Femoral artery pressure measurement during aortography. Femoral artery pressure (FAP) measurements were carried out to evaluate the hemodynamic significance of aorto-iliac occlusive disease in 150 patients (173 limbs) at the time of transfemoral angiography. Clinical assessment based upon traditional criteria of claudication level, pulse examination, and monoplane angiography were at variance with the results of this physiologic testing in approximately one-third of the patients. Results were most variable, and FAP testing most helful in evaluating patients with moderate diffuse disease on angiography, who are usually difficult to evaluate clinically. Strong correlation existed between FAP evaluation and the results of arterial reconstructive surgery. Of the patients with a positive FAP result who underwent proximal vascular reconstruction, 96% had satisfactory relief of ischemic symptoms despite uncorrected distal disease in the majority. In contrast, 57% of the patients undergoing proximal operation despite a normal FAP result were unrelieved of symptoms and required subsequent distal procedures. Similar correlation existed with results of femoro-popliteal and femoro-femoral grafting. This simple physiologic test has been found of great value in selecting the proper level of arterial reconstruction and in accurately predicting the results of surgery.


The elderly patient with severe arterial insufficiency of the lower extremity: limb salvage by femoro-popliteal reconstruction. To determine the feasibility of limb salvage in elderly patients in whom severe ischemia of the lower extremity is present, the results of femoro-popliteal reconstruction done primarily for limb salvage were reviewed. Of 310 femoro-popliteal bypasses, 72 were performed on patients 70 years of age or older. In the over-70 group, ischemic necrosis was present in 70.8% rest pain in 22.2%, and claudication in 7.0%. Initial limb salvage patients 70 years of age or older was 71.4%. Cumulative limb salvage at 5 years was 51.1% and at 10 years was 44.8%. Operative mortality, including mortality of subsequent amputation, when required, was 8.3%. Appreciable limb salvage can be achieved by femoro-popliteal arterial reconstruction in lieu of primary amputation in elderly patients in whom severe arterial insufficiency of the lower extremity is present.


Asymptomatic coronary artery disease managed by myocardial revascularization: results at 5 years. A consecutive series of 17 patients surgically treated for asymptomatic coronary artery disease was surveyed for survival, clinical status, and graft patency after a mean follow-up of 75 months. Documented myocardial infarction (MI), 14 transmural and 3 subendocardial, was the major indication for catheterization. All patients were asymptomatic for at least 4 months prior to surgery. Six patients had greater than 70% obstruction in one vessel, seven in two vessels, and four in three vessels. The indication for revascularization was critical stenoses in vessels supplying large areas of viable myocardium. All patients received left internal mammary artery (LIMA) grafts to the left anterior descending coronary artery; seven patients also received saphenous vein grafts (SVG) to other vessels. There was no operative or late mortality.  In 12 patients, postoperative angiography (mean interval, 12 1/2 months) showed 11/12 LIMA and all SVG patent. One incompletely revascularized patient with an occluded LIMA is symptomatic. All others are fully active without symptoms or interval MI after a minimum follow-up of 5 1/2 years. The safety and long-term results of myocardial revascularization warrant its consideration for selected asymptomatic postinfarction patients.


Comparison of myocardial protection with nifedipine and potassium. Nifedipine, a slow-channel calcium blocker, is thought to provide useful myocardial protection during prolonged total ischemia and reperfusion. An isolated, isovolumic, feline heart model was used to asses the effectiveness of nifedipine in both cardioplegic (100 microgram/10 ml) and noncardioplegic (10 microgram/10 ml) doses for providing myocardial preservation during 90 minutes of hypothermic ischemic arrest and 45 minutes of normothermic reperfusion. Use of nifedipine was compared to hypothermia (27 degrees C) alone and to hypothermia with potassium cardioplegia. Ventricular function was assessed by recovery of isovolumic left ventricular developed pressure and dP/dt. Myocardial carbon dioxide tension (PCO2) and myocardial oxygen tension (PO2) were measured by mass spectrometry. Potassium cardioplegia and the higher dose of nifedipine resulted in immediate asystole. The rates of rise of PCO were greatest in the group receiving 10 microgram nifedipine and in the control group. The rates of rise in the two cardioplegic groups were significantly lower. Recovery of ventricular function was significantly lower with low-dose nifedipine than with potassium cardioplegia. Higher dose nifedipine resulted in a return of function, which was no different than with potassium cardioplegia. Morphologic protection was better with higher dose nifedipine and potassium cardioplegia than with either low-dose cardioplegia or hypothermia alone. These results demonstrate that nifedipine in a cardioplegic dose results in preservation of myocardial structure and function that is similar to that obtained with potassium cardioplegia. In lower noncardioplegic dose, nifedipine does not appear to offer additional protection compared to hypothermia alone. Whether persistent depression of ventricular contractility will limit nifedipine's clinical usefulness as a myocardial protection agent will require further study.


Unstable angina pectoris: an examination of modes and costs of therapy. Debate exists over the most appropriate form of treatment for patients with unstable angina pectoris. This study examined 106 patients randomized at the University of Alabama in Birmingham as part of the National Cooperative Study Group and focuses on the phenomenon of patients who fail medical therapy and thus require late surgery, and the costs of therapy. Discriminant function analysis revealed that the significant predictors (p less than 0.01) of patients who would later require surgery were: total number of vessels diseased, angina severly, presence of congestive heart failure, hypertension, and number of years that the patient had had angina. By means of this analysis, 85% of the late surgery patients were correctly predicted. Late surgery patients averaged 2.4 diseased vessels vs 1.5 for persistent medical patients (p less than 0.01). Mean charges for the first 2 years in the study were $6,226 (SD $2,967) for persistent medical patients, $10,416 (SD $2,146) for surgery patients, and $20,059 (SD $10,748) for late surgery patients (p less than 0.001). These data indicate that surgery is clearly an expensive procedure; but that it is more expensive for late surgery patients, who have total costs that are twice as high as surgical costs and 3.5 times as high as persistent medical costs.


A new cardiac prosthesis: the St. Jude Medical cardiac valve: in vivo results. The St. Jude Medical cardiac valve prosthesis is a low profile, lightweight, bi-leaflet, central-flow device constructed entirely of pyrolytic carbon. In vivo testing was performed in 24 cows in which the tricuspid valve (n = 14) or mitral valve (n = 10) was replaced by a St. Jude Medical prosthesis with a 26 mm tissue annulus diameter. Eight animals died in the operative period. The 16 surviving animals were sacrificed at 4, 8, 12, or 18 weeks. There were no valve-related deaths nor mechanical valve failures. Anticoagulation was not used in the postoperative period during which time monthly laboratory parameters were obtained including hemoglobin, hematocrit, white cell count, red cell count and indices, lactic acid dehydrogenase, serum haptoglobin, and, additionally at sacrifice, platelet and red cell morphology. Values indicated this prosthesis did not cause hemolysis. At sacrifice the pulmonary arterial tree and peripheral organs showed no evidence of thromboemboli. There was smooth endocardial ingrowth on all valve sewing rings. One valve had thrombus formation on the valve sewing ring. Nine animals were anesthetized prior to sacrifice and underwent open cardiac catheterization. Ventriculography (n = 6) showed minimal transvalvar reflux, and atriograms (n = 6) demonstrated central flow. Transvalvar gradients were 0 to 22 mm Hg (n = 9). One valve of an 18-week tricuspid implant was examined for wear; valve life was calculated to be greater than 2500 years. These data in conjunction with in vitro test results justify clinical trial of the St. Jude Medical prosthesis.


Primary clinical experience with the Hall-Kaster valve in the aortic position: results at 3 months including hemodynamic studies. The Hall-Kaster pivotal disc prosthetic heart valve was introduced in 1977. The primary goal of the design was to obtain the least possible obstruction to flow. Toward this end, innovations in the tilting axis, disc guidance mechanisms, and disc translational freedom combine to improve flow through both orifice segments of the open valve. The present study reports the primary clinical and hemodynamic findings in 28 patients (mean age, 53.8 years) with aortic valve disease, examined 3 months after insertion of the Hall-Kaster pivotal disc valve. The hemodynamics findings displayed low gradients and high calculated orifice areas. Satisfactory flow was observed through both the major and minor openings of the prosthesis. There were no arterial thromboembolic episodes. The increase in serum lactate dehydrogenase activity was moderate, indicating a slight-to-moderate intravascular haemolysis.


In vitro hydrodynamic comparison of mitral valve bioprostheses. With the use of the pulse duplicator built in our laboratory, the hydrodynamic characteristics of three sizes of the four commercially available mitral bioprostheses, Hancock, Carpentier-Edwards, Angell-Shiley, and Ionescu-Shiley, were studied and compared. A wide range of performance was found: for example, during pulsatile testing, at peak flow of 15 1/min (corresonding to a normal resting cardiac output) transvalvular gradients varied from as high as 20 mm Hg (Angell-Shiley) to 5 mm Hg(Ionescu-Shiley) in the 25 mm mounting diameter size. Effective orifice areas (EOA) are significantly different in valves of the same mounting size, e.g., at peak flows of 20 1/min, the Ionescu-Shiley 25 provides an EOA of 1.7 cm2 while the Angell-Shiley provides only 1.17 cm2. The EOAs of all bioprostheses have been found to increase with increasing flow (e.g., from 10--30 1/min peak flow, the Hancock 25 changed from 1.25 cm2 to 1.50 cm2). The Gorlin formula, as constituted for calculating the area of stenotic mitral valves, is inappropriate for prosthetic valves. But the discharge coefficients of the bioprostheses have been found to be around 1 when the planimetered area of the open valve orifice is determined at a given flow. By using this discharge coefficient, the Gorlin formula will give an excellent estimate of the true orifice area of mitral bioprostheses.


Preoperative evaluation of subvalular fibrosis in mitral stenosis. A predictor factor in conservative vs replacement surgical therapy. To assess the degree of mitral subvalvular fibrosis (SVF) in patients with mitral stenosis, left ventriculograms were reviewed, and a mitral subvalvular distance ratio (DR) was determined by dividing the distance from the papillary muscle tips to the closed mitral leaflets in systole by the distance from the aortic valve to the left ventricular apex in diastole. In 15 patients with normal ventricles, the mean DR was 0.244 +/- 0.017. In nine patients with minimal SVF, the mean DR was 0.181 +/- 0.025. In 10 patients with moderate SVF, the mean DR was 0.148 +/- 0.033. In 5 patients with severe SVF, the mean DR was 0.087 +/- 0.009. All mean DRs were mutually distinguishable at p less than 0.01. The clinical results and preoperative DR of 28 patients who had mitral commissurotomy were reviewed. A DR of less than 0.140 precluded a good longterm result from mitral commissurotomy alone. The DR reliably predicts the degree of SVF preoperatively and identifies patients with mitral stenosis who require valve replacement or a direct surgical attack on the subvalvular mechanism.


Surgery in active infective endocarditis. Controversy persists concerning the role of early surgical intervention in severe infective endocarditis (IE). We therefore reviewed 163 episodes of well-documented IE in which 32 cardiac operations were performed during the active phase of IE. Congestive heart failure (CHF) was the principal indication for surgery in 88% (28/32); systemic emboli, 1/32; and persisting sepsis, 3/32. Staphylococcus and enterococcus were the most common infecting organisms in the operative group (44% and 16% respectively). Surgical mortality (11/32,37%) did not differ (p greater than 0.05) from medical mortality (26/131,20%). All 11 operative deaths occurred in patients moribund prior to surgery, including three with preoperative cardiac arrest. Surgical patients undergoing preoperative cardiac catheterization demonstrated marked CHF: a mean left ventricular end-diastolic pressure of 25.3 mm Hg. The mean cardiac index in 8/11 surgical deaths was lower (p less than 0.05) vs surgical survivors: 2.21/min/m2 vs. 3.21/min/m2. Postoperative complications were rare in the 21 surgical survivors. There were no episodes of continued infection, prosthetic dehiscence, or advanced heart block; only one paravalvular leak; and one systemic embolus. These findings emphasize the high medical and surgical mortality in patients with IE, suggest that delayed operative intervention may be a major causative factor resulting in a high surgical mortality, and justify an aggressive surgical approach in patients with valve dysfunction and heart failure. These data indicate that survivors of surgical intervention during active IE have eradication of infection and few postoperative complications.


Late hemodynamic evaluation of Hancock Modified orifice aortic bioprosthesis. Nineteen patients with Hancock Modified Orifice prosthesis (HMO-250), size 19 to 23 mm, were recatheterized 6 to 16 months following aortic valve replacement (AVR). Although hemodynamic characteristics varied widely, HMO-250 compared favorably to the standard model 243 (less than 0.05). Mean peak resting gradient across HMO-250 was 14.8 torr at rest and rose to 26.8 torr with exercise. Systolic gradients for HMO-250, both resting and exercise, were improved for 21 mm (p less than 0.01), but not for 23 mm. Increasing the patient's body surface area (BSA) correlated with increasing gradients for 23 mm (p less than 0.05), but was unrelated to 21 mm. Effective orifice areas were similarly found to be improved with 21 mm HMO-250 but unchanged for 23 mm. Use of the 21 or 23 mm size HMO for AVR is supported only when the patient's body surface area is less than 1.8 m2. If the body surface area is greater than 1.8 m2, annulus enlargement and a larger size bioprosthesis should be employed. Use of 19 mm porcine xenograft for AVR is not supported.


An important complication of Hancock mitral valve replacement in children. Nine children ages 2--15 years have undergone mitral valve replacement (MVR) with Hancock porcine heterograft valves for severe mitral insufficiency. The etiology of the mitral valve disease was rheumatic in two patients, and congenital in seven. Porcine valve sizes ranged from 19--31 mm. Follow-up has been from 1.6 to 6.1 years (mean, 4.3 years). All nine children have had marked postoperative improvement, no thromboembolic complications despite no long-term anticoagulations, and no episodes of endocarditis. There have been no early or late deaths. Although six of the nine patients remain asymptomatic, three others developed severe fibrocalcific obstruction of the heterograft, requiring valve re-replacement at 3.5, 3.6, and 4.8 years following the initial valve replacement. This complication has not been previously reported in children. It is a factor that must be considered when deciding on MVR for children and their postoperative management.


Quantification of serum IgE in patients with burns. IgE levels in the serum of individuals with burns were sequentially measured and compared to IgE levels in normal control blood donors. Following a burn, the levels of IgE protein showed a significant, although modest, increase, usually evident of IgE protein showed a significant, although modest, increase, usually evident between days 14 and 22. In an occasional patient, the IgE levels rose by as much as five times in value during this period. Because of the complexity of the clinical situation associated with the burn patients, we cannot ascribe these elevations of IgE to the burn per se, but must consider the possibility of other factors, especially those involved in the treatment of the burn as well as the infection. The magnitude of the elevation of IgE in the burn patients (geometric mean=272 ng/ml) was considerably lower than the magnitude of the elevations seen in atopic dermatitis and generalized neurodermatitis (geometric means=2265 and 2071 ng/ml, respectively). Thus simple trauma to the skin is not a sufficient explanation for the elevated serum IgE levels in atopic dermatitis and generalized neurodermatitis.


Acute asthma compared with exacerbations of chronic bronchitis: changes in complement. Complement levels were measured on admission and at 1 and 7 days following admission in twenty patients with acute severe asthma and ten patients with an acute exacerbation of chronic bronchitis. Although no evidence of hypocomplementaemia was found in any patient, there was a mean fall within the normal range of the individual complement components, C4, C3 and factor B in both groups. The mean fall occurred earlier in the bronchitics than in the asthmatics and this may be related to infection or the administration of corticosteroids. There was a significant fall in C3 (P greater than 0.05) in the bronchitics compared with the asthmatics at 24 hr. From our study, however, we could find no evidence of excessive utilization of complement in acute asthma.


The nature of asthma in Brisbane.

The nature of asthma in Brisbane. Clinical details and skin prick test reactions are described for 183 asthmatic patients who attended an asthma clinic at the Royal Brisbane Hospital in 1976. These features were compared with similar studies reported from London, Sydney, Tristan da Cunha and New Guinea. Asthma in Brisbane was shown to be similar in many ways to asthma in those centres; however, a higher frequency of positive immediate skin test reactions to antigens of A. fumigatus, a larger percentage of skin test-negative patients developing symptoms before the age of 10 years, and a lack of association between the age of onset of symptoms and number of positive skin tests was noted. A difference in mean weal diameter (in mm) on skin testing with house dust mite antigens was not found between patients giving a history of sensitivity to these antigens and those that did not. A seasonal increase in symptoms was only described by 27% of patients.


Atopic disease and month of birth.

Atopic disease and month of birth. Analysis of the month of birth of 1715 children with asthma shows clear evidence of a higher proportion of the group having been born between May and October (54.8%) than would be expected by comparison with the population of England and Wales (50.2%). Inspection of the distribution of month of patients with hay fever and for patients with positive skin reactions to mixed grass pollen does not account for this seasonal variation but children with positive skin reactions to Dermatophagoides pteronyssinus show a high proportion (56.2%) born in the period May to October. Although the reasons for the variation of pattern of month of birth in asthmatic children are uncertain, further study of sensitization in early life might clarify them.


Immunological parameters in perennial rhinitis. As part of a study of the effectiveness of beclomethasone dipropionate in perennial rhinitis five immunologically related parameters were measured. These included skin tests, total IgE, specific IgE, nasal and peripheral blood eosinophil counts. In addition, nasal biopsies were obtained in twenty out of sixty patients. It was apparent that patients with perennial rhinitis formed a heterogeneous group who could be divided into three groups based on the extent of immunological abnormality detected. Group 1 consisted of twenty patients who displayed no abnormality in any of the five parameters studied. Group 2 consisted of twenty-six patients in whom specific IgE was not detected but who had varying degrees of abnormal findings in the other laboratory parameters. The remaining fourteen patients formed a third group in whom specific IgE was detected in addition to abnormalities in other parameters. In general, patients with detectable specific IgE had a higher frequency of abnormal parameters, including abnormal histology of their nasal biopsy, than patients in whom no specific IgE was detected. The heterogeneous nature of perennial rhinitis is discussed. Despite the heterogeneous nature of the total patient group, the majority of patients (80%) treated with beclomethasone dipropionate improved compared to 20% improved in the placebo group. There was no difference in the drug effect between the three groups of patients.


Occupational asthma due to inhaled carmine. Two patients are described with occupational asthma due to carmine, a natural dye extracted from the insect Coccus cactus. Both had dual asthmatic reactons after carmine inhalation. Oral challenge provoked gastrointestinal symptoms in one patient, and asthma in them both, perhaps accounting for their continuing symptoms. One patient worked extracting carmine from the insects and the other used carmine as a cosmetic colouring agent.


An evaluation of the Olympus "Quickrate" analyser. The Olympus "Quickrate", a photometer built for both kinetic and end point analysis was evaluated in this laboratory. Aspartate transaminase, lactate dehydrogenase, hydroxybutyrate dehydrogenase, creatine kinase, alkaline phosphatase and gamma glutamyl transpeptidase were measured in the kinetic mode and glucose, urea, total protein, albumin, bilirubin, calcium and iron in the end point mode. Overall, good correlation was observed with routine methodologies and the precision of the methods was acceptable. An electrical evaluation was also performed. In our hands, the instrument proved to be simple to use and gave no trouble. It should prove useful for paediatric and emergency work, and as a back up for other analysers.


Resolution of age-dependent reference intervals: polynomial regression methodology with applicability to plasma zinc levels in a childhood population. We present a systematic parametric method for resolving age-related reference intervals based on differential-polynomial regression analysis. Application of this method to plasma zinc concentrations in a childhood population results in a third degree polynomial expression from which two statistically independent age-reference intervals are derived. The method appears to be useful in describing age-dependent concentration trends particularly for pediatric and geriatric populations.


Assessment of the Beckman oxygen rate analyzer for the enzymatic assay of cholesterol. We describe an evaluation of the Beckman oxygen rate analyzer for the determination of cholesterol. The precision and accuracy obtained did not fulfill the short-term criteria of the Center for Disease Control but the precision met the criteria of the College of American Pathologist for analysis of cholesterol in screening programs. Good overall correlation between the oxygen rate method and a continuous-flow method with prior extraction was found for patient samples. The results obtained by the oxygen rate method had net positive bias up to the limit of linearity of 8.6 mmol cholesterol/liter. The instrument is not recommended for laboratory or epidemiological studies but may prove useful in screening programs.


Rapid thin-layer chromatographic method for the detection of urinary methylmalonic acid. 1. Simple and rapid thin-layer and micro-thin-layer chromatography techniques are described for the detection of methylmalonic acid in urine. 2. The separation of methylmalonic acid from a crude urine sample is performed by thin-layer chromatography with a mixture of silica gel-cellulose and butanol - acetic acid - water solvent system. The methylmalonic acid spot is visualized with tetrazotized o-dianisidine. 3. This system has been successfully developed for a urinary screening programme; it was shown as simple, convenient and rapid, eliminating false-positives and allowing the detection of even traces of methylmalonic acid.


Assessment of the Beckman creatinine analyzer 2. An evaluation of the Beckman Creatinine Analyzer 2 has been carried out. Good day-to-day and within-day precision was obtained. Analyses of quality control materials, studies of linearity, and comparison of the results obtained for samples from patients with the results obtained by a continuous-flow method evidenced good accuracy. Aceto-acetate in serum caused significant positive interference. The desirable performance characteristics and practicability make this Analyzer attractive to the clinical chemist, particularly for paediatric and emergency laboratory use.


Single column high pressure liquid chromatographic determination of drugs in blood. 1. Analysis of anticonvulsants (phenobarbital, diphenylhydantoin and carbamazepine), theophylline and an antiarrhythmic agent (disopyramide) in blood using a simple high pressure liquid chromatography apparatus equipped with a reversed -- phase column is described. A simple extraction of plasma or serum with organic solvent is used to isolate the anticonvulsants and theophylline. Disopyramide is extracted with ether and is further purified by a back extraction into acid. 2. Hexanesulfonic acid -- methanol solutions are used for chromatography of the anticonvulsants and disopyramide while the mobile phase for theophylline is a NH4H2PO4 -- methanol mixture. Chromatographic analysis time for the drugs is approximately 15 minutes. The drugs are monitored by a UV detector at 254 nm except for theophylline which is measured at 280 nm. Quantitation is accomplished by comparison of peak heights with those of internal standards. Quantities of serum or plasma routinely used for analysis are: 200 ul for the anticonvulsants, 100 ul for theophylline and 0.5 ml for disopyramide. Detection limits are less than 1 ug/ml for these quantities.


Amphetamine metabolism in mice exposed chronically to phenobarbital and to phenobarbital with carbon tetrachloride. The metabolism of amphetamine was studied in three groups of mice, including normal mice (N), mice given chronic doses of phenobarbital via their drinking water (PB), and mice exposed to carbon tetrachloride vapors daily during the course of chronic phenobarbital consumption (PB/CCl4). Renal and hepatic tissue from animals of each group were examined by electron microscopy. Mice in the PB/CCl4 group demonstrated the classical symptoms of carbon tetrachloride-induced hepatic cirrhosis, and structural damage to the kidney. The PB group presented a normal renal pathology, but ultrastructural changes including swollen mitochondria and dilation of the endoplasmic reticulum were evident in the hepatocytes. The N, PB and PB/CCl4 mice excreted 84.5, 61.5 and 72.3 percent respectively of a dose of 14C-amphetamine sulfate in the 0-72 hour urine. Seven major urinary metabolites were detected in the normal group, 4 in PB group, and 3 in the PB/CCl4 group. Unchanged amphetamine, rho-hydroxyamphetamine and benzoic acid were tentatively identified by combined techniques of gas chromatography and thin-layer chromatography with autoradiography.


Evaluation of a new commercial radioassay kit for aldosterone using an iodinated tracer. We have evaluated a new non-chromatographic commercial radioimmunoassay kit for serum, plasma, and urine aldosterone levels which employs 125 iodine as the tracer. Within-run and run-to-run precision data show coefficients of variation of 3 to 6% and 8 to 16%, respectively. Recovery of aldosterone added to serum and urine at several levels range from 92 to 109%. Antibody specificity was tested with six structurally related steroids at grossly elevated concentrations and no crossreactivity was observed. Serum or plasma can be used interchangeably in the assay, and normal levels correspond to generally accepted values.


Hyperprolinemia type II: evidence of the excretion of 3-hydroxy delta 1-pyrroline 5-carboxylic acid. We report the identification of delta 1-pyrroline 3-hydroxy 5-carboxylic acid (hydroxy PCA) in a previously reported patient with hyperprolinemia Type II. This compound had been called pseudo PCA in a previous report.


An ultraviolet spectrophotometric procedure for the routine determination of naproxen. 1. A procedure for the routine assay of Naproxen in serum by ultraviolet spectrophotometry is presented. The absorption coefficient (A1 1% cm) of Naproxen in methanol at 261 nm was found to be 216. 2. The Naproxen procedure appears to be relatively free from interferences of commonly coadministered medications. Salicylate interference is eliminated by a modified procedure. 3. Concentrations of Naproxen in a limited number (40) of clinical samples ranged from non-detected to 12.5 mg/dl. The therapeutic concentration appears to be 4 to 6 mg/dl (174-260 mumol/L).


Simultaneous measurements of acetaminophen and salicylate in plasma by liquid chromatography. We describe a "highly-performance" liquid chromatographic method in which 8-chlorotheophylline is used as an internal standard to determine acetaminophen and salicylate simultaneously in plasma samples. Therapeutic as well as toxic concentrations can be determined on samples as small as 50 micro L, which makes the method particularly useful for determinations on samples from young children. The procedure requires a simple extraction of the drugs, and the chromatography is completed in 6 min.


Evaluation of the Beckman creatinine analyzer. We compared results obtained with the Beckman Creatinine Analyzer (Beckman Instruments, Inc.) to those with the GEMSAEC Centrifugal Analyzer (Electro-Nucleonics, Inc.) and with a manual method for determination of creatinine in serum and urine. Linearity, stability, recovery, and precision were evaluated. Interference from bilirubin, protein, lipemia, uric acid, and hemolysis is negligible, but acetone and acetoacetate can interfere.


Calibration and monitoring of spectrometers and spectrophotometers. We have delineated some of the factors affecting the performance of spectrometers and spectrophotometers in the clinical laboratory and have presented some of the methods for verifying that these instruments are functioning properly. At a minimum, every laboratory should perform periodic inspections of spectrometric functions to check wavelength calibration, linearity of detector response, and stray radiation. Only through such an inspection program can a laboratory ensure that these instruments are not contributing to inaccurate analytical results.


The use of linear models and matrix least squares in clinical chemistry. We present a unified approach to the use of linear models and matrix least squares with the intention of providing a better understanding of the techniques themselves and of the statistics that arise from these techniques as they are used in clinical chemistry. Emphasis is placed on the importance of appropriate experimental designs and adequately precise measurement processes for efficiently obtaining the desired information.


Power functions for statistical control rules. We have studied power functions for several control rules by use of a computer simulation program. These power functions show the relationship between the probability for rejection and the size of the analytical errors that are to be detected. They allow some assessment of the quality available from present statistical control systems and provide some guidance in the selection of control rules and numbers of control observations when new control systems are designed.


An evaluation of the detection capacity of a computer-assisted real-time delta check system. We developed of computer programs to evaluate the clinical reliability of test results by comparing each new result with previous results for the same patient, and to signal discrepancies in real time. These "delta check" discrepancies are noted, and they must be reviewed by the laboratory staff before results can appear on a patient's record. During a month, I reviewed 1403 such delta check messages and detected 55 (3.9%) that could not be explained on the basis of the patient's clinical condition. Of these, 23 represented true laboratory errors, which were corrected. The recognition of discrepancies before they appear on patients' reports has facilitated the operation of the clinical chemistry laboratory. Mislabeled and otherwise mishandled specimens are discovered before erroneous results appear on a patient's record.


Preparation and stability of a liquid creatine kinase isoenzyme control from rabbit serum. The MB isoenzyme of creatine kinase (CK) may be prepared in vitro from rabbit serum containing only the MM and BB isoenzymes, by means of a hybridization technique. The MM and BB dimers dissociate in 4 mol/L urea, which allows random recombination of M and B monomers. A liquid CK-isoenzyme control can be made from mixtures of rabbit sera obtained after hybridization and stabilized with glycerol and 25 mmol of 2-mercaptoethanol per liter. A liquid control stored at 4 degrees C showed good stability over a three-month period, declining to a mean residual activity of CK of approximately 90% after three weeks and a mean residual activity of MM, MB, and BB of 80--85% after six weeks. At 25 degrees C, CK activity of the liquid control declined to 75--80% after the fourth week. CK-BB at 25 degrees C was the least stable isoenzyme, declining to 75% after the third week and reaching 60% of activity after 12 weeks. CK-MB and CK-MM showed approximately 10--15% less stability at 25 degrees C than at 4 degrees C.


Glycohemoglobin and glucose tolerance tests compared as indicators of borderline diabetes. We concurrently measured glycohemoglobin and performed 3-h oral (100 g) glucose tolerance tests on 69 ambulatory patients suspected of having abnormal carbohydrate metabolism. The patients were divided into two groups: (a) The 37 patients for whom the results were normal had plasma glucose concentrations of 0.70--1.15 milligram during fasting and 0.70--1.23 g/L 2 h after glucose ingestion. (b) Borderline diabetics exceeded one or both of these limits. The range of glycohemoglobin in the normal group was 3.0--4.7% of total hemoglobin. Of the 21 borderline diabetics, 11 had increased glycohemoglobin (4.8--8.0%). The difference in tolerance test results between borderline diabetics with and without increased glycohemoglobin was insufficient to predict the status of glycohemoglobin. We suggest a tentative definition for latent diabetes: increased glycohemoglobin in the presence of normal or borderline-abnormal glucose concentration in plasma collected during fasting.


A direct radioimmunoassay of serum cortisol with in-house 125I-tracer and preconjugated double antibody. We describe a radioimmunoassay of serum cortisol in which 125I-tracer and preconjugated double antibody are used. This simpler method involves direct serum assay, and the majority of reagents are prepared in-house. Within-assay precision (coefficient of variation) of assay of Ortho Diognostic RIA Cortisol I and II was 3.2% (mean = 131 microgram/L, n = 10) and 2.2% (mean = 405 microgram/L, n = 10), respectively. Between-assay precision (coefficient of variation) for the same controls was 6.7% (mean = 128 microgram/L, n = 62) and 5.6% (mean = 395 microgram/L, n = 62), respectivley. By using automatic pipetters and a gamma counter with a data-reduction package, a technologist can complete 100 assays in less than 3 h. The operating cost is approximately 10 cents per tube.


Determination of serum 5'-nucleotidase with a centrifugal analyzer. We describe a multi-point method for the determination of the serum enzyme activity 5'-nucleotidase by means of an NADH sensor reaction. Studies show that the assay may be carried out in one step, without preincubation, by using a GEMSAEC Fast Analyzer.


Blood-spot thyrotropin radioimmunoassay in a screening program for congenital hypothyroidism. We describe a highly sensitive and precise radioimmunoassay for thyrotropin in dried blood spots on filter paper cards. In a screening program for congenital hypothyroidism, blood-spot thyrotropin concentrations are measured in infants whose blood-spot thyroxine concentrations are in the lower 10%, and this strategy has reduced the recall rate from 1.7% (thyroxine assay alone) to 0.17%. Thyrotropin assay samples consist of discs 4.5-mm in diameter, containing about 6 microL of blood, punched from blood spots. By appropriate attention to assay conditions, a mean least-detectable thyrotropin concentration equivalent to 2.5 milliunits/L plasma has been achieved. Concomitant measurement of thyrotropin by plasma and blood-spot assays in 91 subjects yielded a Spearman rank correlation coefficient of 0.9732. An analysis of variance of the distribution volume of thyrotropin in blood spots and a covariance analysis of factors affecting blood-spot thyroxine results are presented.


Creatine kinase isoenzymes of mitochondrial origin in human serum. We measured creatine kinase (EC 2.7.3.2) activity in 1009 serum samples from 538 patients in the intensive-care units of the University of Texas Medical Branch hospitals. Creatine kinase isoenzymes migrating cathodal to skeletal muscle creatine kinase (CK-MM) on cellulose acetate electrophoresis were found in sera from 14 of the 538 patients. Creatine kinase, lactate dehydrogenase (EC 1.1.1.27), aspartate aminotransferase (EC 2.6.1.1), and alanine aminotransferase (EC 2.6.1.2) activities were abnormally increased in these 14 patients. Liver lactate dehydrogenase isoenzyme (LDH5) and cardiac creatine kinase isoenzyme (CK-MB) were abnormally increased in 12 and eight of these patients, respectively. Ten of the 14 patients died during their hospital admission. We believe the creatine kinase isoenzymes that migrated cathodal to skeletal muscle creatine kinase (CK-MM) were of mitochondrial origin.


Hyperamylasemia and ovarian carcinoma.

Hyperamylasemia and ovarian carcinoma. We present a case of advanced ovarian carcinoma associated with high concentrations of serum and urine amylase. Biochemical analysis to elucidate the nature and origin of the hyperamylasemia identified seven amylase isoenzymes, of which five appeared to be distinct from normal salivary and pancreatic amylase. We discuss the nature of amylase isoenzymes produced by malignant tumors.


Polychromatic analysis: new applications of an old technique. As a means of correcting for many potential interferences, polychromatic analysis offers an effective alternative to either sample pretreatment or separate blank determinations. Because of the differing spectral characteristics of each interfering species, and the nature of these interferences (static vs. kinetic), the application of polychromatic analysis must be optimized for each analytical procedure to minimize all residual errors. Overall assay precision can be maximized by proper use of flagging procedure to minimize all residual errors. Overall assay precision can be maximized by proper use of flagging procedures (also based on polychromatic analysis). By using a second wavelength measurement, the analyst can also verify the accuracy of an analytical measurement in selected situations. These applications of polychromatic analysis are a departure from conventional analytical procedures in allowing for correction of various interferences in the actual reaction mixture, without making assumptions about the recovery of analyte during pretreatment or the equivalent absorptivity of interferent in both blank and assay solutions.


Fluoroimmunoassay for human choriomammotropin. We describe an immunoassay for human choriomammo-tropin by use of the fluorescein-labeled hormone (of human origin). The technique is generally similar to the radioimmunoassay for this material, but has the advantage of stability of tracer and avoidance of radiation hazard. However, the procedure requires approximately 50-fold more tracer than does the radioimmunoassay, and this would be a disadvantage with materials for which supplies of purified antigen are scarce. Furthermore, both within-assay variation (3.9%) and between-assay variation (7.8--7.9%) were less satisfactory than that of radioimmunoassay (1.5% and 2.2--3%, respectively). This is almost certainly the result of imprecision of end-point detection and could probably be corrected by further attention to equipment design.


Enzymic assay of total cholesterol involving chemical or enzymic hydrolysis--a comparison of methods. Manual procedures for estimating serum total cholesterol by use of cholesterol oxidase (EC 1.1.3.6) and the phenol--aminophenazone--peroxidase chromogenic system are described, in which cholesteryl esters are hydrolyzed either by use of pancreatic cholesterol ester hydrolase (EC 3.1.1.13) or saponification by ethanolic potassium hydroxide. Both methods are linear up to a cholesterol concentration of 12 mmol/L and are reproducible (between-run CV, about 1.1%). The chemical hydrolysis method yields results that are about 10% lower than those obtained by enzymic hydrolysis, because of incomplete removal of interfering thiols generated during the saponification of serum. The chemical hydrolysis procedure is much less susceptible to interferences, particularly by bilirubin, but the enzymic hydrolysis system is simpler to perform and therefore has a greater potential for mechanization.


Application of Bayes's theorem to results of quantitative clinical chemical determinations. The diagnostic implication of a certain test result with regard to a certain condition can be expressed as a single number, L, the likelihood ratio of this result. This ratio allows Bayes's theorem to be written in a convenient form. We show that the practice of calculating predictive values for the results of quantitative tests by use of discrimination limits leads to incorrect predictive values. Including L values in laboratory reports seems a more logical approach to optimum interpretation of laboratory results than the use of discrimination values.


Heterogeneity of chloramine T- and lactoperoxidase-radioiodinated human calcitonin. Radioiodination reportedly damages peptides, but the nature of the damage has not been adequately examined. Utilizing isoelectric focusing, we examined the products of Chloramine T- and lactoperoxidase-directed radioiodinations of human calcitonin. Initially, the reaction products were purified by adsorption onto and elution from microfine silica (QUSO-G32). Radioiodination of the calcitonin by Chloramine T and lactoperoxidase produced a heterogeneous population of 125I-labeled peptides exhibiting apparent isoelectric points that were more acidic than that of unlabeled synthetic calcitonin. Variation in the products among radioiodinations and the inability of QUSO-G32 to resolve the components of the reaction mixture prompted our examination of alternative purification procedures. Anion-exchange chromatography on QAE-Sephadex effectively separated [125I]diiodotyrosine containing calcitonin from free iodine and [125I]iodolactoperoxidase. Our data indicate that: (a) radioiodination of human calcitonin by Chloramine T and lactoperoxidase induced alteration in the peptide as evidenced by isoelectric point, (b) specific [125I]iodopeptides vary in incidence and relative abundance among radioiodinations, (c) identification of the labeled amino acid in [125I]iodopeptides cannot ensure intergrity of the molecule, and (d) isoelectric focusing provides a method of comparing the products of peptide radioiodinations among laboratories.


Glucosuria: accuracy and precision of laboratory diagnosis by dip stick analysis. Two urine dip-stick assays for glucose were studied and compared to a quantitative hexokinase procedure. We determined sensitivity, specificity, predictive value of "normal" and "abnormal" dip stick results, assay efficiency, technologist precision, and method association. Precision was poor. Attempts to estimate urine glucose concentration with the dip sticks frequently produced gross inaccuracies. We believe the dip stick glucose assay should be considered qualitative only; as a qualitative test, the dip sticks are fairly efficient at distinguishing glucose concentrations of less than 0.3 g/L from concentrations greater than 0.3 g/L.


Quantitative analysis of serum lipoproteins by micro-scale thin-layer chromatography. A method has been devised for the complete chemical analysis of serum lipoproteins, in which the constituents are separated by thin-layer chromatography and then measured by means of a flame ionisation detector. Since the response of the detector differs for each constituent, it is necessary to use a previously prepared calibration curve for each one. A complete analysis can be obtained from a single run on about 20 microgram of lipoprotein. However, from 5--10 chromatograms are needed for an adequate degree of precision. The method, which could be adapted to the measurement of tissue lipids, takes less than 2 h to complete. This speed and simplicity seem to give the method considerable potential for the investigation of patients with disorders of lipid transport.


Serum glycylproline dipeptidyl aminopeptidase activity in human hepatic cancer. A method for the assay of glycylproline dipeptidyl aminopeptidase activity in the serum is described. The enzyme activity determination in sera from patients with hepatic cancer opens a possibility in the differential diagnosis of hepatobiliary diseases, because of the significantly higher values found in some cases of hepatic cancer. No correlation with alpha-fetoprotein was found.


Molecular forms of cobalt-activated acylase in human tissues and serum of patients with viral hepatitis. Two molecular forms of cobalt-activated acylase present in human tissues and one or three in sera of patients with viral hepatitis were noted. They have different substrate specificity. Only form 2 is strongly inhibited by alpha-hydroxyisocaproyl-tyrosine and -phenylalanine. Electrophoretic migrations of all enzyme forms are different from those of aminoacylase. Immunoglobulin antiform 2 of the acylase does not precipitate other forms of cobalt-activated acylase or aminoacylase.


Isoelectric focusing of acid hydrolases in human fibroblasts and leucocytes. Lysosomal hydrolases in fibroblasts and leucocytes exhibited the same isoelectric focusing pattern as found in liver. Treatment with neuraminidase had a great effect on the pattern of several glycosidases while treatment with alkaline phosphatase did not significantly change the pattern. These findings are discussed with special reference to the different "uptake" systems that exist for acid hydrolases.


Labile testosterone conjugate in human urine: further evidence. The origin of unconjugated testosterone released in human urine on storage and by dilute sulphuric acid treatment has been studied further. Various extraction procedures of urine have been employed and a new methodology involving anion exchange followed by acid hydrolysis and radioimmunoassay of the released unconjugated testosterone. Results indicate that human urine contains a very labile conjugate of testosterone and 5 alpha-dihydrotestosterone with polar solubility properties and a negative charge.


Quantitation of proteins by electroimmunoassay using a digitizer connected with a programmable calculator. A system is described which considerably facilitates the reading and the subsequent conversion of measured values to protein concentrations, when proteins are quantitated by the electroimmunoassay a.m. Laurell (1972). The rocket heights of calibration samples and unknown samples are read by a cursor on a magnetic table (Digitizer, Hewlett Packard) and the values are automatically transferred to a programmable calculator (HP 9830 A, Hewlett Packard). It is programmed to calculate the protein concentration of samples by interpolation on a calibration curve fitted to the best polynomium of second degree by the method of least squares. The results and sequence numbers are automatically printed out from a printer (HP 9866 A, Hewlett, Packard), Reading and calculation of the results from one plate with 5 calibration samples (in duplicate) and 20 unknown samples are completed in less than 2 min. This is 10--15 times faster compared with a manual procedure where a hand-drawn calibration curve is used for interpolation.


Circulating thyroid hormones in a patient with hyperviscosity syndrome. The elevated T4 levels by one RIA in the patient with hyperviscosity syndrome were probably caused by the interference of the increased protein concentration in the T4 assay rather than by hyperthyroidism or binding of T4 by immunoglobulins.


Analysis of lidocaine and its dealkylated metabolites by high-pressure liquid chromatography. A high-pressure liquid chromatographic method is presented for determining lidocaine and its dealkylated metabolites, monoethylglycinexylidide and glycinexylidide, in plasma. This method uses 20-microliter samples injected directly through a pre-column onto a C18 analytical column. It is fast, sensitive and linear over a concentration range of 1--10 microgram/ml. Since the method requires no preliminary treatment of the plasma, it provides a practical means of monitoring lidocaine and its metabolites in therapeutic situations.


Mechanisms of interference of nonesterified fatty acids in radioimmunoassays of steroids. Addition of nonesterified fatty acids caused an apparent increase in unbound steroid present in supernatants in radioimmunoassays for steroids utilizing dextran-coated charcoal. Nonesterified fatty acid interference occurred at the initial binding interaction between steroid and its antiserum, and also at the step separating bound from unbound steroid. It was determined that nonesterified fatty acids, which had been added to radioimmunoassays, formed micelles and trapped steroids. The extent of the entrapment was inversely related to the number of polar groups in the steroid molecule, that is, hydrophobic steroids more easily interacted with the nonesterified fatty acid micelles. However, if the charcoal concentration were increased, the nonesterified fatty acid effect was eliminated for assays of polar steroids and greatly reduced for non-polar steroid assays.


Hair chromium concentrations in adult insulin-treated diabetics. Hair chromium concentrations have been measured in age- and sex-matched groups of insulin-treated diabetics and normal controls. Average concentration (+/- S.E.M.) was reduced in female (2.9 +/- 0.5 compared with 5.1 +/- 0.7 nmol/g) but not in male diabetics.


A radioreceptor assay for diazepam and its metabolites in serum. A radioreceptor method is described for the estimation of serum concentrations of diazepam and its metabolites. The technique is simple, rapid and suitable for batch analysis. Ad advantage of the technique is that it gives a measure of the total pharmacological activity of the serum samples towards the benzodiazepine receptor and is thus directly applicable to benzodiazepines other than diazepam. The results obtained by the radioreceptor assay and by a GLC technique are correlated.


Comparison of intermethod analytical variability of patient sera and commercial quality control sera. The intermethod analytical variability of 59 commercially available control sera was compared with that of patient sera. For this purpose, patient and control sera were assayed with respect to ten constituents (albumin, alkaline phosphatase, alpha-amylase, cholesterol, glucose, iron, lactate dehydrogenase, creatinine, protein, and urea), each with two analytical methods. Only 6 of the 59 control materials showed an intermethod analytical variability comparable to that of the patient sera for all of the determinations. The use of patient sera for the calibration of routine analytical methods is recommended.


Clinical application of breath analysis for dimethyl sulfide following ingestion of DL-methionine. After overnight-fasting, the concentration of dimethyl sulfide in expired alveolar gas (alv-DMS) was determined serially following ingestion of 2 g of DL-methionine in normal subjects and patients with liver diseases. Alv-DMS rose to a peak in 30 to 90 min, declined markedly within 3 h, and then decreased gradually. Half-disappearance times (T 1/2) (mean +/- S.E. min) in each experimental group were: normal (N = 9) 61.7 +/- 4.7, acute hepatitis (N = 6) 62.5 +/- 6.8, chronic hepatitis (N = 10) 84.0 +/- 13.0, and liver cirrhosis (N = 13) 159.2 +/- 30.4, respectively. Cirrhotics had a T 1/2 significantly longer than that of the other three groups: vs. normal P less than 0.02, vs. acute hepatitis P less than 0.05, and vs. chronic hepatitis P less than 0.05. T 1/2 of alv-DMS following ingestion of DL-methionine seems to be of clinical interest.


Routine identification and determination of 11 barbiturates in biological samples. A very easy, reliable and specific gas-chromatographic method for identification and dosage of 11 barbiturates in plasma is presented. Methylene unit values determined on two types of column (one polar, one non-polar) allows very accurate identification with a minimum risk of error due to fluctuations in operating conditions. Sensitivity of the method is 0.5 microgram/ml plasma with a flame ionization detector. Derivatization procedure is complete, without any degradation phenomenon as tested by mass spectrometry. Such a method can be easily used as routine procedure for toxicological or pharmacological applications.


Prolidase deficiency with imidodipeptiduria. A familial case with and without clinical symptoms. A 23-year-old female with chronic leg ulcer was found to excrete the massive imidopeptides, among which Asp-Pro, Glu-Pro and Gly-Pro were identified. Essentially no prolidase activity was measured in her erythrocytes, while prolinase activity was within a normal range. Her 26-year-old brother also showed imidopeptiduria and erythrocyte prolidase deficiency, but no clinical symptoms were observed. Erythrocytes from her father and 30-year-old brother, who excreted no significant amounts of imidodipeptides, showed intermediate values for the prolidase activity between those for the patient and for normal adults, suggesting that they are heterozygous for this autosomal recessive disorder.


Serum beta-hexosaminidases in pregnancy. Serum contains several hexosaminidase forms. Two, HEX A and HEX B, migrate in both DEAE cellulose and isoelectric focussing systems like their tissue counterparts. A major group of serum hexosaminidases migrate in an intermediate position. These forms, collectively named HEX 1, increase during pregnancy and obscure carrier detection for Tay-Sachs and Sandhoff's disease. Using DEAE-cellulose chromatography, HEX A, I, and B, can be clearly separated. In normals, activity ratios of A/B are 4.03 +/- 1.33. During pregnancy the ratio falls slightly to 3.01 +/- 1.08. In Tay-Sachs heterozygotes the ratio is only 1.08 +/- 0.35 and falls during early pregnancy to 0.53 +/- 0.23. In Sandhoff heterozygotes the DEAE chromatograms appear normal with higher than normal A/B ratios but in sera, from both pregnant and nonpregnant carriers, the HEX B and HEX I forms are 50% heat labile. During pregnancy, serum can be used as a reliable source of HEX for heterozygote identification for both Sandhoff's and Tay-Sachs disease.


An improved extraction method for plasma steroid hormones. An easy and rapid column chromatographic method for the extraction of steroid hormones from plasma is presented. It permits the nearly quantitative separation of the steroids in a single step with smaller expenditure of time and work as compared to the usual liquid-liquid extraction. Problems of emulsions are eliminated. Furthermore, fractionated separation of hormones from plasma is possible. A simple procedure for the selective extraction of estriol (isolated from estrone and estradiol) is described.


Electroencephalographic change in Parkinsonian patients treated with levodopa-carbidopa. Our findings in a relatively small series of cases seem to confirm a lack of statistically significant EEG changes when Carbidopa is combined with Levodopa in the therapy of patients with Parkinson's disease. There appears to be a slight increase in basic background frequency which was one of the earlier findings when Levodopa was first used clinically. From the literature surveyed there appears to be a definite lack of consistency in the effects of Levodopa therapy on the electroencephalogram and on the clinical status of the patients followed. We think this well may be explainable by the fact that no large study has been accomplished in which a neuroanatomical (pathological) correlation has been done with both the clinical and the EEG data. Neurological examination and the electroencephalogram are both clinical tools and have yet to be closely reviewed with the added parameter of neuro-pathologic investigation in this new day of therapy for Parkinson's disease.


Electroencephalographic analysis of malignant melanoma patients. EEGs carried out in 202 patients with melanoma were abnormal in 33%. In the absence of systemic or brain metastasis 14% of the patients had abnormal records. If systemic metastases without brain metastasis were present 45% of the patients had abnormal records and with brain metastasis 88% had abnormal EEGs. Only a third of the patients with abnormal records had brain metastasis but metastatic spread to some organ system was present in 76% of those with EEG abnormalities. The diffuse abnormality was less likely to be a "false positive." Ninety-seven percent of the patients with diffuse EEG abnormality had systemic metastasis but 43% of the patients with focal EEG changes had no detected metastasis.


Variability between and within laboratories in the analysis of structural chromosomal abnormalities. The frequency of structural chromosomal aberrations in two samples (AM and PM of the same day) from each of nine normal subjects, cultured in two different laboratories, was studied by six observers. The results were analyzed in order to determine the relative importance of inter- and intralaboratory factors in the variability of chromosomal abnormalities. In addition to the difference in the frequency of the abnormalities between the subjects studied, there were differences due to observers from different laboratories (P less than 0.01), as well as between laboratories (P less than 0.01). These results could be explained in part by insufficient agreement between observers from different laboratories and by differences in the quality of the method used.


Two XX male brothers.

Two XX male brothers. Two brothers with XX male syndrome with penoscrotal hypospadias are reported. Chromosomal analysis of cells from the peripheral blood, skin, and testes revealed a normal female karyotype in both subjects. Biopsy of both testes in the brothers showed histological features of normal immature testes and no evidence of ovarian structures. Neither vagina, uterus nor fallopian tubes could be detected either by exploratory laparotomy or retrograde urethrography. Results of endocrine studies on serum gonadotropins (LH and FSH) and testosterone levels as well as their responses to LH-RH and hCG stimulation tests were normal for age. Studies of various genetic markers, including the Xg blood type and erythrocyte enzymes, were performed in the probands and their parents. Possible explanations for the paradoxical occurrence of testes in XX males and for the familial occurrence are discussed.


Nonketotic hyperglycinemia. A genetic study of 13 Finnish families. In Finland, 19 children, born 1964--1977, from 13 families, have been diagnosed as suffering from nonketotic hyperglycinemia (NKH). This gives an incidence for NKH in the Finnish population of 1:55,000 newborns. The majority of these children were born in the northern part of the country, where the incidence is 1:12,000. The geographical distribution of the birth-places of the grandparents also seems to point towards an enrichment of the gene in northern Finland. An autosomal recessive mode of inheritance for this disease seems probable, since the corrected proportion of affected siblings (Apert's a priori method) is 0.288. Abnormally high plasma glycine concentration and elevated glycine urinary excretion in the parents of the NKH-children suggest the existence of a minor metabolic defect in heterozygotes of this disease. Some of the healthy siblings of the NKH-patients also show similary elevated levels. However, a definite diagnosis of the NKH-heterozygote state cannot easily be made on the basis of these laboratory findings, as the levels in some individuals are very close to, or even overlap corresponding values in a normal material.


Description of chromosome banding patterns by band transition sequences: a new basis for automated chromosome analysis. For visual and automated analysis of banded human chromosomes, the band pattern features of chromosome profiles considered essential for the cytogeneticist were evaluated. These features were found to be related to each peak (dark band) and its adjacent valley (light band) in the direction p--q. A method for extracting and describing these features was developed and implemented on a computer. The method determines three normalized parameters for each peak and adjacent valley: (1) density of peak; (2) density difference (transition) between peak and valley; and (3) position of peak. Each profile is described by a simple sequence of band transitions (BT-sequence). The BT-sequence was visualized as a profile (BT-profile) using only the information retained in the BT-sequence. Visual classification of BT-profiles shows error rates comparable to visual classification of ordinary density profiles (Lundsteen & Granum 1979). It is therefore concluded that the BT-profiles do retain the important band pattern features of the profiles, and it is supposed that the simple and condensed BT-sequences constitute an appropriate basis for automated karyotyping.


Visual classification of banded human chromosomes. III. Classification and karyotyping of density profiles described by band transition sequences. Band transition profiles (BT-profiles) representing extracted band pattern features of 898 density profiles of banded chromosomes were classified and karyotyped by a cytogeneticist in order to investigate how much information was lost by substituting for the original density profiles their extracted features. The results were evaluated and compared with visual classification and karyotyping of the same 898 density profiles from which the BT-profiles were derived. Six per cent errors were made in classification of isolated BT-profiles and 0.7% errors were made in karyotyping BT-profiles. These error rates were comparable to the corresponding error rates in classifying and karyotyping density profiles, which were 5% and 0.5%, respectively. It is concluded that most of the important band pattern information of the density profiles is retained in the BT-profiles, and it is supposed that the condensed BT-sequences (from which the BT-profiles are derived) constitute a sufficient and appropriate basis for automated karyotyping.


Trisomy 20 mosaicism in amniotic fluid cell culture. Chromosomal mosaicism in cultured amniotic fluid cells presents one of the most difficult problems in prenatal diagnosis in predicting the foetal phenotype. We present a case in which trisomy 20 mosaicism was diagnosed prenatally but not confirmed in the aborted foetus.


Partial trisomy for the distal long arm of chromosome 5 (region q34 leads to qter). A new clinically recognizable syndrome. This report describes a family in which eight individuals in three generations had mental retardation in association with a characteristic pattern of clinical problems and physical abnormalities including short stature, eczema, hernias, delayed puberty, dysmorphic facies and digital anomalies. The family history was consistent with a chromosomal rearrangement with transmission through balanced carriers. Routine ASG banding studies showed extra chromosomal material on a chromosome 16 but failed to demonstrate any differences between the affected individuals and the presumed carriers. However, subsequent studies utilizing trypsin banding and microspectrophotometry of individual chromosomes demonstrated that the affected individuals were partially trisomic for the distal band of the long arm of chromosome 5 and that 0.273 units of a chromosome 5 were translocated to chromosome 16. This definitive cytogenetic diagnosis permitted accurate prenatal diagnosis to be carried out on the fetus of a balanced carrier female. The application of these techniques to previously obscure familial dysmorphic syndromes is recommended.


Evaluation of ankle fractures: non-operative and operative treatment. A relatively great number of supination abduction fractures did not need surgical treatment because displacement was not present. Significantly better results occurred with operative intervention in supination--eversion and pronation--eversion ankle fractures. Supination--abduction and supination--eversion ankle fractures are best treated by open reduction, anatomical restoration and stabilization of the fractures.


The role of early internal fixation in the management of open fractures. A series of 101 victims of multiple trauma and open fractures were treated by early open reduction and internal fixation. Some of the fractures included associated vascular injury. Some of the patients had extensive intraarticular fractures. Femur fractures in the elderly were included. All wounds were left open. In 94 patients, the early infection rate was 1.9% in small clean open (type I) wounds, 8% in large open (type II) wounds, and 41% in extensively contused large open (type III) wounds. In 94 cases the overall infection rate was 10.6%. In only one infection (1%) a long-term chronic osteomyelitis ensued; there were no non-unions in long bone fractures. Open fractures with type I wounds have the same infection rate as reported for closed fractures. In fractures with types II and III wounds salvage of limb, life, or joint function must justify the high risk of infection. Immediate plate fixation of severe open fractures of the tibia could save a limb from amputation. Closed intramedullary nailing of open fractures of the femur carries a high rate of success.


Open fractures. Long-term results in 200 consecutive cases. Two hundred consecutive patients admitted with 214 open fractures were reevaluated 6--10 years following injury. All patients were seen in follow-up by the authors. The average hospital stay was 36 days. Many of the patients sustained multiple injuries in automobile accidents. Concomitant head, chest or abdominal trauma occurred in 41% of the patients; 38% sustained multiple fractures. The average patient achieved full weight-bearing at 28 weeks. Late complications were infrequent. All postoperative bone infections (7%) were eradicated with appropriate treatment an average of 27 months postinjury; all of the infected fractures united, and no major limitations of motion resulted. Roentgenograms taken an average of 8 years postinjury revealed only 9 patients with major joint incongruities or arthritic changes. All of the fractures were united except for one with an asymptomatic fibrous union of the patella. Anatomic restitution was possible in most patients. Only one patient had an axial malalignment which necessitated correction by osteotomy and 6 patients had shortening of 1 cm or less. The functional results were excellent with only minor limitations of motion having been found in 25 patients. Disability payments were made to 39 patients and all patients (except for the one who retired due to age) had returned to their prior jobs.


Compression treatment of long bone pseudarthroses. In 122 cases of non-union and delayed union, rigid fixation with Swiss compression plates without the use of casts, produced 92.6% success with the first operation. Half of the cases, especially in the well aligned fractures with hypertrophic callus, were treated without bone grafts and without resecting the pseudarthrosis. Non-resection did not adversely affect the healing time or rate. There were 9 failures or 7.4% chiefly in the difficult hypovascular atrophic bone-grafted group. Many of these cases were treated with shingling and grafts as well; 4 cases showed signs of healing but refractured secondary to trauma; 4 of 5 failures were replated and eventually healed. About 83% of the 24 infected cases healed with one compression plate operation. All of the fractures that were dry pre- and post-operatively united. In a few with drainage and poor skin coverage or cicatrix, rigid fixation with external fixators and Steinmann pins were applied. Early active exercises with delayed weight-bearing until union, gave remarkable return of function even in the difficult metaphyseal pseudarthroses. The compression method of rigid fixation is an excellent adjuvant to pseudarthrosis therapy.


A radiological and histological analysis of fracture healing using prebending of compression plates. The use of an exactly contoured compression plate to the surface of a bone will lead to asymmetrical loading of that fracture line with possible gapping of bone opposite the plate. The stability of fixation can be increased through the use of compression combined with prebending. The present study in 19 sheep demonstrates the biological effects of 3 modes of plating fixation: (1) no compression; (2) compression; and (3) compression after prebending using 2 types of compression plates with different stiffness evaluated radiographically and histologically. Compression together with prebending, especially when using plates of adequate stiffness, can prevent bone resorption at the fragment surfaces even under immediate weight-bearing conditions in the sheep tibia. Prevention of interfragmentary bone resorption lowers the risk of non-union and/or implant failure secondary to motion at the fracture site.


Orthopedic problems in hemophilia.

Orthopedic problems in hemophilia. Orthopedic management of the various complications resulting from musculo-skeletal bleeds in the hemophiliac, has now become standard and routine. However, the orthopedist should never minimize the threat of iatrogenic disease resulting from his surgery, or from the hemostatic control necessary for all operations. Operations should be properly indicated with standard and established techniques always being used. The development of antibodies, the risk of wound breakdown and secondary infection, and the need for further operative intervention, all create serious hazards to the hemophiliac patient. The orthopedist must be fully supported by a hematologist and laboratory back-up. Finally he should understand coagulation control and the necessity for its monitoring.


Idiopathic protrusio acetabuli. A histological study. Histological features of the acetabular floor in idiopathic protrusio acetabuli consist of replacement of the marrow spaces with active vascular fibrous granulation tissue and in some areas disruption of the trabecular pattern. This process could possibly elucidate the pathogenesis of protrusio.


Treatment of pertrochanteric and subtrochanteric fractures of the femur by the Ender method. The Ender method consists of insertion of round, flexible, condylocephalic intramedullary nails. In 104 patients with a median age of 77 years and 80% older than 70 years, the morbidity was high (owing to concomitant diseases in 73%). Follow-up examination of survivals showed good functional results. There was some tendency to shortening, more than 2 cm in 15% of the patients. External rotation deformity of more than 20 degrees was observed in 15% of patients. Towards the end of the series when precautionary measures were taken to avoid this, the number of patients with such deformity decreased. The advantages of the Ender method are: a short operation time, minor operative trauma and early mobilization and weight-bearing. Because of some rotational instability the method should be reserved for patients older than 65--70 years.


Closed insertion technique for the prebent Sampson femoral rod. This is a descriptive summarization of the technique employed in doing closed intermedullary nailings of fractured femurs using a cannulated prebent nail system. With slight modifications the same approach and techniques can be used for a noncannulated solid nail system. The fine points of this technique which will help in preventing difficulties during the procedure are accurate preoperative positioning of the patient before draping; adequate preoperative traction to assure that slight over pull of the fracture fragments has been achieved; the use of the piriformis recess as the prime site for entry into the medullary canal. With proper attention to detail the technique can be employed successfully with a minimum of hazard.


Clostridial myonecrosis in a patient undergoing oxacillin therapy for exacerbation of chronic foot ulcers and osteomyelitis. A case report. Gas gangrene developed from a chronic foot ulcer in the absence of periferal vascular disease or diabetes mellitus in a hospitalized patient undergoing parenteral antibiotic therapy. Within a 6 hour period the patient developed profound toxemia necessitating emergency and life saving leg amputation. Classically clostridial myonecrosis is diagnosed by the clinical course and the gram stain. In this case, 2 preoperative gram stains failed to show gram-positive rods. At the time of surgery, frank fasical and muscle necrosis in the peroneal compartment dictated extending the below knee amputation to above the knee. In retrospect demonstration of clostridial species and myonecrosis in the pathological specimen confirmed the clinical impression. The identified organism, Clostridium sporogenes has rarely been implicated as a cause of gas gangrene.


Negative experiences with pins-in-plaster for femoral fractures. Six healthy young men sustaining femoral shaft fractures in traffic accidents were treated in pins-in-plaster. Complications included pintract infection (3/6), shortening, angulation (1), malrotation (2). Recasting and rehospitalization was frequent. These adverse experiences with this method of treatment of femoral shaft fractures should discourage its further use.


Experimental study of measurement of regional bone blood flow in the adult mongrel dog using radioactive microspheres. To date, no one has conclusively accurately measured the regional bone blood flow mainly due to the lack of a proper investigative method. In this study, regional blood flow in the femur and tibia in adult mongrel dogs were studied using 85Sr-and 141Ce-labeled microspheres with a diameter of 15 +/- 5 microns. The blood flow rates were calculated by relating the radioactivity from tissue samples that from sample blood with a known flow. The highest rate of blood flow, 48.7 ml/min/100 g, was found in the femoral marrow and the lowest, 3.0 ml/min/100 g, in the diaphyseal cortex of the tibia. Flow rates in the metaphyseal regions, about 15 or 20 ml/min/100 g, were one and a half or 2 times greater than those in the epiphyseal regions. These values were mostly within the range of values reported by other investigators. Radioactive microspheres can be applied not only to physiological conditions but also to various pathological conditions if their size and the dose, the site and method of injection and tissue sampling are investigated further.


Effects of different commercial diets on several orthopedic experiments. In experiments involving disuse osteoporosis induced by plaster cast immobilization, 2 commonly used commercial feeds (Wayne Lab Blox and Purina Laboratory Chow) gave different results. Preliminary evidence suggests that this dichotomy of results is due to an interaction between metabolic changes caused by physiologic stress and different levels of manganese in the 2 commercial diets. By feeding the 2 diets to groups of rats under various conditions, and examining the strength, cortical area, and length of their femurs, and by immobilization of a fracture in a cast, and associated physiologic stresses, dietary differences are manifested in the growth and developmental changes in the femur. Under normal, stress-free conditions, however, no such differences occur. Investigators should be wary of such dietary variables when comparing various experimental results. The implications of such effects insofar as human medicine is concerned should be further investigated.


Effects of synovial fluid on fibroblasts in tissue culture. The ability of the torn anterior cruciate ligament of the knee to heal is unpredictable, despite early surgical repair. A popular explanation has been that synovial fluid inhibits ligament healing. Other variables of ligament healing could reside with the fibroblasts, themselves, from different ligaments. With the use of tissue culture techniques, populations of fibroblasts were cultured from human anterior cruciate ligaments, deep and superficial medial collateral ligaments of the knee. Growth of fibroblasts from the anterior cruciate ligament was always diminished when exposed to synovial fluid and, on the average, plating efficiency was reduced by 46% when the culture medium contained synovial fluid. Growth rates demonstrated that fibroblasts from the superficial medial collateral ligament grew an average of 35% more than the others. Information gained from this study provides some data to explain the clinical frustration of the torn anterior cruciate ligament. The combination of synovial fluid inhibition of cell proliferation and the variable growth rates of fibroblasts, may explain the unsatisfactory healing of cruciate ligaments.


Comminuted trochanteric femoral fractures in geriatric patients: the results of 231 cases treated with internal fixation and acrylic cement. Instability, osteoporosis and the requirement of early mobilization are the main problems in comminuted trochanteric fractures in elderly patients. Correct reduction and the use of acrylic cement as an adjunct to internal fixation provide the stability for immediate weightbearing and subsequent bone union. In 213 patients there was no evidence of femoral head necrosis or non-union.


Closed intramedullary nailing of the femur. Küntscher technique with reaming. Closed intramedullary reaming and nailing with a prebent cloverleaf nail provides a biomechanically ideal method of internal fixation for femoral fractures. With a properly trained surgical team and careful technical control, all the theoretical advantages of this technique can be realized. These include a very high union rate, minimal risk of infection, early mobilization, and shortened hospitalization. Reaming and insertion of the nail is performed through a starting point at the junction of the base of the femoral neck and trochanter. When reaming is done, the nail can be sufficiently large to withstand the forces of early ambulation, thereby allowing an early return to normal function for most patients. In comminuted fractures an intramedullary nail can be used as an internal splint. In conjunction with traction and/or guarded weight-bearing and/or cast-brace, this procedure can assure earlier and more anatomic union and earlier return to function. In 300 fresh femoral fractures treated with closed intramedullary nailing, most patients had early and nearly anatomic union with excellent knee function and maintenance of muscle strength. Significant complications included one non-union, which required renailing, and 19 malunions, most of which were relatively minor. Because the procedure is technically demanding and requires extensive special equipment, it is best suited for use in trauma centers.


Medullary nailing according to Swiss study group principles. Internal fixation of long tubular bone fractures by intramedullary nailing has become established worldwide as an efficient and successful procedure, besides the methods of interfragmentary compression, buttress and adaptation, intramedullary splinting and stabilization constitute the basic principles of osteosynthesis. Improvements in knowledge of equipment, indications, technique, aftercare and possible complications have increased the success of intramedullary nailing. The results of 1,905 intramedullary nailings of femur and tibia demonstrate that with other methods of osteosynthesis poor results usually are attributable to an inappropriate indication and/or a faulty surgical technique. Occasionally a failure may stem from the surgeon's technical incompetence or inexperience.


Results after internal fixation of comminuted fractures of the femoral shaft with DC plates. A series of 131 comminuted fractures of the femoral shaft in 123 patients were externally fixed by the ASIF plating method. Of the 126 fractures in 118 patients, that could be reviewed one to 3 years postoperatively, 115 of 92% presented a good functional result. The most common complication was a fatigue fracture of the plates which, however, only occurred after biomechanically faulty application, without medial buttress of the bone, and in the absence of a cancellous autograft. The application of a bone graft therefore appears mandatory in all fractures of the femoral shaft that are fixed by a plate.


Neonatal subcapsular hematoma of the liver presenting as an abdominal mass. Report of two cases. Two infants with hepatic subcapsular hemmorrhage presenting as abdominal masses at age 17 days and 49 days are reported. The first had a slowly progressive course and the second had initial internal bleeding. Aortography assisted in the management of the second case.


Review of intensive care unit admissions for asthma. A review of ICU admissions for asthma to the Childrens Hospital of Los Angeles was conducted for the period January 1969 through July 1977. The admission rate remained relatively constant during this period. Patients requiring ICU admission tended to be young, intractable severe asthmatics whose asthma started at a very young age. There were three patients who had no previous history of asthma. The incidence of pneumonitis/atelectasis was somewhat greater than has been reported for patients hospitalized for status asthmaticus. A significant number of children received neither intravenous corticosteriods, sympathomimetics nor oxygen therapy while hospitalized prior to transfer to the ICU. Those children receiving mechanical ventilation or intravenous isoproterenol tended to be somewhat younger and had a higher incidence of pneumonitis/atelectasis and more abnormal blood gas determinations than their counterparts who were not similarly treated. Mechanical ventilation was administered to 15 patients and 19 patients received intravenous isoproterenol. Intravenous isoproterenol resulted in prompt improvement in most patients; except for one patient who experienced cardiac arrhythmia (reversed when the dosage was decreased), this medication was well-tolerated.


Digoxin in the elderly: pharmacokinetic consequences of old age. A study of single-dose digoxin kinetics was performed in 6 young and 7 elderly patients. The rate of absorption, determined by the time to peak concentration after an oral dose, was more rapid in the younger group. The extent of absorption, as measured by comparison of the area under the plasma concentration/time curve after oral and intravenous administration, was similar in both groups. Mean plasma half-life was longer and individual values were more variable in the elderly patients. The absolute apparent volume of distribution was reduced in the older patients and correlated inversely with age. When corrected for weight, however, the difference in the apparent volume of distribution did not approach significance. Both absolute and weight-corrected values for plasma clearance of digoxin were reduced in the elderly subjects.


Creatinine VIII: saliva levels of endogenous "true" creatinine in normal subjects. Concentrations of endogenous "true" creatinine in saliva and serum were measured in 6 normal subjects using a specific and sensitive high-performance liquid chromatographic method. There were marked intra- and intersubject variations in saliva levels during an 11-wk study. There were also large variations in the ratios of the saliva/serum creatinine level during the one-day study for all the subjects, the average highest intrasubject variation being 481% and the range being 128% to 816%. The average ratio of saliva/serum level was 0.0999 +/- 0.097 (CV = 97%); the highest saliva level was 1.5 mg%. Lower salivary levels were probably due to the extremely low lipid solubility of creatinine resulting in a relatively slower diffusion rate than of the transport of water into the saliva. Salivary monitoring of creatinine is concluded to be of little use in indicating its concentration in plasma or serum because, unlike many other substances it does not follow the pH-partition principle for saliva/plasma distribution.


Influence of congestive heart failure on prazosin kinetics. The kinetics of oral prazosin was studied in 10 healthy normal subjects (NS) and in 9 patients with congestive heart failure (CHF). NS received a single 5-mg dose, and blood concentrations of prazosin (CB) were measured, using a specific HPLC assay, during an 8-hr period. CHF patients received a 2-mg dose after which CB was measured for 10 hr. These patients then received 2 to 5 mg prazosin every 8 hr for 48 hr. After the last dose of prazosin, CB was measured for 24 hr. After the initial dose, time to peak CB did not differ significantly between that of the NS (123 +/- 19 SEM min) and of patients with CHF (132 +/- 31.3 min). AUC/mg prazosin was greater (p less than 0.001) in patients with CHF (3,385 +/- 380 Ng x min/ml) than in NS (1,603 +/- 208 ng x min/ml). Elimination of prazosin from blood was slower in CHF patients (t1/2 = 374 +/- 33.4 min) than in NS (t1/2 = 144.5 +/- 4.3 min) (p less than 0.001). These data suggest that in patients with CHF the elimination of prazosin is substantially slower than in NS and therefore higher steady-state prazosin concentrations can be expected in CHF patients than in NS.


Diazoxide infusion in severe hypertension and hypertensive crisis. Prompted by reports of hypotension with myocardial ischemia after bolus injection, we restudied the efficacy of diazoxide infusion (5 mg/kg, rate, 15 mg/min) in 35 hypertensive patients. In 20 patients with chronic hypertension, mean arterial pressure of 138 mm Hg was 110 (after 30 min) and 121 (after 8 hr). In 15 patients with hypertensive crisis, there was a fall from 159 to 126 (in 30 min) and 133 mm Hg (after 8 hr), similar to findings in 12 patients with hypertensive crisis treated with a 300-mg bolus injection (159, 130, 140 mm Hg). In the latter, the maximal systolic blood pressure decrease was greater (56 mm Hg, reached in 4 min) than in the 15 patients with hypertensive crisis treated by slow infusion (38 mm Hg in 28 min). Thus, infusion of diazoxide causes a gradual decline of blood pressure and is, in contrast to current opinion, also an effective treatment in hypertensive crisis.


Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives. There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.


Diazepam kinetics in acute alcohol withdrawal. We performed a within-subject comparison of the kinetics of diazepam given to 7 alcoholic subjects during acute alcohol withdrawal and again after detoxification. The initial rapid exponential decline of plasma diazepam concentrations (t1/2 alpha) was more rapid during (0.21 +/- 0.03 hr) than after withdrawal (0.44 +/- 0.14 hr, p less than 0.05). Terminal t1/2, clearance, and volumes of distribution changed in individual patients, but mean values did not change. Protein binding was less in patients (93.4 +/- 2.4%) than in healthy controls (97.0 +/- 1.0, p less than 0.05). The effects of alcohol withdrawal on diazepam disposition do not explain the high doses of diazepam commonly required to treat the withdrawal.


Studies with a PNMT inhibitor.

Studies with a PNMT inhibitor. DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N-methyltransferase (PNMT). In animal studies, a plasma level of 0.35 microgram/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single-dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 microgram/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.


Renal excretion of cephapirin and cephaloridine: evidence for saturable tubular reabsorption. Drug concentrations in plasma and urine were determined in 5 healthy subjects after intravenous infusion of 1 gm cephapirin and cephaloridine. Sampling of blood and urine was frequent and prolonged. Specimens were analyzed by high-pressure liquid chromatography (HPLC). Renal clearance of cephapirin decreased to less than 5% of control in all subjects when drug concentrations in plasma and urine declined. Cephaloridine clearance decreased to a lesser extent. Our findings suggest that, besides tubular secretion and glomerular filtration, a saturable and probably active tubular reabsorption is also involved in the renal handling of these two cephalosporins. The saturable reabsorption process was characterized by its Michaelis-Menten constant Km and its maximum transport capacity Tm.


Disopyramide kinetics in patients with acute myocardial infarction. The kinetic behavior of disopyramide was studied in 20 patients with suspected myocardial infarction: in 13 of these, the diagnosis was subsequently confirmed. All received a 400-mg oral loading dose of disopyramide base followed by an oral maintenance regimen of either 100 or 200 mg 4 times daily. The elimination half-life (t1/2beta) was longer (p less than 0.05) in patients with confirmed infarction than in patients with unconfirmed infarction [38.0 +/- 3.7 hr (mean +/- SEM) compared to 24.3 +/- 0.8 hr, and 21.2 +/- 2.1 hr compared to 7.2 +/- 2.4 hr for the 100- and 200-mg maintenance dose regimens, respectively]. The t1/2beta was dose dependent for infarct and noninfarct patients. Two of the patients with confirmed infarction failed to reach trough plasma levels equal to or exceeding the lower end of the manufacturer's recommended therapeutic range (3.3 mug/ml) during the study. For the remaining 11 patients the time taken to achieve trough plasma levels of 3.3 mug/ml varied from 18 to 170 hr; hence plasma disopyramide concentration in these patients was suboptimal at a time when the risk of arrhythmias is high. Modification of existing oral loading dose regimens is therefore required for optimization of oral disopyramide therapy.


Plasma chlorpromazine concentrations in children with behavioral disorders and mental illness. Plasma chlorpromazine (CPZ) levels were studied in children 8 to 15 yr of age who were receiving CPZ for mental disorders. The results showed that children need larger doses of CPZ than adults to attain comparable plasma concentrations. The apparent therapeutic plasma concentration in children (40 to 80 ng/ml) is lower than that reported for adults (50 to 300 ng/ml). In the children studied, the plasma concentrations declined despite maintained dosage, possibly because of autoinduction of CPZ metabolism. Doses of 6 to all mg/kg body weight, and even as much as 850 mg/day, were tolerated without significant side effects when administered in divided doses 3 or 4 times  a day, while doses of less than 6 mg/kg/day frequently failed to produce the desired plasma CPZ levels.


Absorption and excretion of tolmetin in arthritic patients. The absorption, kinetics, biotransformation, and excretion of tolmetin and its metabolites were studied in patients with rheumatoid arthritis (RA) to evaluate the effects of the disease on tolmetin disposition. Five RA patients were stabilized on tolmetin sodium (300 mg, 4 times daily for 14 days) before receiving a single oral solution dose of tolmetin-14C sodium (300 mg as the acid) on day 15. Tolmetin was rapidly and completely absorbed (peak time, 20 to 60 min) and eliminated rapidly from plasma with a biphasic decay curve (t1/2beta congruent to 2.1 hr). MCPA, the oxidative metabolite, appeared more slowly (peak time, 40 to 90 min) but was eliminated rapidly in a biphasic manner (t1/2beta congruent to 1.7 hr). The terminal elimination phases for both tolmetin and MCPA demonstrated a curvature which suggested possible nonlinearity in the kinetic disposition of the drug. There were no apparent effects of the disease on the kinetics of tolmetin or MCPA. Tolmetin, MCPA, and tolmetin glucuronide were recovered quantitatively in urine (0 to 72 hr) with most of the exretion occurring in the 0- to 24-hr period. A significant increase, relative to data on normal subjects, in the renal clearance of both tolmetin and MCPA was noted. Concomitant increase in the apparent volume of distribution secondary to reported decreases in the plasma protein binding of tolmetin appeared to be the reason for increased renal clearance of tolmetin.


Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination. The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.


Lack of effect of bran on digoxin absorption. The effect of dietary fiber on digoxin absorption was investigated in 12 patients taking digoxin. Steady-state serum digoxin concentrations were determined while subjects were on a regular diet and while they were on a diet supplemented with 22 gm bran daily. During the period of bran supplementation, the serum digoxin concentration did not change (average change, +0.5%; 90% confidence interval, -12% to +14%). Bran does not cause a clinically significant reduction in digoxin absorption.


Kinetics of intravenous amoxicillin in patients on long-term dialysis. The kinetics of intravenous amoxicillin was studied in 8 patients with creatinine clearances of less than 7 ml/min who were on long-term hemodialysis. Kinetic parameters were determined using a 2-compartment linear model. The serum half-life (t1/2) of amoxicillin in these patients ranged from 7.5 to 21 hr. The t1/2 fell to 2.84 +/- 0.45 hr during dialysis. Approximately 30% of the dose was recovered in the dialysate during 4 hr of dialysis and there was a 25% reduction per hour in serum concentration. We present a dosage schedule for intravenous amoxicillin in patients with reduced renal function who are undergoing hemodialysis.


Effects of three antibiotics on theophylline kinetics. Nine healthy subjects received single doses of intravenous aminophylline (5 mg/kg) on four occasions separated by at least 1 wk. One trial was a control; the other three were performed during administration of therapeutic doses (250 mg every 6 hr) of tetracycline, erythromycin, and cephalexin. Theophylline concentrations in multiple plasma samples drawn during 24 hr after each dose were determined by high-pressure liquid chromatography. Mean kinetic variables for theophylline during control, tetracycline, erythromycin, and cephalexin trials, respectively, were: volume of distribution, 0.57, 0.61, 0.63, and 0.62 l/kg; elimination half-life (t1/2), 7.9, 9.2, 10.3, and 8.6 hr; total clearance, 0.90, 0.84, 0.78, and 0.89 ml/min/kg. In no case did differences between treatment conditions approach significance. Thus there is no consistent evidence of a kinetic interaction between theophylline and three commonly prescribed antibiotics.