective endocarditis (IE) continues to be one of the most serious complications following cardiovascular surgery, particularly that for replacement of valves. In order to define more clearly the clinical course and the role of surgical therapy, clinical and necropsy data were reviewed in 16 adult patients with prosthetic aortic valvular endocarditis (PAVE) and compared with the experience cited in the literature. Positive blood cultures were obtained in each of the patients with bacterial endocarditis. Gram positive bacteria predominate and the onset of infection is usually later than 25 days postoperatively. In 11 of 16 patients, aortic insufficiency was recognized. Autopsy material demonstrated large perivalvular abscesses which loosened the attachment of the prosthetic valve in each case and which made successful operation unlikely. Aortic insufficiency appears to be of prognostic importance, since patients who developed aortic insufficiency early in the course of PAVE died. Survivors included patients who made an excellent response to medical therapy and who either did not develop aortic insufficiency or developed aortic insufficiency either late in the course or even after cure of PAVE, Poor response to medical therapy and progressive aortic insufficiency even in the absence of left ventricular failure appear to be indications for prompt surgical replacement of the prosthetic aortic valve.


Observations on the heat stability and electrophoretic pattern of alkaline phosphatases extracted from various tissues. Various tissues were extracted with either normal saline or heat inactivated serum (HIS) and the heat stability and electrophoretic migration of the alkaline phosphatase enzymes (AP) of the extracts were compared to the heat stability and electrophoretic properties of serum AP. The electrophoretic pattern of HIS extracts of liver and bone differed from that of saline extracts but the pattern was unaffected if HIS was added to the saline extracts. The heat stabilities of the tissue AP also differed depending on whether they were extracted with saline or HIS. However, serum AP heat stability can help differentiate between liver and bone disease. It is concluded that the comparison of serum and tissue AP heat stabilities or the comparison of serum and tissue AP electrophoretic patterns as criteria for identification of the tissue source of the serum enzyme may be misleading since both these parameters vary, depending on the medium used for extracting the tissue and the extract(s) may contain a mixture of enzymes different from that in serum. It is further concluded from the electrophoretic studies on tissue AP that the increased serum AP in patients with hepatobiliary disease was unlikely to be due to regurgitation of bile but due to increased synthesis and release of alpha 1 and alpha 2 AP isoenzymes from liver, bile ducts or gall bladder. In patients with bone disease the increased serum AP is derived from bone. The source of the serum AP of "normal" subjects may be either liver or vascular tissue or both.


Effectof dialysis on tissue and serum alkaline phosphatase heat stability. Tissue extracts and serum samples were dialyzed against TRIS buffer and the heat stability of the alkaline phosphatase (AP) was examined before and after dialysis for various periods of time. The effect of adding a mixture of ions or heat inactivated polled serum (HIS) to the dialyzed samples was also investigated. Dialysis of tissue extracts or of serum resulted in an increase in the mean AP heat stability. Addition of the ion mixture to dialyzed bone or liver extracts decreased the AP heat stability. Addition of HIS to these extracts decreased the AP heat stability of dialyzed bone extract but had little effect on dialyzed liver extract. These results are discussed.


The influence of chronic uremia on hepatic glycogen in the rat. Long term maintenance of male Wistar rats following sub-total nephrectomy has been shown to alter carbohydrate metabolism. These rats frequently became hypoglycemic and concurrently demonstrated increased hepatic glycogen stores. Chemical analysis of glycogen revealed a significant increase in branching, with a concomitant decrease in glucose residues per segment. The influence of food intake and glycosuria are discussed. Decreased glycogen autolysis is attributed to increased glycogen branching in the uremic liver.


Semi-automated colorimetric determination of triglycerides. 1. A semi-automated procedure for the determination of triglycerides based on the manual procedure of Fletcher and the semi-automated procedure of Kessler and Lederer has been developed. 2. Reaction conditions and flow-rates have been optimized to result in a trouble-free procedure which produces 99+ per cent recovery on added recovery tests, and a standard deviation of 4.8 on specimens in the low normal range. 3. An inexpensive scale expansion device is used to increase accuracy by improving chart readability. 4. Analysis of commercial control sera produced results which correlated well with stated values.


Serum immunoglobulins after surgical operation. We measured immunoglobulins in the sera of 33 patients on days 1, 3, 6, 10, and 17 and three to four weeks after surgical operations (mostly hysterectomy or appendectomy) or (six patients) after spinal injury. In the absence of infection or blood transfusion, IgG usually decreased slightly and transiently after hysterectomy or appendectomy, as did IgA or IgM after hysterectomy. IgD concentrations showed no consistent changes, but in one patient after hysterectomy and with minimal infection IgD concentration decreased sharply, which contrasted with significant and early increases in IgG, IgA, and IgM. IgD concentration was not correlated with type of operation, presence of infection, or changes in the other immunoglobulins. IgE concentrations either die not change or, in some patients, increased or decreased initially, after operation. We conclude that immunoglobulin concentrations in serum are subject to multiple, unpredictable influences after trauma.


Comparison of radioimmunoassay with thin-layer chromatographic and gas-liquid chromatographic methods of barbiturate detection in human urine. A radioimmunoassay (I) for barbiturates was compared with thin-layer chromatographic (II) and gas-liquid chromatographic (III) methods for barbiturate detection in human urine. Timed urine samples were obtained from volunteers who had ingested 100 mg of a barbiturate. I detected barbiturate in all urines tested up to 76 h after the dose, and III in all up to 52 h and in 90% up to 76 h. II detected barbiturates in 90% of all urine samples for only 30 h, after which is reliability declined. Glutethimide interfered with radioimmunoassay of barbiturate, producing false positives. I is sensitive, reliable, and fast, and lends itself to screening large numbers of urine samples for barbiturates. For routine urine surveillance, however, we found I to be less useful than II, which is still the method of choice. I has, however, proved to be an excellent method for confirming results of II.


Evaluation of the new "System Olli 3000" kinetic ultraviolet analyzer for measuring aspartate ana alanine aminotransferase and lactate dehydrogenase activities in serum. A new fast kinetic analyzer, System Olli 3000, is evaluated as an instrument for the routine clinical laboratory measurement of the activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in serum. The System Olli 3000 consists of dispensers for simultaneous multiple dispensing of sample and reagents, incubators, vortex-type shakers, and a photometer with quartz fibre optics connected to a computer, allowing cycling measurements of 24 cuvets 24 times in 2 min. An unique slope search algorithm is described. The system shows a high degree of precision and a wide linearity range; activities of at least 10-fole the normal upper limit for all three of these enzymes can be measured without diluting the serum sample. As many as 380 analyses per hour (including calibration and blanks) can be carried out by one technician. For comparison, enzyme measurements were also made with an LKB 8600 Reaction Rate Analyzer and a Pye Unicam SP 8005 spectrophotometer coupled on-line to an IBM 1800 computer. Results obtained with the different instruments correlated well, especially in the region of main interest, i.e., above the normal upper limit. We conclude that the new instrument has many potentialities in kinetic analyses of nonenzymatic constituents in biological fluids.


Direct determination of total serum cholesterol by use of double-wavelength spectrophotometry. We describe a simple, accurate method for direct determination of total cholesterol in serum. Systematic investigation of a previously described modified Liebermann-Burchard reagent has indicated the necessity of accounting for both bilirubin interference and decreased specificity owing to exothermia. Double-wavelength spectrophotometry was used to optically null out bilirubin as an interfering factor, whereas adding serum to the cold reagent increases its specificity for the cholesterol color reaction. Comparison of 106 cholesterol values with those obtained by the procedure of Abell et al. [J. Biol. Chem. 195, 357 (1952)] yielded a correlation coefficient greater than 0.99; our inter-run coefficient of variation of polled laboratory serum was 1.7%.


Radioimmunoassay of plasma testosterone, with use of polyethylene glycol to separate antibody-bound and free hormone. We have developed a reliable radioimmunoassay for testosterone in plasma, polyethylene glycol ("Carbowax 6000") being used to separate antibody-bound and free hormone. Testosteron is separated from interfering steroids, notably dihydrotestosterone, by liquid-liquid partition chromatography on infusorial earth (Celite). The assay is sensitive (9 pg for standards), precise, and accurate. The lowest measurable concentration fo testosterone is 350 ng/liter for plasma from men and 70 ng/liter for plasma from women. Intra- and inter-assay coefficients of variation were 6.9% and 9.7%, respectively, for plasma from men, and 9.6% and 11.8%, respectively, for plasma from women. Our method for separating antibody-bound and free hormone is practical and convenient and may be generally applicable to all radioimmunoassays of steroid hormones in plasma.


Nonchromatographic radioimmunoassay of plasma 11-deoxycortisol, for use in the metyrapone test, with polyethylene glycol as the precipant. We have developed a simple, reliable radioimmunoassay for plasma 11-deoxycortisol. The method does not require chromatography but instead makes use of a simple extraction procedure which, in combination with the antibody characteristics, is highly specific for the metyrapone test. Polyethylene glycol was used to separate free and antibody-bound steroid. The smallest amount measurable is 15 pg (2.0 mug/liter of plasma). The method is shown to be precise and accurate. Intraassay precision of the method for two plasma pools was 26.7 plus or minus 2.5 mug/liter (CV equals 9.4%) and 61.2 plus or minus 3.7 mug/liter (CV equals 6.0%). The respective inter-assay precision was 27.0 plus or minus 1.7 mug/liter (CV equals 6.3%) and 59.9 plus or minus 2.3 mug/liter (CV equals 3.8%). The validity of the assay was further verified by evaluating the plasma 11-deoxycortisol response to metyrapone administration. The relative simplicity of the method and the commercial availability of all reagents, including antisera, makes this radioimmunoassay procedure practical for use in clinical laboratories.


Above-normal urinary excretion of urinary ceramides in Farber's disease, and characterization of their components by high-performance liquid chromatography. We compared the sphingolipid content of urine from a patient with Farber's disease with that of control urine. The ceramides were measured by high-performance liquid chromatography. The patient's urine contained 1.2 mug of ceramides per milligram of creatinine, more than 200-fold the normal amount. The urinary ceramides were isolated by high-performance liquid chromatography for further identification. They contained mainly nonhydroxy fatty acids and only a small quantity of those with 2-hydroxy fatty acids. This contrasts with the previously described composition of the patient's renal and cerebellar tissue. The fatty acid and long-chain base compositions of the urinary ceramides containing nonhydroxy fatty acids were nearly identical to those of the patient's kidney.


Gas-liquid chromatography of phenylalanine and its metabolites in serum and urine of various hyperphenylalaninemic subjects, their relatives, and controls. Phenylalanine and its metabolites were determined in serum and urine of phenylketonuric subjects and in subjects with milder hyperphenylalaninemia in whom blood phenylalanine concentrations were usually less than 200 mg/liter. Metabolite concentrations were related to serum phenylalanine, and in hyperphenylalaninemic subjects were between those for treated and untreated phenylketonuric subjects. Phenyllactic and phenylpyruvic acids were excreted by all of the mild hyperphenylalaninemic subjects except for the youngest (one-year-old twins) and the only subject with a serum phenylalanine of less than 100 mg/liter. Serum and urinary metabolites of heterozygotes of both conditions were similar before and after a phenylalanine load. The similar pattern of metabolites in phenylketonuric and mild hyperphenylalaninemic subjects reinforces the belief that the latter have some phenylalanine hydroxylase activity, and that this is the essential difference between the two groups.


Thermochemical determination of glucose in serum, plasma, and whole blood without prior deproteinization. Glucose can be determined by phosphorylation in the presence of hexokinase (EC 2.7.1.1) by using Mg2+/(ATP)2- as the phosphorylating agent. A novel instrumental quantitation method is described, direct injection enthalpimetry, whereby the heat of the enzymatically catalyzed reaction was measured. The reaction was allowed to proceed to virtual completion (99.5+%) in an adiabatic Dewar vessel at 25.00 plus or minus 0.01 degrees C (range). Samples were sequentially injected into a reaction mixture consisting of hexokinase, ATP, Mg2+, and a tris(hydroxymethyl)aminomethane buffer (pH 8). Single analyses required less than 2 min for 0-3 g/liter samples. The linear dynamic range was 0.3-10 g/liter, with zero intercept and a precision and accuracy of 2%. Electrical calibration in situ obviated the need for chemical standards, and because protein and color do not interfere, no sample pretreatment was necessary before analysis.


Ultramicroscale determination of clinical chemical values for blood during the first four days of postnatal life. Ultramicro procedures requiring 5-10 mul of serum or blood per analysis were used in determining blood constituents of healthy full-term newborns during the first four days of life. The resulting values appeared to be influenced by age, sex, and race. Values for total protein, albumin, urea nitrogen, and uric acid in serum decreased with time; serum inorganic phosphorus and whole-blood aldosaccharoses increased. Serum from females had higher values than that from males for total proteins, albumin, and inorganic phosphorus. The values for serum calcium and alkaline phosphatase were consistently higher in Negro than in white infants; values for uric acid were higher in the latter.


Flash-heater ethylation of some antiepileptic drugs. We describe a modification of the MacGee method [Anal. Chem. 42, 421 (1970)] for rapid determination of phenytoin (diphenylhydantoin) in plasma by gas-liquid chromatography, in which an ethylaing reagent is used instead of the more common methylating reagents. With this modification, several N-methylated antiepileptic drugs can be separated from their demethylated metabolites. Our results agree well with those of Butler and Waddell [Neurology 8, 106 (1958)], who showed that in patients receiving the N-methylated compounds mephenytoin and mephobarbital, the N-demethylated products, 5-ethyl-5-phenylhydantoin and phenobarbital are found in higher concentrations in plasma than are their respective parent drugs. The method is also useful for routine determinations of phenobarbital, primidone, and phenytoin in serum, cerebrospinal fluid, or saliva.


Automated determination of serum ceruloplasmin activity with o-dianisidine dihydrochloride as substrate. An automated method for the enzymatic determination of ceruloplasmin with o-dianisidine dihydrochloride as substrate is described. The method enables the measurement of 30 samples per hour with a coefficient of variation (day-to-day) of 2.8%. Results correlate well (r equals 0.99 with those obtained by the corresponding manual method


Preparation of a modified glucose oxidase reagent for the polarographic determinationof glucose with the Beckman "glucose analyzer". In this modification, glucose oxidase, 140-180 U/ml, is dissolved in acetate buffer (pH 6):ethanol (96%):glycerol (80:10:10 by vol). Iodine and molybdate are used as catalysts, formaldehyde and mercuric iodide as preservatives, and octanol as an antifoaming agent. The reagent is suitable for use in the Beckman "Glucose Analyzer", it is stable at room temperature for at least six months, it is sensitive, it has a lubricating effect, and its cost is less than a fifth as much as the "Certified" Beckman reagent. It is not suitable for the measurement of glucose in samples containing maltose, cellobiose, gentiobiose, starch, and glycogen.


Simple manual procedure for determination of serum triglycerides. We describe a modified method for determining serum triglycerides (triacylglycerols), which is based on the heptane extraction procedure of Gottfried and Rosenberg [Clin. Chem. 19, 1077 (1973)] with the stable saponification, oxidation, and color development reagents of Neri and Frings [Clin. Chem. 19, 1201 (1973)]. This modified method eliminates one heating step, reduces saponification time to 5 min, absorbances are read at room temperature, and the calibration curve is linear to 3.0 g/liter. A sample comparison between the proposed method and the automated Block and Jarrett [Am. J. Med. Technol. 35, 1 (1969)] procedure showed no significant difference (r equals 0.98). The coefficient of variation (47 duplicate samples) for the modified method was 6.3%. Further validation was obtained from analysis of quality-control samples; the proposed method gave equivalent values.


Improved radioimmunoassay of plasm cortisol. We report a simplified radioimmunoassay procedure for determination of plasma cortisol. The method offers the advantage that tracer, antibody, and assay buffer are added in a single step with the use of semi-automated equipment. Thus, critical pipetting procedures are minimized, and assay time is reduced to 4 h. No prior extraction or chromatographic purification of cortisol is required. The procedure is simple, reliable, and accurate. For either between-assay or within-assay determinations, the coefficients of variation are about 6%. Our results compare well with those obtained from a procedure that included extraction and chromatographic purification of cortisol in several plasma samples. Conditions for optimizing the assay are also discussed.


Procedure for calibrating the Technicon Colorimeter I. We describe a rapid method for calibrating the Technicon AutoAnalyzer colorimeter I. Test solutions of bromphenol blue are recommended for the calibration, in preference to solutions of potassium dichromate, based on considerations of the instrument's working range and of the stray light characteristics of the associated filters.


[Phenylalanine hydroxylase activity in the liver as a parameter for distinguishing various forms of hyperphenylalaninemias (author's transl)]. The activity of phenylalanine hydroxylase in the liver without the cofactor 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropterin is similar in cases of classical PKU (14 cases), mild hyperphenylalaninemias (2 cases), heterozygotes (1 case) and normal controls (18 cases). The addition of cofactor increases the activity 30-40-fold in normal controls and 2-5 fold in mild hyperphenylalaninemias or heterozygotes. In classical PKU the addition of cofactor is without effect or causes even a diminution of activity. Therefore, for classification of the various forms of hyperphenylalaninemias the effect of cofactor on enzyme activity is important. For decisions from this findings to be made as to whether treatment should or should not be used further investigations are needed.


In vivo studies on the metabolism of hexanedioic acid. 1. Using the combined gas-liquid chromatography-mass spectrometry technique it was shown that ketotic patients excreted up to 273 mg of hexanedioic acid daily in their urine, whereas serum samples from these patients contained only trace amounts of this acid. Healthy humans excreted 2-5 mg daily. Hexanedioic acid was not detectable in normal serum. 2. An experiment with the infusion of large amounts of 3-hydroxybutyrate into a dog indicated that the increased urinary hexanedioic acid excretion in ketosis is not due to a competition between 3-hydroxybutyrate and hexanedioic acid for the same renal reabsorption mechanism. 3. [ 1,6-14-C]Hexanedioic acid intravenously injected into a dog was at first distributed in the extracellular space, followed by a partial equilibration with the intracellular space. About 11% of the injected dose was expired as 14-CO2 in 220 min. The maximal 14-CO2 production rate was obtained after about 20 min. In 240 min, 47% of the injected radioactivity was recovered in the urine. The large urinary excretion of labeled hexanedioic acid observed in the presence of only trace amounts in serum, showed that the high excretion by ketotic patients of the dicarboxylic acid may be explained without postulating an exclusive renal synthesis for hexanedioic acid.


Cystathioninuria and homocystinuria.

Cystathioninuria and homocystinuria. Three circumstances prompted us to reexamine the relationship between abnormal cystathionine accumulation and possible homocystinuria resulting from this condition: (a) discovery of an infant girl with apparently alternating massive cystathioninuria and homocystinuria; (b) the presence of homocystinuria in some, but not all, previously reported cases of cystathioninuria probably due to gamma-cystathionine deficiency; and (c) the recent demonstration that mammalian cystathionine beta-synthase can cleave cystathionine to homocysteine. The following conclusions were reached: (a) Homocystine may arise as a result of bacterial contamination of a urine sample initially containing cystathionine, but not homocystine. (b) After a methionine load, a cystathioninuric patient may excrete readily detected amounts of homocystine. (c) However, homocystinuria is not a necessary concomitant of even massive cystathioninuria. These findings and some of their implications are briefly discussed.


Urinary total oestrogen values determined by an automated method in normal and abnormal pregnancies. Urinary total oestrogen values in late pregnancy have been determined by an automated, fluorimetric method based on the Kober reaction and Ittrich extraction. The normal range was obtained from 360 samples from 56 patients. The mean value at 40 weeks gestation was 52.6 mg/24 h and the 95 per cent probability bounds were 29.1 and 95.3 mg/24 h, obtained after initial calculations on logarithm values. "Small for dates" foetuses in good condition at birth were associated with oestrogen values generally below the normal mean. They were usually well discriminated from foetuses that died in the uterus. These were always associated with oestrogen values below or approaching 10 mg/24 h before death except when growth had been normal and death was due to mechanical complications at delivery.


Serum alpha-fetoprotein (AFP) in benign and malignant gastrointestinal diseases: evaluation of an immunoenzymatic assay. A quantitative immunoenzymatic assay has been developed for alpha-fetoprotein which is sensitive and specific. Seventy-eight percent of United States hepatoma patients have detectable serum alpha-fetoprotein elevations over 50 ng/ml, whereas only 2 of 93 other gastrointestinal tumors were positive. Thirteen percent of patients with acute viral hepatitis, 44% of patients with massive hepatic necrosis, and 23% of patients with chronic active hepatitis had measurable serum alpha-fetoprotein concentrations. However, patients with non-viral acute or chronic liver disease were largely alpha-fetoprotein negative and alpha-fetoprotein was undetectable on multiple postoperative samples from 6 patients after hepatic lobectomy in the rapidly regenerating phase. Therefore, alpha-fetoprotein elevations in nonmalignant liver diseases are not due solely to hepatic regeneration but appear to be related to viral injury. The immunoenzymatic assay does not require purified antigen or radioisotope equipment and can detect and quantitate clinically significant alpha-fetoprotein levels greater than 50 ng/ml.


The behaviour of LDH-3 in patients with malignant diseases during therapy with cytostatic drugs and prednisone, studied by LDH-isoenzyme electrophoresis on cellulose acetate. A modified method used for the quantitative estimation of LDH-isoenzymes in serum after electrophoresis on cellulose acetate is described. Total LDH-activity and isoenzyme distribution in serum samples of capillary blood are compared to those in samples collected by venipuncture. Total LDH-values and LDH-distributions both in 29 normal children and 14 children with malignant diseases are given. When studying the LDH-distribution in serum samples of children with malignant diseases a significantly decreased LDH-3 was found in many patients. LDH-4 and LDH-5 were also reduced. It was noted that these children all received therapy with prednisone. Possible explanations are discussed.


Lactosuria - a new metabolic feature of severe cerebrocranial trauma. Under controlled dietary conditions the urinary excretion of lactose was studied in 15 healthy persons, 15 patients with cerebrocranial trauma and 15 patients with extracranial trauma. Urinary lactose levels were found to be markedly increased in patients with head injury and ranged from 10.3 to 147.7 mg/24 h with a mean 63.4 mg/24 h in contrast to patients with other injuries (3.1 to 17.0 mg/24 h, mean 9.4 mg/24 h; P less than 0.001), and healthy individuals (3.3 to 17.93 mg/24 h, mean 7.6 mg/24h; P less than 0.001). In the head injury group the lowest values were found in drowsy or disoriented patients with cerebral concussion and the highest in comatose subjects. The level of lactosuria decreases after approximately 12 to 16 days to normal levels even when the patient remains unconscious. An earlier return to normal excretion parallels or preceeds the reappearance of consciousness. Unlike alimentary lactosuria, caused by ingestion of milk or other dairy products in large quantities, the elevated lactose levels in head injury patients were not usually accompanied by a comparable rise in galactose excretion, mean 11.45 mg/24 h versus 9.17 mg/24 h in controls; P less than 0.2. The mechanism of enhanced lactose excretion in severe cerebrocranial trauma remains unknown. It is suggested that it may be associated with either an increased catabolism of brain gangliosides or a stimulated lactose synthesis in peripheral tissues probably due to the participation of the lactogenic hormone prolactin.


Catecholamines in urine; an evaluation of alumina-trihydroxyindole methods and a description of an improved method. A critical assessment of the accuracy and practicability of five alumina-trihydroxyindole methods for the estimation of urinary catecholamines, including our proposed method, was undertaken. The recovery of noradrenaline added to urine obtained by these methods was quantitated against different types of standards, and varied from 22.9 per cent to 104.8 per cent. The major analytical problems (fluorescence suppression and loss of catecholamines during column chromatography) were evaluated and related to the recovery of the respective procedures. The improved method we developed is simple, rapid and reliable. The low fluorescence suppression and column losses of noradrenaline of this method, averaging 2.9 per cent and 5.3 per cent, respectively, resulted in a mean recovery of 92.0 per cent against an external standard. Both the chromatography step and fluorescence development are simple and short, and a batch of ten cases can be completed within 3 hours.


The assay of glycogen phosphorylase in human blood serum and its application to the diagnosis of myocardial infarction. Methods are described (a) for the estimation of glycogen phosphorylase activity (EC 2.4.1.1) in human blood serum based on the chemical determination of liberated orthophosphate or on the enzymic determination of glucose 1-phosphate in a coupled assay system and (b) for the electrophoretic separation of isophosphorylases I, II, and III in human. Glycogen phosphorylase activities ranging from 1.5 to 18 mU/ml were found in the serum of patients with acute myocardial infarction. In contrast, no glycogen phosphorylase activity was detected in the serum of healthy persons. The enzyme appears in the serum 4 hours after the onset of the infarction and reaches a maximum after 20 to 30 hours. Acrylamide gel electrophoresis of serum after a myocardial infarction revealed only muscle isophosphorylase I, the isoenzyme characteristic of the heart. No phosphorylase activity was detected in serum of patients with angina pectoris, endocarditis, and uncomplicative congestive heart failure. From these findings it appears that the new serum enzyme test may prove to be a valuable addition to presently existing methods for the early differential diagnosis of acute myocardial infarction.


Diagnostic meaning of the urinary output of Nepsilon-methylated lysines. Investigation of healthy individuals and patients with malignant diseases, myopathies or renal failure. In the urine of 36 healthy persons the excretion of the three Nepsilon-methylated lysines and some other basic amino acids was determined. The following average values, related to 1 g creatinine, were found: Lys(Me) 16.2 mumol, Lys(Me2) 31.2 mumol, Lys(Me3) 40.5 mumol. The 24-hour excretion in 6 adults related to 1 kg body weight, had the following average values: Lys(Me) 0.37 mumol, Lys(Me2) 0.88 mumol, Lys(Me3) 0.92 mumol. In patients with degenerative or inflammatory myopathies (6 cases) as well as with generalized tumors (7 cases) urinary output of methyllysines was not significantly altered. In a patient with extremely impaired renal function, it was found that the plasma level and the excretion pattern of the methylated lysines were unequivocally altered. Metabolic stability and renal excretion of 3H-labelled l-Lys(Me3) were investigated in man. During a 24 hour period 65 per cent of Lys(Me3) was excreted into the urine unmetabolized after intravenous injection but not more than 20 per cent after oral administration.


The raising and characterization of cortisol-binding antiserum. Synthesis of a cortisol-albumin compound and the raising of antibodies against cortisol in rabbits are described in detail. The steroid-protein complex is characterized by a number of reactions regarding the amount of cortisol coupled and the ability of the coupled steroid to react as such. The specificity of the harvested antiserum and transcortin towards the coupling of several related steroids are compared; the rabbit antiserum appears to be the more selective binding agent.


Para-O-methylation of the catecholamines in neuroblastoma. By means of thin-layer chromatographic methods, iso-homovanillic acid (iso-HVA), iso-vanillactic acid (iso-VLA) and iso-vanilmandelic acid (iso-VMA) were determined in the urine of 10 children with neuroblastoma. The mean excretion of iso-HVA was 10.1% of total HVA excretion. Three patients excreted VLA; in their urine no iso-VLA was detected with certainty. All patients excreted high amounts of VMA; there was no detectable excretion of iso-VMA. Those results suggest that para-O-methylation could be limited to dopamine catabolism.


Creatine kinase reactivation by thiol compounds. It is now commonly accepted that thiol activated creatine kinase (CK) assay systems measure CK activity more accurately and more reproducibly than non-activated systems. However, some differences have arisen in the literature in regards to the nature and course of CK activation. Some thiol compounds have been reported to yield higher enzyme activities than others. Dalal et al. (1) reported that mercaptoethanol at 6.5 mM is suboptimal in the Siegel and Cohen assay (2); whereas, dithiothreitol (DTT) at 4 mM yields maximum activity. Warren has shown that DTT and mercaptoethanol produce significantly greater CK activities than cysteine, dithioerythritol (DTE), glutathione, or mercaptoacetate (3). Bishop et al. (4) and Kar and Pearson (5) reported that CK was equally activated independent of the thiol activator. We report here our findings on the relative effectiveness of mercaptoethanol, cysteine, glutathione, and DTT in the reactivation of serum CK using the Oliver-Rosalki method (6,7) and some characteristics of the reaction process.


[Results of a study on the circadian rhythm of catecholamine excretion on normal subjects and those with high excretion levels (author's transl)]. The circadian rhythm of the excretion of the catecholamines and some main metabolites is investigated in five normal subjects and two patients with a high excretion. In the normal subjects there are remarkable differences in the amplitudes of the variables. At high catecholamine excretions these differences seem to disappear.


Determination of phosphate in serum and urine by a single step malachite-green method. The highly sensitive malachite-green method for the determination of phosphate requires a protective colloid in order to avoid precipitation of the formed dye salt. A polyvinylalcohol proved to be suitable and permit the determination of phosphate in urine and in serum without prior precipitation of the proteins. The present method is suitable for a one-step procedure which allows the analysis of several hundred samples per man-hour and is applicable to microquantities of serum or urine.


The difference between the glucose concentrations in plasma and whole blood. The glucose concentrations in whole blood (WB) and plasma (P), both prediluted with distilled water and saline, and in their protein-free filtrates, were determined with the Hoffman ferricyanide method. In whole blood prediluted with distilled water the glucose concentration appeared to be 13% higher than in whole blood prediluted with saline. In plasma, predilution with distilled water or saline did not result in different glucose values. Plasma glucose is significantly higher than whole blood glucose independent of the method of pretreatment. A direct relationship between the two values exists, which for protein-free filtrates is represented by Glu(P) equals 1.07 Glu(WB) + 0.11. The glucose concentrations in erythrocytes were calculated and also correlated to plasma glucose values. A good correlation was found when protein-free filtrates were used. Apparently, conversion factors from whole blood to plasma glucose may be used only in cases where samples are deproteinized.


Erythrocyte transketolase activity in adult Ghanaian subjects. The erythrocyte transketolase activity, and the effect of thiamin pyrophosphate stimulation (TPP effect) on this enzyme, was determined in 263 adult Ghanaian subjects who included normal males and females, male labourers known to consume a diet high in carbohydrate, diabetics and pregnant women. Using the guideline that a TPP effect of greater than 25% indicates thiamin deficiency, it was found that a significant proportion of apparently healthy subjects (36%-47%) may be regarded as thiamin deficient. The results are discussed in the light of similar studies carried out by other workers.


Serial measurements of vitamin B-12 and vitamin B-12-binding capacity in marasmic kwashiorkor. Vitamin B-12 and total vitamin B-12-binding capacity (TBBC) have been determined by a radio-saturation assay in the blood of a large group of patients suffering from marasmic kwashiorkor on admission, and during their whole re-feeding. The results have been compared with values obtained in control children of the same ethnic group and with normal children living in Belgium. Vitamin B-12 levels are high on admission and only normalize during the second month of re-feeding. TBBC is normal on admission but significantly increases during re-feeding.


Urinary excretion of free hydroxylysine, peptide-bound hydroxylysine and hydroxylysyl glycosides in physiological conditions. The amount of urinary hydroxylysine is an index of collagen metabolism. Of the total hydroxylysine measured in normal urine 80 percent is associated with sugars in two glycosidic compounds, glucosyl-galactosyl-hydroxylysine and galactosyl-hydroxylysine, ten percent is free and unglycosylated and the remainder is bound to urinary peptides. The excretion of hydroxylysyl glycosides follow the same physiological variations as urinary hydroxyproline, but it is not influenced by a collagen-free diet. The urinary excretion of hydroxylysyl glycosides, free hydroxylysine and peptide-bound hydroxylysine increases from 6 months of age to puberty. When corrected for urinary creatinine excretion, the largest amounts are found before one year of age. The glucosyl-galactosyl-hydroxylysine/galactosyl-hydroxylysine ratio is lower in the urine of children. After correction of the values to either the body surface area or to the creatinine excretion, no significant differences can be found  between the sexes. The different forms of hydroxylysine are discussed.


The role of prolactin in the restoration of ovarian function during the early post-partum period in the human female. I. A study during physiological lactation. Serial plasma levels of prolactin, follicle-stimulating/ml hormone (FSH), luteinizing hormone (LH), 17beta-oestradiol (E) and progesterone (P) were determined by radio-immunoassay in ten healthy women during late pregnancy and puerperium until the occurrence of the first menstruation, at which moment an endometrial biopsy was taken. Prolactin concentrations, which were high during late pregnancy and the early post-partum period, declined thereafter but remained above 30 ng


The role of prolactin in the restoration of ovarian function during the early post-partum period in the human female. II. A study during inhibition of lactation by bromergocryptine. Serial plasma levels of prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-oestradiol (E) and progesterone (P) were determined by radioimmunoassay in ten healthy women during late pregnancy and the puerperium during inhibition of lactation by Bromergocryptine. This medication was continued until the occurrence of the first menstruation, at which point an endometrial biopsy was taken. Prolactin was very effectively suppressed by Bromergocryptine in all patients, as was lactation. FSH was nearly undetectable during late pregnancy and the first week post-partum with an increase back to normal levels between day 7 and 12. Thereafter FSH levels were within the normal cyclic range. Following clearance of human chorionic gonadotrophin (HCG) during the first 2 weeks post-partum, LH was found within the normal cyclic range in all patients. From day 7 E increased in nine of ten patients to reach levels during the fourth week which are seen normally at the moment of the pre-ovulatory E-surge in cycling women. In eight of the ten cases this was concomitant with high levels of LH. The tenth patient showed a high E level at day 36. P was fully excreted within 7 days and remained low until approximately day 20. Thereafter an increase was demonstrated with levels as found during the luteal stage of the menstrual cycle in nine patients within 33 days and within 40 days in all ten patients. The endometrial biopsies showed clear signs of secretory activity. The probable action of prolactin on ovarian function is discussed. It is suggested that during the puerperium the ovaries are the more refractory part of the hypothalamicpituitaryōvarian axis, due probably to an influence of prolactin on the ovarian steroid synthesis.


Assessment of oral glucose tolerance data. Characteristics of the 'clinical value index' (Harding et al., 1973) are examined. It is shown that the definition of the index makes it unsuitable for the comparative evaluation of various methods of assessing the results of an oral glucose tolerance test.


Treatment of acromegaly by transsphenoidal hypophysectomy with cryoapplication. The therapeutic effect of transsphenoidal hypophysectomy with cryoapplication has been studied in twenty-nine patients with active acromegaly. The mean follow-up time was 15 months (354 months). A significant improvement of symptoms and signs occurred in all but three patients. The level of plasma immunoreactive growth hormone (IRGH) was reduced in all but two patients and a normal level of plasma IRGH was achieved in sixteen patients. Skin thickness, the level of serum inorganic phosphorus and the urinary excretion of hydroxyproline and calcium were significantly decreased in the great majority of the patients. The operation was not accompanied by any visual complications, but cerebrospinal rhinorrhoea, subsiding spontaneously, developed in two and postoperative meningitis in one patient. Hypothyroidism and adrenocortical deficiency developed in eight, gonadotrophin deficiency in thirteen, and persistent diabetes insipidus in one patient. It is concluded that transsphenoidal hypophysectomy with cryapplication is a safe and effective method for the treatment of acromegalic patients.


Cyproterone acetate: a study involving two volunteers with idiopathic hirsutism. Two female volunteers, of menstrual age, with severe idiopathic hirsutism were treated for eight cycles and fifteen cycles respectively with cyproterone acetate 50 mg twice daily on days 5-14 of the cycle. In all but one cycle, ethinyl oestradiol in a dose of 50 mug daily from day 5 to 21 was given in addition. Cyproterone acetate when given alone abolished the mid-cycle LH surge. Combined therapy with cyproterone acetate and ethinyl oestradiol produced a significant improvement in both patients' hirsutism and was accompanied by a marked reduction in the urinary excretion of LH, FSH and androgens and by a fall in plasma testosterone. However, the clinical benefit derived from this drug was due principally to its action as a peripheral antiandrogen.


Hypogonadism and parathyroid adenoma in congenital poikiloderma (Rothmund-Thomson syndrome). In two adult patients with congenital poikiloderma (Rothmund-Thomson syndrome) the following endocrine abnormalities were found: Patient 1, female, with short stature had primary amenorrhoea and did not develop secondary sexual characteristics. Despite lacking an oestrogen effect on the vaginal smear and the low urinary oestrogen excretion, basal LH and FSH and their response to LH-RH were normal. At age 36 a parathyroid adenoma was diagnosed because of increased immunoreactive plasma parathyroid hormone and persistent hypercalcaemia. After removal of the tumour the patient remained normocalcaemic. The result of growth hormone response to insulin in the intermediate range was suggestive of partial deficiency. In patient 2, male, hypergonadotrophic hypogonadism with small testes and high basal LH and FSH levels as well as increased LH and FSH response to LH-RH were found. Plasma testosterone was normal. Endocrine abnormalities in previously published cases are summarized.


Plasma free fatty acid turnover in total lipodystrophy. Basal free fatty acid (FFA) turnover was found to be elevated or at the upper limit of normal in a patient with total lipodystrophy. The decrease in plasma FFA concentration which occurred after intravenous administration of insulin was shown to be primarily due to a fall in the inflow of FFA into the circulation. These results provide support for the suggestion that adipocytes in total lipodystrophy are able to synthesize triglycercide, but that they are unable to store it because of rapid lipolysis.


Prognosis of chronic glomerulonephritis in adult patients estimated on the basis of the Markov process. The prognosis of chronic glomerulonephritis based on renal function was assessed using a statistical technique of the Markov process, where the absorbing state was assumed to be an uremic state, 194 adult patients with different types of disease were subjected to study. The 15 min value obtained in the intravenous PSP excretion test was divided into five states; SI (greater than 34%, normal), SII(25-34), SIII(15-24), SIV(5-14) and SV (greater than 5, uremic). The rates of SV with time were calculated with respect to several clinical characteristics. The prognosis of the patients with hypertension, distinct proteinuria and hematuria, or cellular cylindruria appeared to be relatively poor. The estimated number of years from each state to SV were also calculated. The results were similar to those already reported and gave us more exact information about the prognosis.


Hypertension, renal vein thrombosis and renal failure (occurring in a patient on an oral contraceptive agent). A case of accelerated hypertension leading to renal failure in a young woman taking an oral contraceptive agent is described. During the course of her disease the left kidney was documented to decrease in size. Renal vein plasma renin activity was found to be elevated on the left in the absence of renal artery stenosis. Left nephrectomy, prompted by continuing poor blood pressure control, resulted in amelioration of the hypertension. Left renal vein thrombosis was found at surgery. It is suggested that renal vein thrombosis was a contributing factor to this patient's accelerated hypertension and may represent an unusual thrombotic complication of oral contraceptives.


Determination of propoxyphene and norpropoxyphene by chemical ionization mass fragmentography. The kinetics of propoxyphene and its primary metabolite, norpropoxyphene, have been simultaneously re-evaluated in man by using gas-liquid chromatography/mass spectrometry, deuterium-labeled mass internal standards, and multiple ion monitoring. Plasma concentrations in 4 volunteers determined for as long as 240 hr after single oral doses of 2 propoxyphene salts indicate the overall half-life of propoxyphene to be 11.8 hr and of norpropoxyphene to be 36.6 hr.


Blood flow in muscle groups and drug absorption. Resting human muscle blood flow (MBF) was determined simultaneously in the usual intramuscular injection sites to resolve whether variance in MBF could account for differences in drug absorption. Three pairs of muscles (gluteus maximus, vastus lateralis, and deltoid) were studied in each of 20 adult subjects. Use of dual, matched linear rate meters allowed two muscles to be studied simultaneously, with the order of injection random within an incomplete block design. MBF was calculated from the 133xenon washout rate using a single exponential that the computer found to best fit the data. Deltoid MBF (11.6 ml/100 gm/min plus or minus 0.5) was significantly (p smaller than 0.05) greater than gluteus MBF (9.6 plus or minus 0.5), with vastus or between right and left sides for each muscle. These data indicate that there are consistent differencies in resting MBF among specific muscle groups of sufficient magnitude (19%) to affect the rate of absorption and peak serum levels following intramuscular administration of drugs.


Altered plasma half-lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction. In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.


Hemolysis induced by 6-N-hydroxylaminopurine riboside, an adenosine analogue. 6-N-Hydroxylaminopurine riboside (HAPR) was studied in man because of its therapeutic activity in several transplanted animal neoplasms. It was not cross-resistant to other antimetabolites useful in the treatment of human neoplasia. HAPR produced marked hemolytic anemia at doses far below those that might have produced any cytotoxic or therapeutic effect. There was evidence of hemolysis at total doses as low as 0.5 mg/kg given intravenously. For man, HAPR is one of the most active hemolytic drugs.


Thioridazine: central dopamine turnover and clinical effects of antipsychotic drugs. Thioridazine was administered to 14 patients diagnosed as within the "schizophrenic spectrum" with the result that substantial improvement in psychotic symptoms was achieved while significant extrapyramidal side effects occurred in only 1 patients. Under these conditions lumbar cerebrospinal fluid homovanillic acid following probenecid was significantly elevated (48%). Cerebrospinal fluid probenecid and 5-hydroxyindoleacetic acid declined significantly during treatment with thioridazine. Taken in conjunction with the results of other studies, it appears that cerebrospinal fluid homovanillic acid can be moderately elevated in man during successful treatment with antipsychotic drugs when extrapyramidal side effects are virtually absent. Possible interpretations of these results are discussed with regard to the clinical effects of antipsychotic drugs as they relate to central dopaminergic activity.


Hemodialysis in an infant with propoxyphene intoxication. A 10-month-old infant was treated with intensive supportive care and hemodialysis for severe propoxyphene intoxication. Dialysis clearance studies demonstrated that propoxyphene was removed from the serum at approximately 50% of the rate of blood urea nitrogen removal. Possibly because of tissue binding of the drug, the absolute quantity of propoxyphene removed by dialysis was small. The child survived the acute episode of intoxication but died of pulmonary complications several days later. The role of dialysis in propoxyphene intoxication remains to be established.


Nicotine regulation and cigarette smoking. A study was conducted to determine whether there is nicotine regulation in cigarette smoking. Tar levels, which often covary with nicotine manipulations, were controlled for by the use of nicotine in chewing gums. Nicotine in cigarettes was also used for preloading. High nicotine cigarette preloads were followed by longer latencies to the next cigarette than were the low nicotine cigarette preloads. High nicotine gum preloads were followed by less puffing on the subsequent cigarettes than were the low nicotine gum preloads.


The effect of pindolol on exercise-induced cardiac acceleration in relation to plasma levels in man. The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10-mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.


Antiarrhythmic potency of N-acetylprocainamide. Compared to procainamide in an animal arrhythmic model, the antiarrhythmic potency of the N-acetylated metabolite of procainamide (NAPA) was 92% with respect to dose and 70% with respect to plasma level. The antiarrhythmic effects of combinations of the drugs were additive. Measurements of procainamide and NAPA plasma levels needed to suppress ventricular extrasystoles suggested that both compounds are nearly equipotent in patients as well. The average plasma level required for arrhythmia control in these patients was equivalent to 5.1 mcg/ml procainamide. Since patients on long-term procainamide therapy have plasma concentrations of NAPA that are usually comparable to, and occasionally greater than, their procainamide levels, dose regiments based on procainamide levels alone need revision to include consideration of the levels of this metabolite.


Effect of nortestosterone decanoate on red cell 2,3 diphosphoglycerate and hematocrit in hemodialysis patients. The effects of intramuscular 200-mg nortestosterone decanoate (ND) on red cell 2,3 diphosphoglycerate (DPG) concentration and packed cell volumes (PCV) were compared in 9 patients undergoing chronic hemodialysis for renal failure and in 18 control patients undergoing hemodialysis but not receiving ND. Subjects had received the drug 4.3 plus or minus 0.3 (SEM.) months at the time of DPG determinations. DPG was similar in treated patients and in the control subjects: 6.27 plus or minus 0.22 mM/L RBC and 6.16 plus or minus 0.23 mM/L RBC, respectively. The initial PCV was also similar: 21.72% plus or minus 1.36 and 20.13% plus or minus 0.91. Although the mean PCV during treatment was higher for 5 of 9 ND-treated patients (p smaller than 0.01), the final PCV prior to termination of therapy was greater than the initial pretreatment PCV in only 2 of these 5 patients (p greater than 0.05). We conclude that 200 mg ND weekly has no effect on the red cell DPG and a transient unsustained effect in raising the PCV in male chronic hemodialysis patients over a 5-month period of treatment.


Pharmacological activity, metabolism, and pharmacokinetics of glycinexylidide. Glycinexylidide (GX) is a metabolite of lidocaine that is frequently present in mug/ml concentrations in the plasma of patients treated with lidocaine infusions for 24 hr or more. Plasma levels of GX have 26% the antiarrhythmic activity of lidocaine in an animal model, and GX adversely affects the mental performance of normal subjects at plasma concentrations comparable to those found in patients. The total volume of GX distribution in man is similar to that of lidocaine but the plasma clearance is less, so that the 10-hr elimination phase half-life of GX is much longer than the 1 1/2 hr half-life reported in normal subjects for lidocaine. About half of an administered dose of GX is excreted unchanged in urine, roughly 15% appears in urine as conjugates of xylidine and p-OH xylidine, and the fate of the rest is unknown.


Neurologic and electroencephalographic correlates in glutethimide intoxication. Neurologic and electroencephalographic (EEG) examinations were performed every two hours during a case of severe glutethimide intoxication resulting from the acute ingestion of at least 15 grams of glutethimide. Neurologic data were reduced to 10 measurements of brainstem function and plotted as an index that varied cyclically in amplitude during the clinical course. Electroencephalographic data were computer-processed by power spectral methods and related to the brainstem function index. Good positive correlation existed between the frequency and reactivity of EEG activity and the level of brainstem function as reflected in the index. The cyclic and, sometimes, unilateral nature of the clinical findings previously reported in glutethimide coma was confirmed and seen to be reflected in the EEG. The present case also indicates that, in the absence of cerebral ischemia or hypoxemia secondary to cardiopulmonary depression, complete clinical recovery from glutethimide-induced coma is possible no matter how severe the presenting neurologic and EEG signs.


Determinants of the renal clearance of digoxin. The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.


Acetylation of procainamide in man and its relationship to isonicotinic acid hydrazide acetylation phenotype. To assess the extent of the acetylation of procainamide (PA) to N-acetylprocainamide (NAPA) in man, and its relation to isonicotinic acid hydrazide (INH) acetylation phenotype, the following study was done. Fourteen subjects received 500 mg of PA - HCL orally. INH acetylation phenotype was determined by the serum half-life of INH after 4 mg/kg of INH orally. Each urine voided for 96 hr after procainamide was saved and levels of procainamide and NAPA measured by gas-liquid chromatography. The 14 subjects eliminated 52 plus or minus 4 percent of the dose as procainamide and 16 plus or minus 2 percent of the dose as NAPA. Four fast INH acetylators eliminated 23 plus or minus 3 percent of the dose as NAPA compared to 12 plus or minus 1 percent by the slow acetylators (p smaller than 0.05). The amount of unaltered procainamide excreted by the fast and slow INH acetylators was not significantly different, 50 plus or minus 4 percent and 53 plus or minus 4 percent, respectively. Of the total amount of drug recovered in the urine of the fast and slow INH acetylators, NAPA accounted for 32 percent and 19 percent, respectively (p smaller than 0.01). There appears to be a positive correlation between the ability to acetylate INH and the ability to acetylate procainamide.


Effect of glucagon on digital circulation. The effect of glucagon on the digital circulation was studied in 7 subjects using the digital rheoplethysmograph (RPG). Rheoplethysmograms were continuously recorded while glucagon (0.1 to 2.0 mg) was injected into the brachial artery of the same extremity being studied with the RPG. The injection of glucagon was associated with a "tingling" or "burning" sensation in 3 subjects. The initial response, which was maximal 8 to 27 sec after the injection of glucagon, was constriction of the arteries, veins, and A-V shunts. The late response consisted of reopening of the arteries and veins. However, in some patients, there was RPG evidence of persistent constriction of the A-V shunts. It is suggested that the late response is similar to that observed in reactive hyperemia and following injection of bradykinin and, therefore, may be related to local release of vasoactive substances by glucagon.


Pharmacokinetics of procainamide intravenously and orally as conventional and slow-release tablets. Pharmacokinetics of procainamide were studied in healthy volunteers after single doses intravenously and orally as conventional and slow-release tablets and after repeated oral doses to steady state. The initial distribution after intravenous administration was rapid and the overall elimination in the beta-phase corresponded to t1/2 of 2.7 hr. The mean volume of the central compartment was small and only 4 percent of V-d (beta), which was 2.3 l/kg body weight. About 65 percent was excreted unchanged after intravenous administration and about 55 percent after a single oral dose of 500 mg. The recovery of the metabolite N-acetylprocainamide was 12 percent after both routes of administration. Procainamide was completely absorbed from the gastrointestinal tract and the first-pass elimination was very limited. The rates of absorption from the tablet compositions were well correlated to the in vitro dissolution properties. Administration of slow-release tablets every 8 hr gave about the same mean plasma level at steady state as ordinary tablets given every 4 hr, and the availability was the same from both preparations. The occasional high plasma concentration peaks after ordinary tablets were not observed after the slow-release tablets. Renal clearance was about 500 ml/min, indicating an active secretion in the tubules.


Plasma protein binding of carbamazepine. The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from disease persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a slightly lower percentage of carbamazepine than did normal plasma (p smaller than 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.


Ticarcillin vs carbenicillin: clinical pharmacokinetics. The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared to those of carbenicillin in 12 healthy volunteers. Following an intravenous infusion of 2 gm in 5 min, there was a lower average serum level for ticarcillin (218 mug/ml) than for carbenicillin (301 mug/ml), but after 2 hr the differences were not significant. The biologic half-life of ticarcillin was slightly longer than that of carbenicillin (72 and 65 min, P smaller than 0.01) and its volume of distribution was larger (15.7 and 12.3 l, P smaller than 0.01). Eighty-six per cent of the dose of ticarcillin and 99 percent of the dose of carbenicillin was recovered in the urine in 24 hr. Similar but much less marked blood level differences were noted with 2 gm, 30-min infusions. An intravenous infusion of 1 gm/hr gave average steady-state blood levels of about 124 mug/ml for both antibiotics. Probenecid, administered 1 hr before the infusion, caused significant and similar increases in blood levels, half-lives, and volumes of distribution of the 2 antibiotics. Protein binding in 100 percent human serum was 50 percent and 65 percent for carbenicillin and ticarcillin, respectively. These relatively small but definite differences in the pharmacokinetics of ticarcillin and carbenicillin are not likely to be of clinical significance.


Effects of etiocholanolone-induced fever on plasma antipyrine half-lives and metabolic clearance. The plasma half-life and metabolic clearance rate of antipyrine, a drug metabolized by hepatic microsomal enzymes, were determined in 33 normal volunteers during a basal state and during fever induced with a single intramuscular injection of etiocholanolone. Of the 14 normal volunteers who achieved significant fever (fever index greater than 50), in 11 plasma antipyrine  half-life was prolonged after a single oral dose of 10 mg/kg and antipyrine metabolic clearance rate was decreased. There was no significant change of these mean values in 19 normal volunteers who failed to develop significant fever (fever index smaller than 50). Therefore, under the conditions of this study plasma antipyrine half-life was prolonged, probably due to impaired hepatic metabolism, during etiocholanolone-induced fever, although no correlation was observed between the magnitude of fever and the extent to which plasma antipyrine half-life was prolonged. Failure to obtain such a correlation may be attributable to the very small range of temperature elevation, extending from 37.9 degrees C to 39.2 degrees C, in the group of 14 subjects achieving significant etiocholanolone-induced fever (fever index greater than 50). A higher dose of antipyrine (18 mg/kg) suppressed induction of fever by etiocholanolone; antipyrine is the only orally administered drug thus far shown to be effective in repressing etiocholanolone-induced fever.


Pseudoproteinuria in tolmetin-treated patients. In a clinical study of the new nonsteroidal anti-inflammatory drug tolmetin, the urines of 5 patients reacted positively when tested for protein by the standard sulfosalicylic acid method. Pseudoproteinuria, due to the precipitation by acid of the major metabolite of tolmetin, was suspected. The urines were subsequently tested for protein by the following alternate methods: solubility of acid precipitate test, heat coagulation test, Upjohn modification of the sulfosalicylic acid test, biuret test, Albustix, and electrophoresis. All were negative for protein. These results confirmed that the reactions with the sulfosalicylic acid test did not indicate true proteinuria but pseudoproteinuria. It is suggested that patients who receive tolmetin be tested for proteinuria by methods other than those involving acid precipitation.


Influence of diet and fluid on bioavailability of theophylline. The influence of various test meals, and of fluid volumes, on the bioavailability of theophylline from a solid dosage form has been studied in healthy male volunteers. Absorption of a drug was faster after dosing immediately following a high protein meal than after a high fat or a high carbohydrate meal. Absorption from a solution was faster than from a solid dosage form in all treatments; areas under serum level time curves after dosing were also significantly higher up to 12 hr. Areas up to 12 hr after dosing also tended to be higher after the high protein meal and after dosing with 500 ml water on an empty stomach than after other solid dose treatments.


Diphenylhydantoin elimination kinetics in overdosed children. Diphenylhydantoin (DPH) elimination was studied in 4 overdosed children who presented with serum concentrations ranging from 44 to 76 mg/l. Serum was assayed for DPH and urine was assayed for both DPH and 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The serum and urine data were subjected to simultaneous computer nonlinear regression analysis using a one-compartment pharmacokinetic model, which accounts for much of the known disposition kinetics of DPH. Computed values for the apparent in vivo Michaelis-Menten constants, K-M and V max, were compared with values derived from data in the literature for normal adult subjects. A trend toward relatively lower K-M and higher V max/K-M values was seen in children. Patients with higher V max values had greater urinary excretion rates of HPPH which, at high serum levels of DPH, were relatively constant except for an apparent diurnal rhythm. The time of onset of DPH toxicity in the children was related to the magnitude by which the rate of DPH administration exceeded the V max values.


Pharmacokinetics of ifosfamide.

Pharmacokinetics of ifosfamide. A multicompartment pharmacokinetic model for ifosfamide has been employed using a system of first-order differential equations, which includes a term for metabolism according to Michaelis-Menten kinetics in order to describe the distribution and elimination parameters of ifosfamide in man. The model satisfactorily accounts for all the administered drug. The pseudometabolic rate constant for ifosfamide in man is found to be less than 20 percent of that reported for cyclophosphamide in man, in agreement with the more extensive metabolism of cyclophosphamide than ifosfamide. A number of the pharmacokinetic parameters for ifosfamide differ substantially from those reported for cyclophosphamide. The volume of distribution for ifosfamide metabolites was found to be approximately equal to the plasma space volume. The central compartment volume for intact ifosfamide is slightly larger than for cyclophosphamide and includes the easily diffusible extravascular space of the body and suggests lack of protein binding. The renal clearance of ifosfamide is low and about twice that of cyclophosphamide. The model indicates that only a small fraction of the total metabolites distribute into the peripheral compartment and suggests that multiple doses of the drug may be useful.


Clinical and radiological features of aberrant insertion of the common bile duct. Five examples of aberrant insertion of the common bile duct into a duodenal diverticulum are reported. One is thought to be the fifth published case diagnosed pre-operatively by simple radiological techniques. The association with biliary and pancreatic disease is emphasised, together with the possibility of surgical relief. The literature is reviewed and the radiological features discussed with a view to increasing the frequency of preoperative diagnosis.


Primary lymphoreticular tumours in the orbit. This paper reviews 46 cases of primary lymphoreticular tumours presenting in the orbit treated at the Christie Hospital between 1932 and 1969. Primary control of the orbital disease was readily achieved with a single exposure of 800 rad of orthovoltage X-rays to a single anterior field of 7 cm diameter and no case recurred in the orbit. The extent of the disease is a more important factor than the exact histological diagnosis in determining the prognosis, but none of five cases of benign lymphoma has developed disease elsewhere in a period of 5-7 years after treatment. The prognosis is good with a crude five-year survival of 54 percent, but if the disease is initially confined to the orbit 70 percent survive five years.


A comparison of thermography, radioisotope scanning and clinical assessment of the knee joints in haemophilia. Thermography, radioactive scanning and clinical assessment of the knee joints of a series of patients with haemophilia or Christmas disease have been performed. A positive correlation was found between the abnormalities of the thermograms, radioactive scans and the clinical signs in acute haemarthrosis, but not in chronic haemophilic joint disease nor in patients without clinical joint disease. No correlation between the thermograms, radioactive scans and the number of previous joint bleeds was shown. Thermography and radionuclide scanning provide rapid means of quantifying changes within the haemophilic joint and may be useful in assessing treatment of haemophilic haemarthrosis.


Congenital fusion of bones: radiology, embryology and pathogenesis. Congenital fusion of bones of the limbs, a recurrent feature in thalidomide embryopathy, is discussed in terms of embryology. It is deduced that congenital fusion is neither a bone disease nor a cartilage disease, but a disorder of organisation of mesenchyme in the fifth week of life. It is suggested that the organising tissue is the sensory nerve. Hereditary influence is briefly mentioned.


Congenital absence of a pedicle in a cervical vertebra. The importance of agenesis of a pedicle lies in its resemblance to a destructive lesion of the pedicle or to an expanding lesion in an intervertebral foramen. The correct diagnosis can be made roentgenologically by demonstrating a widened intervertebral foramen at the level of an absent pedicle with posterior displacement of the maldeveloped lateral mass. Two cases of agenesis of a pedicle in a cervical vertebra are presented.


The value of tomography of the sterno-clavicular region. Nine patients out of a series of 20 are presented illustrating some of the conditions which may affect the sterno-clavicular region (SCR). The value of tomography as a routine procedure in the study of the SCR is stressed, as in many cases the plain film studies fail to reveal clear-cut evidence of pathological changes. Establishing the exact aetiological nature of the lesion is not always possible by means of radiology alone. However, the radiological demonstration of disease in the SCR is invaluable as a guide to the further management of the patient.


Total hip prosthesis: real and apparent dislocation. Asymmetry of the femoral head within the acetabular cup shown in an antero-posterior radiograph of the hip is an indication of dislocation of the prosthesis after a Charnley-Müller procedure. However, this rule does not apply to modifications such as the Aufranc-Turner prosthesis.


Cumulative radiation effect. part IV. Normalisation of fractionated and continuous therapy - area and volume correction factors. In three previous papers, a scale of accumulated sub-tolerance radiation damage, the Cumulative Radiation Effect (CRE), was described for fractionated treatment regimes and continuous radiation therapy from both long-lived and short-lived sources. This scale provides a means of assessing and comparing the biological effects of various treatments. In this paper, it is intended to further the scope of application of the CRE-system by describing in detail the normalisation between the assessments of fractionated and continuous therapy. To do this, it is necessary to consider area and volume correction factors, whose roles are to modify the values of uncorrected CREs so that a specific biological effect, regardless of the area or volume treated, is described by a unique value of the corrected CRE. The problem arising when the CRE achieved by a treatment regime is not constant over a volume is briefly discussed and a simple hypothesis is proposed which may stimulate interest in this problem. The establishment of a normalisation procedure between fractionated treatment regimes and continuous radiation therapy, which is the primary aim of this paper, serves to integrate the concept of the CRE into a unified system of assessment of biological damage, so that a unique value of the CRE describes a specific level of biological damage regardless of the area or volume treated, or the time course of administration of the radiation employed.