Innervation of the pineal gland in the mongolian gerbil (Meriones unguiculatus). A fluorescence microscopical study. The innervation of the pineal gland in the Mongolian gerbil, Meriones unguiculatus, was investigated light microscopically by the Falck-Hillarp fluorescence technique and by conventional light microscopy. The pineal gland displayed a superficial portion just beneath the confluens sinuum and a deep part (lamina intercalaris) connected by a slender pineal stalk, which contained pinealocytes. The superficial part of the pineal gland consisted of dark-stained pinealocytes arranged in lobules, and separated by interstitial cells and connective tissue spaces. Many larger chromophobe cells were scattered throughout this region. A heavy catecholaminergic innervation of the superficial portion of the pineal organ, probably via the conarian nerve, with green fluorescent nerve fibres showing excitation/emission maxima of 415/475 nm was observed. Green fluorescent nerve fibres were also observed in the pineal stalk, from where some fibres turned rostrally indicating a nervous connection between the brain and the pineal organ. The pinealocytes showed a yellow fluorescence displaying a broad excitation curve with a maximum of 380-430 nm and an emission maximum at 505 nm. This indicates the presence of both serotonin and a catecholamine in the pinealocytes. Yellow fluorescence of the cells in the lamina intercalaris was also observed.


B-cells of the synovial membrane. I. A comparative ultrastructural study in some mammals. Comparative ultrastructural study of the B-cells in the intimal layer of the synovial membrane in mouse, rat, rabbit, guinea-pig and man clearly distinguishes these cells from both the histiocytic A-cells (macrophage-like cells) and the fibroblasts. In addition to the marked development of the rough endoplasmic reticulum and Golgi apparatus, typical dense secretory vesicles apparently of Golgi origin are always found in mouse B-cells and frequently in those of the rat. These secretory characteristics clearly relate these cells to glandular cells engaged in polypeptidic secretion. The variations in the other species studied concern only the figuration of secretory material. Thus, the B-cells appear to constitute a category of secretory cells specific to the synovial membrane, but the function of which has yet to be determined.


"Naked" spinal cord on a non-segmented baton-like bony structure in the tail of the electric fish Eigenmannia virescens (gymnotoidei). The caudal spinal cord of Eigenmannia virescens is not enclosed in a neural canal of the vertebral column. In fact, a segmented vertebral column with neural and ventral arches is lacking and replaced by a non-segmented baton-like bony structure on which the free spinal cord is located. The baton cosists of calcified bone tissue with bone cells. Individual differences exist as far as the length of the rod is concerned. The "electromotor neurons" of this caudal part of the spinal cord are histochemically acetylcholinesterase-positive. The electrocytes which surround this part of the spinal cord show strong enzymatic activity on the posterior innervated face. However, there is also activity on the non-innervated lateral and anterior faces.


Discocilia--a new type of kinocilia in the larvae of Lanice conchilega (polychaeta, terebellomorpha). A modified type of kinocilia has been found in the Aulophora-Iarva of the sedentarian polychaete Lanice conchilega. For this newly described cilium type the term "discocilium" is proposed. The only structural difference from usual locomotory cilia is the tip, which possesses a discoidal head. The head is formed from the terminal part of the cilium shaft, which is bent to give rise to a loop-like ring covered by the ciliary membrane. Three types of discocilia can be distinguished: a) discocilia having swollen, bulblike heads with a central straight axoneme; b) discocilia having heads with a curved lateral axoneme and c) discocilia in which the axoneme forms a loop. The internal structure shows the usual 9 + 2 arrangement of the filaments. The head shows no sign of secretion; it appears structureless in electron microscopical examination. There are two kinds of discocilia arrangements: 1) isolated bunches of cilia especially at the tentacles and in the frontal region, and 2) segmental dorsal rows of cilia. The possible formation of discocilia is described.


The distribution of capillaries in the somatic musculature of two vertebrate types with particular reference to teleost fish. The distribution of capillaries in teleost and rat striated muscles was investigated using a number of different methods. A new method for directly viewing capillaries was developed. Teleost white muscle has a capillary: fibre (C:F) ratio of between 0.2 and 0.3; and 0.6 to 1.0 peripheral capillaries per muscle fibre. 26-49% of fibres had no peripheral capillaries. Values for the rat gastrocnemius were 1.2, 2.6 and 4.8% respectively which compares well with literature values. Flathead red muscle had a C:F ratio of between 1.9 and 2.5; and between 5.3 and 6.6 peripheral capillaries per muscle fibre depending on the method used. Values for rat soleus were 1.8 and 4.1 respectively. Teleost pink fibres had an intermediate number of capillaries. Rat striated muscle, particularly the gastrocnemius, was found to be heterogeneous with respect to the distribution of capillaries. Flathead red muscle was homogeneous whilst teleost white muscle was only slightly variable. Flathead red muscle fibres are well suppled with subsarcolemmal mitochondria. These show a clumped distribution corresponding to the position of capillaries. In contrast teleost white fibres are almost totally devoid of these and all other mitochondria. No differences were observed in the vascularisation of either muscle type along the length of the fish. The results are discussed in relation to the division of labour between fibre types during swimming.


Morphological changes in the ultrastructure of the thyroid epithelium of Notophthalmus viridescens after hypophysectomy and TSH- and prolactin stimulation. In the newt, Notophthalmus viridescens, hypophysectomy results in progressive atrophy of the thyroid cells to the point of irreversible degeneration. After exclusive TSH-stimulation of hypophysectomized newts, increased endocytotic activity of the follicular epithelium is observed. Prolactin stimulation under the same conditions prevents atrophy but does not result in increased cell activity, as expressed by the reduced amount of microvilli and the lack of endocytotic activity. Combined TSH- and prolactin stimulation also results in cell activation, but the activation level of exclusively TSH-stimulated cells is not reached. Although prolactin prevents cellular atrophy and degeneration of the follicular epithelium, it reduces the TSH-induced activation of the thyroid epithelium.


Ultrastructural changes in contents of membrane-coating granules after extrusion from epithelial cells of hamster cheek pouch. Membrane-coating granules of the epithelium of the hamster cheek pouch displayed a lamellated internal structure consisting of alternating thick and thin electron dense bands separated by translucent bands of equal width. The repeat distance of the contents was 8.5 nm +/- sd. 0.7 nm and the thickness of the major electron dense band was 3 nm +/- sd 0.4 nm. After exocytosis from the cells the lamellated material became organised into extensive sheets and the dimensions changed so that the repeat distance was 10.9 nm +/- sd 0.6 nm but the major electron dense band was virtually unchanged at 3.33 nm +/- sd 1.1 nm. The narrower or intermediate dense band became progressively less easy to see and was virtually invisible at the surface of the epithelium. It is suggested that the changes observed may be due to an increase in hydration of a phospholipid/protein complex in the granules by permeaton of water along the intermediate dense band.


Studies on the midgut of Centropages typicus (copepod, calanoid). I. Structural and Ultrastructural Data. From a structural study of the midgut of Centropages typicus, three main zones presenting different cellular associations may be defined. The ultrastructural study carried out allows us to distinguish several cell types. The four principal cell categories (E, R, F and B) show a more or less marked resemblance with those identified in the Malacostraceans, especially in the hepatopancreas of Decapods. The three types R, F and B, which are subdivided according to their localization (R and R') or their developing stages (F1, F2; B1 to B5), are recognized by the following characteristics: R-cells with smooth endoplasmic reticulum and high microvilli (zones I and III); F-cells with rough endoplasmic reticulum and short or spherical microvilli (zones I and II); B-cells with a large vacuolar apparatus made up of lysosome-like dense bodies associated with vacuoles originating from pinocytosis (zone II). From the comparisons of morphological, ultrastructural and histochemical results concerning Centropages typicus with author's data, we propose and discuss these functions for the three principal cell types: synthesis and secretion of pre-digestive enzymes (F1 and F2-cells); enzyme synthesis, intracellular digestion and extrusion (B1 to B5-cells); absorption (R and R'-cells).


The ultrastructure of the non-neurosecretory components in the brain of the midge, Chironomus riparious Mg. (diptera: nematocera). The ultrastruct of the neural sheath, glial cells and neurons in the brain of the neoimaginal male Chironomus riparius is described. The neural sheath comprises a neural lamella and underlying perineurium. The neural lamella consists of an amorphous matrix in which fine fibrils occur. The perineurium is composed of two cell types forming a continuous layer around the brain. The subjacent cortical layer, composed of the cell bodies of neurons and glial cells, varies considerably in thickness and surrounds the centrally located neuropiles. Three types of glial cells are distinguished on the basis of their positions and appearances. Five types of neurons are described which differ in size and relative frequency of organelles. Four types of axons, including those of neurosecretory cells, are distinguished by their size and content.


Presence of elongation factor 1 in nuclei and nucleoli of rat liver. Purified rat liver nuclei contain 11% of the total cellular translation elongation factor 1 activity. Ninety percent of the nuclear EF-1 activity was in the nucleoplasm and 10% was nucleolar. The specific activities of the nuclear and nucleolar EF-1 were 2 to 3 times higher, respectively, than EF-1 activity of the liver homogenate. The presence of EF-1 in the purified nuclei did not result from cytoplasmic contamination since only 0.14% of the cellular lactate dehydrogenase was present in the nuclei. These results provide the first evidence for the presence in the cell nucleus of translational factors of protein synthesis.


Alternating polarity in rRNA genes.

Alternating polarity in rRNA genes. Spread nucleolar material from A. exigua exhibits an unusual arrangement of rDNA cistrons. The cistrons form head-to-head "diamond-shaped" doublets with a short spacer separating the members of the doublet. Single cistrons are usually terminal and arrange tail-to-tail with the adjacent doublet, suggesting the possibility of a repeating unit with a tail-to-tail, "bow-tie" doublet configuration in which the cistrons (average length: 1.44 micron) could be explained by an extraordinary shrinking of the DNA strand during transcription. This suggestion is supported by the estimation of the molecular mass of an early, or the primary, transcription product (2.2 X 10(6)).


The inhibitory effect of heparin and warfarin treatments on the intravascular survival of B16 melanoma cells in syngeneic C57 mice. Heparin and warfarin inhibit the intravascular survival of B16 melanoma cells in syngeneic C57B1/6J mice in a dose-related manner. The anticoagulant properties of these drugs appear to mediate their inhibitory effects on the survival of intravascular tumor cells. Despite the administration of large doses of heparin, a constant fraction of tumor cells survive to form lung tumors. These data indicate that coagulation dependent and coagulation independent populations of B16 cells normally survive following the intravenous injection of tumor cells.


Inhibition of human prostatic tumour acid phosphatase by N,N-p-di-2-chloroethylaminophenol, N,N-p-di-2-chloroethylaminophenyl phosphate and other difunctional nitrogen mustards. Potent inhibition of human prostatic carcinoma tissue acid phosphatase by N,N-d-di-2-chloroethylaminophenol (AMOH) and N,N-p-di-2-chloroethylaminophenyl phosphate (AMPh) is described. Certain other difunctional nitrogen mustards were also inhibitory but N,N-p-di-2hydroxyethylaminophenol, the non-alkylating fully hydrolysed product from AMOH, was not. Inactivation of the enzyme by AMPh was progressive with time, showed apparent first order reaction kinetics and was not reversed by extensive dialysis. The results suggest that the inability of the enzyme to catalyse the hydrolysis of AMPh was due to inhibition in the presence of AMPh, possibly involving an alkylating mechanism. The implications for possible chemotherapy with AMPh are discussed.


Some antitumor derivatives of ellipticine deprived of mutagenic properties. Seven derivatives of the antitumor alkaloid ellipticine were assayed for activity against murine leukaemia L1210 and for mutagenicity in Ames' Salmonella-microsomes test. Not only did the results show a complete lack of correlation between these two properties, but it was possible to choose a highly efficient analog which was completely devoid of mutagenic and hence, probably, carcinogenic effect. The lack of interaction of this product (2-methyl-9-hydroxyellipticinium acetate) with Cytochrome P-450 of hepatic monooxygenases prevents the formation of reactive intermediates and their subsequent binding to DNA. These data are discussed in view of the currently admitted mode of action of ellipticines i.e., intercalation in DNA and their therapeutic use.


The reaction of trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene with DNA involves attack at the N7-position of guanine moieties. The reaction of trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE) with DNA prelabelled with [14C] and [3H]-purine precursors has indicated that in addition to the N2-position of guanine previously reported [10--12] reaction also involves the N7-position of guanine. The hydrocarbon-N7-guanine product was not detected earlier because it is lost from the DNA very readily at pH 7. The same N7-product was obtained by reaction of anti-BPDE with guanine in dimethylformamide.


The biological fate of vinylidene chloride in rats. The main eliminative route for [14C] vinylidene chloride ([14C]DCE) after intragastric, i.v. or i.p. administration to rats is pulmonary; both unchanged DCE and DCE-related CO2 are excreted by that route and other DCE metabolites via the kidneys. Part of the urinary 14C is of biliary origin. After intragastric dosing, the plot of the pulmonary output of unchanged DCE against the logarithm of reciprocal doses in biphasic. Pulmonary elimination of DCE and CO2 and urinary excretion of DCE metabolites after an intragastric dose occupy 3 days. In comparison, 80% of a small i.v. dose is excreted unchanged within 1 h of injection; more than 60% within 5 min. Biotransformation of DCE affords thiodiglycollic acid, and an N-acetyl-S-cysteinyl-acetyl derivative as major urinary metabolites together with substantial amounts of chloroacetic acid, dithioglycollic acid and thioglycolic acid. It is probable that chloroacetic acid, which is a DCE metabolite per se, lies on a main metabolic pathway for DCE, since it affords several metabolites in common with DCE. Furthermore, electrolysis of one molecular proportion of the [14C]thiodiglycollate metabolite from [1(-14)C]DCE or [1(-14C]chloroacetic acid gives 1 equivalent of 14CO2, and this evidence is consistent with the transformation of DCE into chloroacetic acid by a mechanism involving the migration of one Cl atom and the loss of the other one. CO2 (and hence urea) may be produced through the action of epoxide hydratase on 1,1-dichloroethylene oxide or by a minor oxidative pathway for chloroacetic acid. The N-acetyl-S-cysteinyl-acetyl derivative is probably formed via the reaction of 1,1-dichloroethylene oxide and glutathione S-epoxide transferase.


Nitrosamine carcinogenicity: a quantitative Hansch-Taft structure-activity relationship. Statistically significant correlations have been demonstrated between carcinogenic activity, water-hexane partition coefficients and electronic factors for an extensive series of N-nitroso compounds. Electronic factors were expressed by the Taft sigma* values of substituents on the carbon atoms alpha to the N-nitroso group. Such correlations indicate that transport of the carcinogen to its active site has an important effect on its potency. The correlations also implicate reactivity at the alpha-carbon in the determination of carcinogenic activity and point out various structural types which do not follow the general rule.


Interactions between tetrahydrofolate and palladium(II) complexes. Interactions between folate derivatives and palladium(II) complexes are monitored in 1 : 1 molar ratio mixtures by circular dichroic spectra. The results are consistent with the following conclusions, i.e., tetrahydrofolate forms a chelate complex with palladium(II) through nitrogens 5 and 10 which is characterized by a unique circular dichroic spectrum. Mixtures of pallodium (II) complexes and dihydrofolate on methylenetetrahydrofolate could not be expected to, nor do they, give rise to similar circualr dichroic spectra for the following reasons: (1) The N5, N10 chelation site of tetrahydrofolate is blocked in methylenetetrahydrofolate, so coordination of a palladium(II) species must occur at some secondary site. (2) The N5, N10 chelation site is available but carbon six of the pteridine ring system is no longer asymmetric in dihydrofolate. Mixtures of dihdrofolate and palladium(II) complexes have no measurable circular dichroic spectra under the experimental conditions used.


Some properties of vicinal diol-epoxides derived from benzo(a)anthracene and benzo(a)pyrene. The alkylating properties of pairs of syn- and anti-isomers of 2 diol-epoxides derived from benzo(a)pyrene (BP) and of 1 derived from benz(a)anthracene (BA) have been investigated. Of the anti-diol-epoxides, anti-BP 7,8-diol-9,10-oxide was the most reactive compound towards DNA, towards sodium p-nitrothiophenolate in a non-aqueous solvent system, and towards 4-(p-nitrobenzyl)pyridine in aqueous solution; anti-BP 9,10,-diol-7,8-oxide was of intermediate reactivity and anti-BA 8,9-diol-10,11-oxide was least reactive. The syn-diol-epoxides gave unsatisfactory results with DNA and 4-(p-nitrobenzyl)pyridine because of their rapid solvolysis in aqueous solution, but with sodium p-nitrothiophenolate showed the order of reactivity syn-BP 7,8-diol-9,10-oxide greater than syn-BA 8,9-diol-10,11-oxide greater than syn-BP 9,10-diol-7,8-oxide. The products of the reaction between diol-epoxides and nucleic acids were examined by Sephadex LH-20 chromatography followed by high-pressure liquid chromatography (HPLC) and the diol-epoxides were shown to react principally with the guanosine and adenosine moieties of RNA.


Evidence of DNA repair in the guinea pig pancreas, in vivo and in vitro, following exposure to N-methyl-N-nitrosourethane. The nature of DNA damage induced by N-methyl-N-nitrosourethane (NMUT) in the guinea pig pancreas, both in vitro and in vivo, and subsequent repair was investigated by alkaline sucrose density gradient analysis, using a non-radioactive fluorimetric procedure for DNA determination in gradient fractions. In vitro exposure of pancreatic slices to 20 mM NMUT for 30 min damaged DNA to less than 2.24 . 10(6) dalton fragments. However, incubation of NMUT-treated slices for 3 h in a fresh medium resulted in the repair of most of DNA damage, as indicated by the conversion of low molecular weight DNA fragments into heavy DNA of molecular weight comparable to DNA from control slices. Additionally, a single administration of NMUT (30 mg/kg, i.p.) to guinea pigs induced extensive DNA damage, to less than 2.24 . 10(6) dalton fragments in the pancreas within 4 h; similar DNA damage was observed in the liver. However, in the pancreas and liver of guinea pigs sacrificed at increasing intervals after NMUT administration, there was a gradual conversion of shortened DNA fragments to heavy high molecular weight DNA, indicating repair of DNA damage. It appears that most of DNA damage in the pancreas and liver was repaired by 14 and 7 days, respectively, following NMUT administration.


Effect of hexachlorobenzene and acetone on algal growth: physiology and ultrastructure. The effect of hexachlorobenzene (HCB) and acetone on growth and ultrastructure of the freshwater alga Chlorella pyrenoidosa was studied. The algal cells were grown for 76 h under continuous light in 10 ppm HCB with 0.33% acetone or in 0.33% acetone alone; the control cells were grown in nutrient solution only. As was deduced from determinations of dry matter, carbohydrates, chlorophyll content and total nitrogen, 0.33% acetone in nutrient solution slightly decreased the growth of the cells without having any influence on their ultrastructure while 3.33% acetone affected the ultrastructure of the cells severely. An incubation of Chlorella with 10 ppm HCB in nutrient sultion containing 0.33% acetone led to a drastic decrease of all growth parameters studied, total nitrogen and chlorophyll content being affected most strongly. These latter observations were in accord with the changes in ultrastructure showing damage to the cell membranes, disintegrated cytoplasm and sometimes even break down of cell organells leaving only starch grains, the pyrenoid and some endomembranes. In addition to these cells with severe lesions, quite normal cells were found.


Intercalation with DNA is a prerequisite for daunomycin, adriamycin and its congeners in inhibiting DNAase I. DNAase I from bovine pancreas is inhibited by Daunomycin, Adriamycin, Adriamycin-14-acetate and Adriamycin-14-octanoate, whereas it is not inhibited by N-trifluoroacetyladriamycin-14-valerate or N-trifluoroacetyl-adriamycin. The present study suggests that these inhibitors act not directly on the enzyme, but on DNA, forming stable complexes and thus interfering with enzyme activity. The correlation between DNA binding and enzyme inhibition is demonstrated by the fact that the compounds forming complexes with DNA inhibit DNAase I activity, whereas those which do not form complexes with DNA cause no inhibition.


An introduction to behavioural principles in teaching the profoundly handicapped. The principles of behavior modification in severely handicapped subnormal children are outlined and discussed.


Home intervention with parents of severely subnormal, pre-school children: an interim report. A programme of home-based intervention with two groups of pre-school severely subnormal children and their parents has produced apparently contradictory results; frequently visited children after initial superiority over infrequently visited children, later showed a deceleration in intellectual growth. Less frequently visited children conversely showed a rise in performance after an initial decrement. The interpretation is advanced that parents in the latter group were less dependent on the visiting therapist, and more able to take positive action to assist their children, and improve their own situation.


Childhood housing experiences and school attainment. The housing conditions of children in the National Child Development Study are related both to 16-year school attainment and also to progress through secondary school from 11 to 16. Children in homes which are crowded or lacking amenities, or in council homes at sixteen have relatively low scores on tests of reading and mathematics at the same age. The relationship between 16-year attainment and housing conditions is shown to be similar whether the child experienced the unsatisfactory housing at the age of 7, 11 or 16. Crowding and amenities are shown to be slightly associated with progress through the secondary school, although tenure is more strongly associated. The overall conclusions from this study are that children who have ever lived in unsatisfactory housing perform relatively poorly at school when they are 16, but no evidence emerged that there is any particular age at which housing circumstances are crucial for eventual school attainment. Consideration is also given to the importance of the wider environment in which the child lives.


Division, duplication and neglect: patterns of care for children with chronic disorders. The care of forty-four children with chronic arthropathies (usually juvenile rheumatoid arthritis) was studied by parental interview. The goal was to determine parents' perceptions of how management responsibilities are shared between primary physicians and specialists. Responses to questions about each of nine specific areas of care, ranging from diagnosis and treatment of the chronic disorder to the care of minor, acute illnesses, enabled the investigators to determine which physician had assumed major responsibility for each area. The results suggest a pattern whereby basic care is either divided or duplicated, but with many of the supportive aspects of care neglected in a high proportion of families. A comparison of these results with those of a similar study of children with meningomyelocele provides support for the view that such patterns are typical of the care of most children with chronic disorders.


The relationship between body fluid volume, sodium ion concentration, and sensitivity to pressor effect of angiotensin II in dogs. Extracellular fluid volume, plasma electrolyes, and plasma angiotensin II (A II) were individually controlled to determine their influence on the acute pressor responsiveness to A II. Hemodialysis of nephrectomized dogs was used to simulate and control the changes of major variables which occur in the intact state during changes in sodium balance. A II dose-pressure response curves were determined in 11 dogs at three volume states with plasma [Na+] maintained constant and in five dogs at low, normal, and high plasma [Na+] with body fluid volume maintained constant. Parallel shifts of the log dose-response curves were obtained in the three volume states. The same rise in arterial pressure with identical doses of A II was obtained at normal, contracted, and expanded volume states, with the change of arterial pressure based on the uncompensated basal pressure level at each volume state. When the fall in pressure observed during volume depletion was returned to control levels with norepinephrine, there was no change in the A II dose-response relationship from the control state. No difference in the A II dose-pressure response relationship was obtained between states of 140, 146, and 156 mEq/liter plasma [Na+] with body fluid volume held constant. The studies indicate that short-term alterations in either sodium or water balance do not alter the "real" vascular sensitivity to A II. The "apparent" changes normally observed result from preexisting endogenous levels of circulating A II present at the time the dose-response curve is determined which probably alter the availability of receptor sites to A II.


Assessment of regional myocardial blood flow and regional fractional oxygen extraction in dogs, using 15O-water and 15O-hemoglobin. A new approach to the assessment of regional myocardial blood flow and fractional oxygen extraction has been developed using 15O-water (H2-15O) and 15O-hemoglobin (15O-Hb). Bolus doses (1 mCi) of H2-15O and 15O-Hb were injected 10 minutes apart into the left main coronary artery of 12 normal dogs. Sequential images of regional myocardial tracer clearance were obtained over 5 minutes with a positron camera. Myocardial blood flow calculated from the monoexponential washout of H2-15O after background correction was 78 +/- 6 (SE) ml/100 g per min. Functional images of regional blood flow in which the image of peak activity was divided by the integrated image of H2-15O washout were derived by computer processing. These images demonstrated homogeneous blood flow in the normal myocardium. Fractional myocardial O2 extraction was determined from an image of initial distribution of O2 used (obtained by extrapolating back to time zero the series of images obtained after 15O-Hb administration), divided by initial distribution of O2 delivered (obtained by back extrapolating H2-15O washout). These functional images showed uniform distribution of fractional O2 extraction in the normal myocardium. Thus, these studies show that regional myocardial blood flow and regional oxygen extraction can be measured simultaneously by sequential imaging after serial intracoronary injections of H2-15O and 15O-Hb.


Mechanically dependent changes in action potentials recorded from the intact frog ventricle. The wall of the ventricle contracts inhomogeneously during an isovolumic beat of an isolated, intact frog ventricle. Some epicardial segments actually lengthen while the pressure is rising. Almost simultaneously, the early repolarization phase of the monophasic action potential recorded from such a segment is accelerated, compared to the same phase for an isotonic beat in which the segment shortens. Segment lengthening during the isovolumic beat also may be seen during the late repolarization phase when, in contract to the above, it produces an afterdepolarization. These electrical changes disappear when isotonic contraction is restored. Corroborative findings were obtained from microelectrode and insulated gap recordings from isolated frog ventricular strip. Both electrical changes can be seen clearly when the segment is lengthened by intraventricular injections of Ringer's solution. There also is a short transition period toward the end of the action potential plateau when lengthening produces neither depolarization nor repolarization. The accelerated repolarization is manifest as a shortening of the Q-T interval in the ventricular electrogram. In all experimental preparations, the afterdepolarizations reached threshold for a propagated action potential. This mechanism may explain the generation of extrasystoles in myocardial ischemia.


Changes in central catecholaminergic neurons in the spontaneously (genetic) hypertensive rat. Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and dopamine-beta-hydroxylase (DBH) activities were decreased in specific nuclei of the hypothalamus and in the nucleus interstitialis striae terminalis ventralis, in both young and adult rats. The decrease in the formation of norepinephrine can result in a reduced activation of central alpha-adrenergic receptors which may be related causally to the onset of hypertension. The activity of the epinephrine-forming enzyme, phenylethanolamine-N-methyltransferase (PNMT), was increased in the A1 and A2 areas of the brainstem in young SH rats, but it was normal in adult hypertensive animals. These results implicate adrenergic neurons in the brainstem and noradrenergic neurons in the hypothalamus in the development of spontaneous (genetic) hypertension in rats.


Continuous local electrical activity. A mechanism of recurrent ventricular tachycardia. Although the mechanism of most episodes of recurrent ventricular tachycardia (VT) is believed to be re-entry, definitive proof of this hypothesis has heretofore been unavailable in man. Using programmed stimulation and ventricular endocardial mapping we studied three patients in whom the initiation of VT was dependent upon developing a critical degree of fractionation and delay in local left ventricular electrograms. When electrical activity spanned diastole, VT ensued. Maintenance of VT was associated with continuous electrical activity resembling "local fibrillation" while termination of VT required cessation of this continuous activity. During sinus rhythm the electrogram recorded from the areas which subsequently developed continuous activity showed markedly fractionated and prolonged electrical activity exceeding 100 msec in duration. We feel these observations of the temporal relationship of continuous activity with the development of VT represent the first documentation of the re-entrant nature of this arrhythmia in man.


The limitations of epicardial mapping as a guide to the surgical therapy of ventricular tachycardia. The adequacy of intraoperative epicardial mapping as a guide to surgical procedures performed to terminate ventricular arrhythmias was investigated. Ligation of the anterior septal or left anterior descending coronary artery in 28 dogs produced ventricular arrhythmias that were studied 24-36 hours following occlusion. The sites of origin of 26 tachycardias were determined to be in the subendocardium by using extensive epicardial, endocardial and intramural mapping techniques and were verified by demonstrating unaltered activation sequences during pacing from these earliest sites. Epicardial breakthrough followed earliest directly recordable ventricular activity by as little as 7 msec. Without endocardial mapping many of these tachycardias would have been incorrectly identified as originating in the fascicles or epicardium. The sites of epicardial breakthrough were anatomically distant from the sites of origin by a markedly varying extent (5mm to 6cm). Two rhythms might be close in their sites of earliest epicardial appearance yet distant on the endocardium or vice versa. We conclude that epicardial mapping may not be sufficient to identify or predict the origins of many ventricular tachycardias and that the success of surgery to abolish these arrhythmias may be enhanced by preoperative and intraoperative endocardial mapping.


Determinants of antegrade echo zone in the Wolff-Parkinson-White syndrome. Forty-five patients with the Wolff-Parkinson-White syndrome and reciprocating tachycardia which utilized the atrioventricular (A-V) node for antegrade conduction and an accessory pathway for ventriculo-atrial (retrograde) conduction were studied. The extrastimulus technique in the right atrium and coronary sinus at multiple pacing cycle lengths was used. Three types of "echo zones" were defined by the relationship of the antegrade effective refractory period (ERP) of the accessory pathway, the longest coupling interval accompanied by an atrial echo, the ERP of the A-V node, and the functional refractory period of the atrium. Eighteen of 45 patients (40%) had more than one type of echo zone demonstrated by changing either pacing site or pacing cycle length or both. Pacing site and intraventricular conduction delay were found to have important effects on the longest coupling interval accompanied by an atrial echo in those echo zones in which the longest coupling interval accompanied by an atrial echo was less than the antegrade ERP of the accessory pathway. The echo zone is a useful concept to explain the physiology of the common reciprocating tachycardia in patients with the Wolff-Parkinson-White syndrome. However, the echo zone is profoundly affected by pacing site and pacing cycle length. When these variables are changed, many patients can be shown to have more than one type of echo zone. Studies of the echo zone have limited value as therapeutic guides.


The risk of advanced heart block in surgical patients with right bundle branch block and left axis deviation. The risk of advanced atrioventricular block during anesthesia was studied prosepctively in 44 patients with right bundle branch block and left axis deviation who underwent a total of 52 operations over a 14 month period. All patients had continuous electrocardiographic monitoring throughout anesthesia induction, operation, and surgical recovery. Of the 52 operative procedures, 24 were done under general anesthesia, 11 under spinal, and 17 under local. The preoperative cardiac rhythms were atrial fibrillation in two patients, atrial tachycardia with block in one patient, atrial flutter in one patient, and sinus rhythm in the remaining patients. Temporary pacemakers were inserted preoperatively in six patients, usually because of PR interval prolongation on the preoperative electrocardiogram. There was only one episode of transient complete heart block in 51 of the 52 operative procedures. In two of the six patients with temporary pacemakers, significant pacer-related ventricular irritability occurred. This study indicates that temporary pacemaker insertion is rarely required in patients with chronic right bundle branch block and left axis deviation who require noncardiac surgery.


Antiarrhythmic effects of aspirin during nonthrombotic coronary occlusion. To study the action of aspirin upon the myocardium per se, independent of thrombosis, coronary occlusion with a balloon catheter was induced in 53 anesthetized dogs divided into two groups. One group (N = 20) was  treated daily with aspirin (600 mg/dog) for seven days and another (N = 33) was untreated. Left ventricular hemodynamics and precordial ECG mapping were used to assess the influence of myocardial ischemia over a four hour period. There were no significant differences in left ventricular function or extent of injury as judged by ECG mapping between the two groups. However, there was a significant decrease in the incidence of ventricular fibrillation in the treated dogs (5% vs 39%). Serial plasma samples for free fatty acid determination showed a significant rise in the untreated group. Aspirin blocked the FFA increment in the treated animals. Tissue samples from the ischemic area of left ventricle exhibited a significant reduction of the sodium and water increments, as well as a lesser potassium loss in the treated animals compared to the controls and may have been the basis for the lower incidence of arrhythmias. Since infusion of 51Cr labelled platelets showed no myocardial accumulation of platelets in either group, microthrombi did not appear to contribute to the observed differences.


Clinical electrophysiologic effects of tocainide. The electrophysiologic properties of tocainide were evaluated by electrophysiologic studies in 11 patients before, during and after a constant intravenous infusion of the drug for 15 minutes. Peak plasma tocainide concentrations averaged 11.0 +/- 1.7 microgram/ml (SEM), range 3.7 to 22.7. AH, HV, QRS, QTc and RR intervals were measured every 5 minutes during sinus and atrial-paced rhythms and showed small changes which were not statistically significant for HV and QRS. Mild shortening of RR was significant (P less than 0.05) at 15 minutes only. AH tended to increase slightly for spontaneous (but not paced) rhythm, becoming significant at 15 minutes only (P less than 0.05). QTc decreased slightly, a change which was significant (P less than 0.05) for paced but not spontaneous rhythm. A progressive rise in mean arterial pressure occurred during infusion and persisted through 30 minutes (P less than 0.001). Comparison of electrophysiologic studies at 0 and 30 minutes showed decreased in mean effective refractory periods of atrium, A-V node, and right ventricle by 17, 22, and 23 msec, respectively (P less than 0.05, 0.01, 0.01). Functional refractory period of the A-V node showed an average decrease which was not significant. Sinus node recovery time and Wenckebach cycle length were unchanged. The drug was well tolerated in all 11 patients. Hypotension in a twelfth patient may or may not have been drug related. These results obtained at therapeutic plasma concentrations suggest qualitative similarities between the conduction system effects of tocainide and those published for lidocaine.


Comparison between apexcardiographic and angiographic indexes of left ventricular performance in patients with aortic incompetence. Left ventricular (LV) apexcardiogram (ACG) and its first derivative (dA/dt) was obtained in 104 normal subjects and 34 patients with chronic aortic incompetence (AI). In the patients with AI the ACG was recorded simultaneously with LV pressure (tipmanometer). The systolic upstroke time (SUT), the time to peak dA/dt (t-dA/dt) and the a wave percentage amplitude (a/H) of the ACG was measured. In normal subjects SUT averaged 99 +/- 17 (SD) msec. In 17 patients with AI and normal ejection fraction (EF) (group 1) SUT was within normal limits; in 17 patients with AI and decreased EF (group 2) it was prolonged (142 +/- 19 msec) (P less than 0.001). The SUT was closely correlated with EF (r = 0.85) and less with contractile indexes derived from pressure curves. The indexes t-dA/dt and a/H were not significantly different in groups 1 and 2; they were weakly correlated only with the time to peak rate of LV pressure rise (r = +0.56) and the LV end-diastolic pressure (r = +0.59), respectively. These results demonstrate the superiority of SUT over the other apexcardiographic parameters. The measure provides another means of noninvasive assessment of the LV performance in patients with AI.


Accuracy of echocardiography in assessing left ventricular dimensions and volume. The accuracy of determining left ventricular function from echocardiography was assessed in 26 children (group I) with cineangiographically-determined normal left ventricular volume (LVV) and 28 children (group II) with large left ventricular volumes. Conventional LV echo dimensions were compared to the cineangiographic LV anterior-posterior minor axis (LVmA) and LVV. Very good correlations were found in group I between LV end-diastolic echo dimensions (LVEDD) and cine LVmA (r = 0.91) and between LVEDD and LV end-diastolic volume (LVEDV) by cine in group I (r = 0.86). In group II correlations were less accurate between LVEDD and diastolic LVmA and between LVEDD and LVEDV. There was poor correlation between the cine and echo percent of shortening (r = 0.41) and velocity of circumferential fiber shortening (VCF) (r = 0.51). This study demonstrates that M-mode echocardiography is a very useful method for determining LV dimensions in children with normal LV volume, but is less accurate in children with left ventricular volume overload or with abnormal septal orientation or postoperative status after ventriculotomy.


Noninvasive study of early diastole in mitral stenosis. Cardiac events of early diastole were studied in 50 normal subjects and 46 patients with mitral stenosis (MS) by simultaneous recordings of the mitral valve echogram (MVE), phonocardiogram, and apexcardiogram (ACG). Left ventricular isovolumic relaxation time (IRT), measured between A2 and onset of the MVE opening motion, had almost the same values in normals 54 +/- 7 msec, and MS 51 +/- 16 msec. The interval between A2 and the ACG "O" point was approximately double that of IRT: 99 +/- 11 msec in normal subjects, 109 +/- 20 msec in MS. The normal MVE opening motion had a velocity 293 +/- 76 mm/sec and duration 45 +/- 6 msec, values significantly different (P less than 0.001) from 536 +/- 271 mm/sec, 23 +/- 7.5 msec found in MS patients. In atrial fibrillation the length of the cardiac cycle did not affect A2-O interval or mitral valve opening movement duration; however cycle length was clearly related to isovolumic relaxation time. This resulted in a variation in the interval between completion of the mitral valve opening (opening snap) and O point. This interval was longer after a short diastole and vice versa.


Thallium-201 scintigraphy in unstable angina pectoris. Thallium-201 scintigraphy was performed during the pain free period in 98 patients with unstable angina. Scintiscans were positive in 39 patients, questionable in 27 patients and normal in 32 patients. Eighty-one patients responded favorably to treatment (group I). Seventeen patients had complicated courses (group II) and despite maximal treatment with propranolol either developed infarction (six patients) or continued to have angina necessitating coronary surgery (11 patients). In group I during the pain free period 26 of 81 patients had positive thallium-201 scans, whereas 20 patients had an abnormal ECG at that time; during angina 18 patients had transient ECG changes. In group II during the pain free period 13 of 17 patients had positive scans, whereas two patients had abnormal ECG at that time; during angina 12 patients showed transient ECG changes. The sensitivity to recognize group II was 76% for thallium-201 scintigraphy, 11% for ECG during the pain free period; 70% for ECG during angina; 94% for the combination of either positive scans or abnormal ECG. Thus, 1) positive thallium-201 scans occur in patients with unstable angina, 2) positive scans can be obtained during the pain free period, 3) thallium-201 scans are more frequently positive in patients with complicated course.


Verapamil in the management of supraventricular tachyarrhythmias occurring after a recent myocardial infarction. In 16 patients, a sustained supraventricular tachyarrhythmia occurring less than 72 hours after the first symptom of an acute myocardial infarction was treated with titrated doses of verapamil. The drug was given intravenously in 1 mg increments every minute under continuous monitoring of electrocardiogram and blood pressure. Endpoints for the administration of verapamil were the following: reversion to sinus rhythm; a ventricular rate slower than 100/min; hypotension; a pulmonary capillary wedge pressure rising above 15 mm Hg; signs of intolerance; a maximum dose of 20 mg. Reversion to sinus rhythm was observed in 7/8 patients in atrial flutter and in 1/8 patients in atrial fibrillation; in all the ventricular rate could be slowed below 100/min without untoward effects.


The "false negative" treadmill exercise test and left ventricular dysfunction. One hundred and fifteen consecutive symptomatic patients undergoing graded exercise testing, selective coronary angiography and left ventriculography were retrospectively evaluated. The sensitivity, specificity, and false negative response rates of the exercise tests were 79%, 81%, and 21%, respectively. Although the magnitude of a positive ST-segment response was related to more extensive vascular disease, the frequency of false negative responses was nearly identical in patients with single, double, or triple vessel disease (22%, 21%, 19%). Analysis of the false negative group demonstrated significant ventriculographic and hemodynamic abnormalities when compared to the true positive responders. Five out of six patients with the most serious motion disorders in the study fell into the false negative group. There were no significant differences in the extent, distribution and severity of vascular involvement, or in the development of collateral circulation in the two groups. However, occluded vessels supplied abnormal ventricular segments more frequently in the false negative group (88% vs 38%); the absence of an "ischemic response" and the presence of segments of abnormal myocardium may be related. Left ventricular dysfunction appears to be an important reason for a false negative response to exercise.


Effect of acute volume alterations on norepinephrine and dopamine-beta-hydroxylase in normotensive and hypertensive subjects. Fifty-six patients with essential hypertension and 29 normotensive controls were hospitalized and volume expanded with saline or volume depleted with furosemide. We measured plasma norepinephrine (NE) and dopamine-beta-hydroxylase (DBH) to evaluate their sympathetic nervous activity. NE and DBH levels and their response to volume changes were the same in normal and hypertensive subjects. Volume depletion increased plasma NE in recumbent subjects by 50% and in standing subjects by 75% but did not alter DBH. Volume expansion with 2 liters of normal saline did not generally alter plasma NE, but led to a small decrease in DBH. Hypertensives have normal plasma levels of NE and DBH and normal responses of NE and DBH to alterations in volume and posture. The human sympathetic nervous system increases NE output during volume depletion, but fails to decrease NE during volume expansion.


Coronary sinus reflux. A source of error in the measurement of thermodilution coronary sinus flow. In seven patients thermodilution coronary sinus flow (TD-CSF) was higher (164 +/- 21 ml/min) during ventricular pacing than during atrial pacing (119 +/- 21 ml/min, P less than 0.005) at identical heart rate, without an increase in the determinants of myocardial oxygen consumption. To assess the possibility of right atrial admixture in coronary sinus blood during ventricular pacing we compared electromagnetic coronary arterial blood flow (CBF) with TD-CSF in nine dogs during interventions that increased right atrial pressure. During ventricular pacing, rapid atrial pacing, pulmonary artery constriction and increased intrathoracic pressure, right atrial pressure increased and electromagnetic CBF was significantly less (41-166%) than TD-CSF. Marked reflux from the right atrium to the coronary sinus was also demonstrated by bolus injection of cold saline into the right atrium and continuous infusion of contrast material into coronary sinus. Caution needs to be exercised in interpreting TD-CSF in the presence of changing right atrial pressure.


The hemodynamic effects of intravenous tocainide in patients with heart disease. In order to evaluate its hemodynamic actions, tocainide, a new orally effective antiarrhythmic drug, was given intravenously over a 15 minute period to 12 patients with compensated left ventricular dysfunction. Doses were 0.5 (4 patients) or 0.75 (8 patients) mg/kg/min. Hemodynamics and drug plasma concentrations were measured at the end and 15 minutes after the end of the infusion. Tocainide infusion produced small but statistically significant increases in the pulmonary and systemic vascular resistance, aortic and pulmonary arterial pressure, and left and right ventricular end-diastolic pressure. There was no significant change in left ventricular dp/dt, heart rate, or cardiac index. In patients with compensated left ventricular dysfunction, tocainide produces a small rise in vascular resistance and arterial pressure. Overall cardiac function is maintained with a small increase in left ventricular end-diastolic pressure.


Left ventricular function following attempted surgical repair of tetralogy of Fallot. Left ventricular function was assessed by angiographic methods in 40 patients (ages 3-27), 1-12 years following repair of tetralogy of Fallot. Twenty of the 40 patients (group A) had a satisfactory repair with a pulmonary-systemic flow ratio (Qp/Qs) less then or equal to 1.5 and a right ventricular systolic pressure of less than or equal to 60% of the left ventricular value. The other 20 patients (group B) had a Qp/Qs greater than 1.5 and/or a right ventricular systolic pressure greater than 60% of the left ventricular value. Group A patients had a normal left ventricular end-diastolic volume (LVEDV), end-diastolic pressure (LVEDP), ejection fraction (LVEF), and mass (LVM), while the group B patients had significantly elevated LVEDV, LVEDP, LVM, and a significantly depressed LVEF. These findings indicate that patients with a satisfactory hemodynamic repair of tetralogy of Fallot have normal left ventricular function while patients with postoperative unsatisfactory hemodynamics have significantly impaired left ventricular function.


Aschoff bodies at necropsy in valvular heart disease. Evidence from an analysis of 543 patients over 14 years of age that rheumatic heart disease, at least anatomically, is a disease of the mitral valve. Among 543 necropsy patients over age 14 years with severe chronic valvular heart disease, Aschoff bodies were found in 11 patients (2%). The ages of the 11 patients ranged from 18 to 68 years (avg. 38), and nine had had a history of acute rhematic fever earlier in life. Clinically, nine of the 11 patients had mitral stenosis with or without dysfunction of one or more other cardiac valves, one had isolated aortic regurgitation, and one had both mitral and aortic regurgitation. All 11 patients had diffuse fibrous thickening of the mitral valve leaflets, and all but one had diffuse anatomic lesions of at least one other cardiac valve. No patient with anatomic lesions limited to the aortic valve had Aschoff bodies. Thus, among patients with chronic valvular heart disease, Aschoff bodies, the only anatomic lesion pathognomonic of rheumatic heart disease, indicate diffuse anatomic lesions of the mitral leaflets and usually also anatomic lesions of one or more other cardiac valves. The functional mitral lesion is usually stenosis.


Calcific deposits in stenotic mitral valves. Extent and relation to age, sex, degree of stenosis, cardiac rhythm, previous commissurotomy and left atrial body thrombus from study of 164 operatively-excised valves. The presence or absence and the extent of calcific deposits in excised stenotic mitral valves was determined by radiographs of the excised valve in 164 patients aged 26 to 72 years. The extent of the mitral calcific deposits was determined by the percent of the valvular circumference containing the deposits = grade 0 (14 patients); grade I = less than 25% (43 patients); grade II = 25-50% (34 patients); grade III = 51-75% (39 patients); and grade IV = greater than 75% (34 patients). The amount of calcific deposits in the stenotic mitral valves correlated with sex and with the mean diastolic pressure gradient across the mitral valve (P less than 0.05), but it did not correlate with the patient's age, cardiac rhythm, pulmonary arterial or pulmonary arterial wedge pressure, previous mitral commissurotomy, presence of thrombus in the body of left atrium or the presence of disease of one or more other cardiac valves.


De subitaneis mortibus. XXIX. Randomly distributed focal myocardial lesions causing destruction in the His bundle or a narrow-origin left bundle branch. Most focally destructive lesions of the heart (e.g., myocarditis) have an essentially random distribution. Any mechanical significance of such diseases depends primarily on there being a very large number of foci. However, single even very small lesions can have profound electrophysiological significance if appropriately located within the cardiac conduction system. Two cases of sudden unexpected death are here reported which had destructive lesions involving the His bundle and a narrow-origin left bundle branch. Not much is known of the electrical or mechanical effects of acute left branch block which is due to complete anatomical transection of that structure in the human heart, and some possible consequences (including sudden unexpected death) are considered. Myocarditis or any other focally destructive disease in the heart may be of little functional importance if it is not widespread, unless some of the lesions happen to damage any of several small but crucially important sites in the cardiac conduction system. Studies to determine the presence or absence of this precise type of damage should be done especially in cases of sudden unexpected death.


Energy requirement for defibrillation of a markedly overweight patient. Recommendations have been made recently that the energy output of present-day defibrillators be increased above the 400 wsec limit. These recommendations are based largely on experimental studies in animals. We report a case of a man weighing 190.1 kg (418.2 lb), successfully resuscitated with a single 400 wsec shock after a prolonged episode of ventricular fibrillation. The observation in this patient as well as data derived from cardiovascular experience indicates that weight is not a significant factor in the successful outcome following defibrillation in adults. Many variables primarily related to the clinical condition of the heart influence the results of countershock. There are no valid studies at present to support the claim that high-energy defibrillators are necessary. In fact, implementation of such a recommendation is premature and possibly dangerous.


A comparison of serum electrolyte results by Technicon's Flame III and Flame IV AutoAnalyser system. A comparison of Technicon's (Technicon, Tarrytown, N. Y., 10591) Flame III and Flame IV electrolyte Auto-Analyzer systems for the determination of Na+, K+, Cl- and CO2 in serum is described. Results from the Flame IV are determined over three periods of time and compared to those of the referee Flame III system. The Optional Digital Printer and Linearizer Modules are not used with the described system. The Flame IV AutoAnalyzer is calibrated with a multi-point calibration technique (aqueous reference standards) rather than the single-point calibration technique (albumin reference material) used by the AutoAnalyzer II. Results for the Flame IV are shown to be comparable with those for the Flame III.


Application of curve regeneration to the determination of electrolytes by the Flame IV Auto-Analyser using a mini-computer. Curve regeneration is applied to the continuous-flow determination of serum Na +, K +, Cl- and CO2 by the Flame photometer IV (Technicon Corp.). A Hewlett-Packard 2100 A mini-computer is used for data acquisition. The continuous-flow parameters of both rise and fall curves are estimated from computer sampled voltage outputs over the standard profile. An additional interaction correction variable designated as Beta (beta) is described and applied to the regenerated peaks of the cresol red CO2 procedure. The phenolphthlalein CO2 methodology, showing improved flow parameters over those for the cresol red procedure is adapted for the Flame IV system. The basic program design is briefly outlined. Typical computer determined calibration curves (linear regression) and sample peak tracings for both the basic and regenerated techniques are illustrated.


A comparison of serum electrolyte results by the Flame III Auto-Analyser and a Flame IV Auto-Analyser which utilises curve regeneration with a data acquisition system. Results obtained with a Technicon Flame Photometer Model IV Auto-Analyzer, which utilizes curve regeneration in conjunction with a mini-computer for the continuous-flow determination of serum electrolytes, is presented. The system, featuring optimal flow conditions, subjects sample peaks to a mathematical treatment to effectively remove exponential deformation. The evaluation, undertaken after 2 months of operation in the routine clinical laboratory, utilizes the Flame Photometer Model III as the "referee" procedure. The comparison includes a statistical analysis of quality control reference material, simultaneously determined patient data and an evaluation of repeated patient data. The system gave comparable results to those obtained for the Flame Photometer Model III and provides the additional benefits of increased sample throughput, decreased reagent comsumption and sample interaction and gives reductions in the clerical tasks associated with the retrieval of data from Auto-Analyzer systems.


Performance evaluation of multi-channel analyzers by use of linearly-related survey specimens. Sets of specimens having quantitative linear inter-relationships for 25 analytes were prepared and used in a small survey of results with multi-channel analyzers. Instrument calibration was evaluated by linear regression analysis of the analytical results, with calculation of the x- and y-intercepts and slopes. The average intercepts and slopes agreed quite well with those expected on the basis of specimen preparation, but the results from individual laboratories and from particular kinds of instruments demonstrated a variety of analytical biases. We conclude that performance of multi-channel analyzers can be evaluated effectively by such use of linearly related specimens in an inter-laboratory survey.


Radioimmunoassay for mono-(2-ethylhexyl) phthalate in unextracted plasma. We report a radioimmunoassay for mono-(2-ethylhexyl) phthalate that has been coupled to a protein carrier as a radioligand. Competitive interference tests with a variety of related compounds indicated the assay to be highly specific. Quantitative comparison of mono-(2-ethylhexyl) phthalate values in plasma and serum samples between the radioimmunoassay and gas chromatographic procedures indicated a high reliability. Because this potentially toxic compound can leach into plasma from polyvinyl plastics, this assay should be particularly useful for those involved in the manufacture or use of medical devices made of them.


An enzymatic assay for determining free and total cholesterol in tissue. We describe a method for determining free and total cholesterol in extracts of rat-liver lipids by use of a cholesterol esterase/cholesterol oxidase enzymatic kit (Boehringer Mannheim Corp). The lipids are solubilized (as micelles) directly into the aqueous reagent mixture. Results of the enzymatic method correlate well with those obtained by an acid/ferric chloride assay of digitonin precipitates of the extracts. The enzymatic assay of free and total cholesterol in tissue offers advantages of simplicity over previously used methods.


Archival storage of clinical laboratory data. This paper describes a data-base system for the maintenance of  cumulative clinical data. A unique aspect of this data base is its ability dynamically to alter its two-level format to create an alternative three-level hierarchical structure in order to optimize retrieval efficiency. The relative advantages of these two types of data-base structures are discussed and examples of their use in clinical resrarch are presented.


Amperometric nonenzymatic determination of serum glucose by means of a nickel-catalyst electrode. We describe a new, nonenzymatic method for determining serum glucose. This method is based upon the direct electrochemical oxidation of glucose by means of stable nickel-catalyst that is electrodeposited onto a lead dioxide electrode surface. Linear calibration plots are obtained for glucose in the 0.1 to 4500 mg/liter range. Values for 23 sera with glucose concentrations ranging from 300 to 4300 mg/liter showed a linear correlation coefficient of 0.996 when compared with values reported by a hospital laboratory using the hexokinase method. Typically a 25-microliter sample is used, but samples as small as 5 microliter have been successfully analyzed. The sample is added to 25.00 ml of pH 13 electrolyte containing 1 mmol of NiSO4 per liter; the amount of increase in anodic current comproses the analytical signal. For 20 repetitive analyses of a serum specimen, the CV was less than 4%. Ascorbic acid is rapidly decomposed in the electrolyte used and thus does not interfere. Uric acid is inactive at the concentrations present in serum samples. The sensitivity and simplicity of the new method suggest it as an alternative to currently available procedures.


A solid-phase radioimmunoassay for vitamin B12 in serum, with use of radioiodinated tyrosine methyl ester of vitamin B12. Although radioassays for vitamin B12 with use of any of several binding proteins have been available for many years, a radioimmunoassay for B12 has not been reported. We describe here such a radioimmunoassay, incorporating, for the first time, a radioiodinated tyrosine methyl ester of B12 as the radioactive tracer. Polypropylene tubes are coated with antiserum raised in a rabbit against B12/bovine serum albumin to simplify the separation of bound and free radioactivity. Factors affecting the preparation of coated tubes are described. The assay is accurate, sensitive, precise, and specific for vitamin B12. Accuracy of the assay is unaffected by the presence of denatured protein. The advantages of this radioimmunoassay over conventional radioassays are discussed.


Purification of human prostatic acid phosphatase by affinity chromatography and isoelectric focusing. Part I. The main isoenzyme of human prostatic acid phosphatases was purified by affinity chromatography on L(+)-tartrate linked to agarose and by isoelectric focusing. The enzyme was a single protein when examined by polyacrylamide gel electrophoreses, either as a native protein or in the presence of sodium dodecyl sulfate. The analytical recovery of enzyme activity was 19%. The specific activity was 40 18 mumol/(min X mg) for hydrolysis of 5.5 mmol/liter p-nitrophenyl phosphate at pH 4.8 and 37 degrees C. The purification factor was as great as 1900. The molecular weight of the enzyme as measured by gel filtration was 109 000 and by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate 54 000, indicating that the enzyme had been isolated in the dimer form. By this method we have achieved the best purification of human prostatic acid phosphatase so far.


Flameless atomic absorption spectrophotometric determination of manganese in rat brain and other tissues. I describe a method for determining manganese in biological tissues by flameless atomic absorption spectrophotometry, It is simple to perform and does not require prior extraction with solvents. Small tissue samples are dried for 48 h at 110 degrees C and dissolved in concentrated nitric acid; the clear acid solution is introduced into the furnace and the sequential drying (120 degrees C, 20 s), charring (800 degrees C, 70 s), and atomization (2400 degrees C, 8 s) are automatically performed. The technique of standard additions was used ot overcome matrix effect. The detection limit is 0.86 X 10(-11) g of Mn. The CV is 4.7%. Only sodium and potassium interfere at 500-fold concentrations, and their interferences were overcome by using the Deuterium Arc Background Corrector.


Improved column method for separating lactate dehydrogenase isoenzymes 1 and 2. Lactate dehydrogenase (LD) isoenzymes 1 and 2 in human serum were separated on a column of diethylaminoethyl-Sephadex. Samples layered on mini-columns were eluted with buffered sodium chloride (100, 150, and 200 mmol/liter). Lactate dehydrogenase activity in column effluents was measured by the Wacker method, and their isoenzyme content was evaluated by electrophoresis on polyacrylamide gel. Results for column-fractionated LD-1 and LD-2 were expressed in two ways: LD-1/LD-2 ratios and total LD-1 + LD-2 activities. The former is a more specific indicator of myocardial infarction than the latter. Sera from 10 patients with acute myocardial infarction (increased creatine kinease isoenzyme MB activity) exhibited ratios in the range of 0.92 to 1.56, ratios for 10 patients without heart disease (normal creatine kinase MB) ranged from 0.33 to 0.69.


Quantitation of anticonvulsant drugs in serum by gas-chromatography on the stationary phase SP-2510. A new column packing, SP-2510 DA (Supelco, Inc., Bellefonte, Pa. 16823), is an excellent stationary phase for the determination of a wide variety of anticonvulsant drugs by gas--liquid chromatography without derivatization. However, when uncomplicated extraction procedures are used, serum cholesterol interferes with the determination of primidone. By the simple expedient of adding a short "pre-column" containing another phase (SP-2250 DA) the problem is overcome.


Preservation of acid phosphatase activity in medico-legal specimens. Vaginal acid phosphatase has been preserved with a protective broth containing, per liter, 50 of bovine albumin, 0.2 g of sodium azide, 10 mmol of phosphate (pH 7.4), and 9.0 g of NaCl. Samples may be maintained at ambient temperature for one month without loss of activity. Several other commonly used preservative methods are compared and are shown to be inadequate. With a constant 2.5 ml volume of the support medium, and use of a sodium thymolphthalein monophosphate method (Worthington Diagnostics), vaginal acid phosphatase activity in non-coital women is less than 10 U/liter of broth, and in recently post-coital women is more than 50 U/liter (242 +/- 104 U/liter). In vivo degradation of vaginal activity follows a nearly logarithmic course until four days after intercourse, when it reaches nearly normal values.


Evaluation of the Du Pont aca ammonia procedure. We evaluated the determination of ammonia used in the Du Pont Automatic Clinical Analyzer (aca). Correlation studies were done with a manual method, based on the same enzymatic principles as the aca and with a method involving a cation-exchange resin, followed by the Berthelot color reaction. In either case, the results agreed well with the results found with the aca. For the aca the mean analytical recovery of ammonia in plasma samples was 104%. Within-run and day-to-day precision had coefficients of variation of 6% for normal values and 1 and 2% for above-normal values. The linearity, tested with primary standards and plasma samples, was good up to 1000 mumol of NH3 per liter.


Natural fluorescence in serum of patients with chronic renal failure not to be confused with creatine kinase-BB isoenzyme. We assessed the reported presence of creatine kinase-BB isoenzyme in the serum of patients with chronic renal failure. Our study showed that the blood of these patients contains a fluorescent material with an electrophoretic mobility similar to that of the BB isoenzyme on cellulose acetate strips. The fluorescing material is, however, completely distinct from BB isoenzyme and its nature is as yet undetermined.


Spurious underestimation of results for digoxin radioimmunoassay with a commercial kit. Estimates of digoxin in serum with a commercial redioimmunoassay kit (Schwarz/Mann) occasionally result in more counts in the patient's "bound" fraction than in the "bound" fraction for the zero standard. This phenomenon has been investigated in 26 serum samples obtained from patients who were ingesting known amounts of digoxin. The problem appears to relate to environmental differences in at least the zero standard and affects results when serum digoxin concentrations are less than 0.8 microgram/liter. Apparently dose estimates are more accurate with other methods or by calculating results after omitting the zero standard.


Some factors affecting the utility of bovine blood as a control material in lead-screening programs. Bovine blood is used frequently as control material in interlaboratory comparisons for blood-lead analysis, but an erythrocyte protoporphyrin control material is needed. We present data on the rate of changes in blood lead and erythrocyte protoporphyrin in steers fed lead acetate. We also show, by comparison of fluorescence spectra with those of known compounds, that most of the porphyrin in lead-burdened steers probably exists as free protoporphyrin IX along with some zinc-complexed protoporphyrin IX. Bovine blood is suitable as an erythrocyte protoporphyrin control material for laboratories using acid extraction procedures, but not for the proficiency testing of laboratories using hematofluorometers.


Toxicology test-ordering patterns in a large urban general hospital during five years: an update. Analytical data from the clinical toxicology laboratory of a large urban hospital, the Los Angeles County--University of Southern California Medical Center, are reported for the year 1976 and are compared to similar data previously documented for the year 1972. Drugs assayed, number of tests requested, and number of positive results are collated. Data on 58 assays show that the overwhelming majority of the requests continue to be for those tests that were originally classified as tests with 4-h turn-around time in the patient-focused concept for a clinical toxicology service in 1972. Total workload increased by 70%. The number of patients on whom some toxicologic assay was requested doubled in spite of a decrease in the number of patients admitted to the hospital during this five-year period. The data show that assays for some socially and clinically significant drugs--ethanol diazepam, tricyclics, and phencyclidine--increased disproportionally while others remained relatively constant, or even decreased.


Return of ovarian function after abortion. The first menstrual cycle after a therapeutic abortion was studied in eighteen women by measuring plasma oestradiol and progesterone concentrations and the urinary excretion of LH until the first menstruation. The plasma concentrations of oestradiol and progesterone declined rapidly, reaching low values as early as the second day after the abortion. An increase in plasma oestradiol levels was observed from the seventh post-abortal day onwards. P peak of short duration in the plasma progesterone concentrations occurred during the increased oestradiol synthesis. The concentration of progesterone during the luteal phase of the cycle was lower than in a normal cycle, indicating an inadequate luteal function. Return of ovulation was observed in 83% of patients during the first cycle; as judged by a biphasic oestradiol profile in plasma, a mid-cycle LH peak, and subsequent elevation of progesterone. The first LH peak was observed 16 days after the abortion. The rapid return of the ovulatory function makes immediate post-abortal contraception a necessity.


The effect of pain on plasma arginine vasopressin concentrations in man. The effect of pain on plasma AVP concentration in man has previously been studied only during major surgery with general anaesthesia. Plasma AVP concentration (pAVP) and plasma osmolality (pOsm) were measured in thirty-six patients seen in a surgical emergency department complaining of pain and in fifty-one control subjects. No significant difference in pOsm was found, but pAVP was significantly higher in the emergency room patients in pain (M +/- SEM = 4.94 +/- 0.98 pmol/1 compared to 2.31 +/- 0.32 pmol/1 in control subjects, P less than 0.01). In the control subjects, age was found to have a low but significant inverse correlation with pAVP (r = 0.37, P less than 0.01). Chronic smoking was associated with significant elevation of pAVP (3.81 +/- 0.99 pmol/1 in smokers vs. 1.89 +/- 0.28 pmol/1 in non-smokers, P less than 0.02). Neither smoking nor age could account for the difference in pAVP between the pain and control groups. Thus, pain is a non-osmolar factor capable of elevating AVP in conscious man.


Oral essential amino acids in children on regular hemodialysis. Plasma amino acids were measured by ion-exchange chromatography in 10 children on regular hemodialysis for renal failure before and after a 6 month period on an oral supplement of 8 essential amino acids. The supplement constituted 14.7 +/- 9.7 (1 SD) of the protein intake, the proportion varying inversely with protein intake, and mean energy and protein intakes which were normal for body size did not change significantly during the study. Before supplementation there were significant reductions compared to normal in the concentration of valine, leucine, isoleucine, lysine, histidine, tyrosine and serine, and elevations in glycine, proline and the methylhistidines. After supplementation methionine levels were abnormally high, isoleucine levels were in the lower range of normal and otherwise there were no significant changes. These modest changes suggest that supplemental essential amino acids in uremic children on adequate energy and protein intakes may not only be superfluour but may induce new imbalances which may themselves be harmful.


Activity of intraperitoneal heparin during peritoneal dialysis. A pharmacokinetic study of intraperitoneal heparin was undertaken in eleven chronic renal failure patients as a guide for its therapeutic use in peritoneal dialysis. The intraperitoneal heparin was assayed as the activated-partial-thromboplastin time (A-PTT) of peritoneal aspirate or outflow dialyzate added to control plasma. This was noted to decay relatively slowly, the mean t 1/2 of heparin in the peritoneal cavity being 10.8 +/- 0.93 hr. The heparin cofactor antithrombin III determined by both immunological and functional methods was found to be present in low concentration in residual peritoneal fluid aspirated prior to commencing dialysis. Generally this was less than one-third of normal plasma values, and with the repeated dilution and outflow sequences of dialysis the cofactor concentrations rapidly fell to negligible levels that were incapable of activating any heparin present. Systemic blood coagulation was unaffected by single 10000 U doses of heparin administered intraperitoneally in that plasma A-PTT values were not lengthened when measured over the ensuing six hours.


Clearance ratios of amylase and isoamylase to creatinine in renal disease. Amylase to creatinine clearance ratios were measured in 66 patients with a variety of moderate and severe renal diseases including 10 patients with renal transplants, and in 13 healthy controls. Only in patients with severe renal insufficiency (serum creatinine level above 660 micronmoles/1) were the amylase to creatinine ratios significantly raised. The ratios correlated neither with the type of renal disease, i.e. glomerular or tubulointerstitial, nor with the degree of proteinuria. Patients with renal transplants did not differ from other patients. Clearance ratios of pancreatic and salivary isoamylase to creatinine changed in parallel to that of total amylase. The results suggest that in severe renal failure the loss of nephrons results in decreased fractional reabsorption of amylase in the tubules.


Malacoplakia of the kidney: apparent improvement following medical management. Malacoplakia of the kidney is a rare histopathologic entity of unknown etiology. Patients may present with a renal mass or with urinary tract infection. The prognosis has been uniformly poor excepting in those patients with unilateral involvement treated by nephrectomy. A 31 year old woman presented with acute renal failure and pyelonephritis. Renal biopsy revealed an interstitial infiltrate of large histiocytic cells with intracytoplasmic PAS-positive granules and calcospherules, findings consistent with malacoplakia. Following antibiotic treatment and dialysis, the patient has had a gradual improvement in renal function.


The effect of a low-protein diet on serum levels of ceruloplasmin and transferrin in patients with chronic renal failure. In patients with chronic renal failure the administration of a diet providing 20 g protein per day for five weeks caused a significant rise in the serum ceruloplasmin level. A low dietary copper content (0.8 mg/day) may have been the limiting factor for any further rise of the ceruloplasmin level. The rise of ceruloplasmin was associated with a continuous decline of total iron binding capacity. The temporarily raised serum iron levels and the continuous decline of unsaturated iron binding capacity suggested enhanced iron mobilization caused by the raised ceruloplasmin level. The rise of ceruloplasmin correlated with the decline of UIBC.


Surgical treatment of infective endocarditis in hemodialysis patients. Congestive heart failure following infective endocarditis in hemodialysis patients has been uniformly fatal in patients treated with antibiotics alone. Thirteen patients on chronic hemodialysis have undergone replacement of the infected valve with an overall survival of 61%. The aortic valve was involved in 10 patients and Staphylococcus aureus the responsible organism in nine. Recurrent bacteremia occurred in two of the eight long-term survivors and was successfully treated with antibiotics in one patient and replacement of the prosthesis in the other. The surgical treatment of infective endocarditis in the hemodialysis patient is an acceptable mode of therapy and its application should not be hindered by reservations concerning operative feasibility or postoperative longevity. As in non-dialysis patients with infective endocarditis and congestive heart failure early operative intervention may substantially improve survival.


Counseling in gynecologic practice: an overivew. We live in a turbulant period with regard to interpersonal relationships. Individuals place great emphasis on their ability to form good relationships. It is a time of desiring and searching; desiring to be engaged in a rewarding relationship and searching for any principles which might promote such involvement. Obstetrician-gynecologists are involved because reproduction and sexuality are so basic to dyadic relationship. Few gynecologists have not pondered how they would accomodate new methods of contraception, sterilization, elective abortion, fathers involved in the birth process, and marital conseling. These areas of obstetrics and gynecology have been profoundly altered in what is occurring with respect to women and their dyadic relationships with men. Anyone practicing obstetrics and gynecology, whether specialist, primary care physician, or other professional, has a special role in a woman's life because he or she is there. We have an obligation to acknowledge and take advantage of this unique opportunity.


History-taking in sex counseling.

History-taking in sex counseling. A formula for obtaining a sexual history that has both diagnostic and therapeutic significance has been presented. By utilizing the relationship between effective stimulation of a sufficient quantity in a nuturing environment, the physician will be able to clarify what has either caused or is maintaining the sexual difficulty. It will be most beneficial if the physician explains the history-taking approach to the woman. In this way she can see how her answers relate to the problem and to the direction of treatment. A history-taking approach structured in this manner is most helpful to the physician and the woman.


Dyspareunia and vaginismus.

Dyspareunia and vaginismus. Dyspareunia and vaginismus are discussed to present information and a structural concept allowing the gynecologist to evaluate these conditions. The presence of subtle pelvic organic factors is frequently found in dyspareunic women referred for sex therapy by physicians. Thus a need for scrupulous evaluation, including laboratory work and other diagnostic tests, with close attention to the history of the patient is urged. In the remaining dyspareunic women and in those with vaginismus, a psychophysiologic conditioned response is present. Treatment approaches are discussed and the techniques of perineal muscle exercise and vaginal self-dilation are presented in detail. Used appropriately, these techniques produce a very high symptom elimination rate in these female sexual dysfunctions.


Utility of combined 99mTc-phosphate and 67Ga imaging in diagnosis of septic arthritis. A case of septic arthritis diagnosed by combined 99m Tc-phosphate and 67Ga imaging, which preceded positive cultures of the infecting organism, is presented. A previously healthy 10-year-old girl complained of pain in her left hip with persistent fever. Initial laboratory studies showed a normal white cell count and negative blood cultures. A septic process was not confirmed. Blood flow studies and bone images with 99mTc-phosphate showed markedly increased perfusion in the left hip joint without extension to bone. Subsequent 67Ga images revealed a marked increase in radioactivity in the same region, indicating the presence of a septic process. Serial blood cultures and arthrocentesis showed Staphylococcus aureus. The patient improved on antibiotics.


Causes and temporal sequence of onset of functional asplenia in adults. To determine the causes and time course of onset of functional asplenia in adults, a four-part investigation was conducted. This consisted of a review of the world's literature, a survey of colleagues, a detailed study of 4,476 consecutive liver-spleen scans in three hospitals, and continued monitoring of 3,500 scans in five hospitals. Based on the findings, a classification was proposed of the causes of functional asplenia. The two major etiologies were circulatory disturbances and effects directly on splenic reticuloendothelial cells. The time course varied from the essentially instantaneous onset of functional asplenia in patients with acute splenic artery obstruction, to a prolonged and gradual onset in those with chronic damage to splenic reticuloendothelial cells. Functional asplenia was found in 0.14% of the adults who had liver-spleen scans for other indications.


Giant lymph node hyperplasia resembling abdominal abscess on gallium scan. A case of giant lymph node hyperplasia with systemic symptoms resembling chronic infection is described which showed intense gallium uptake indistinguishable from uptake seen in an abscess. This rare syndrome may mimic an abdominal abscess and should be considered in the differential diagnosis of patients without prior history of abdominal surgery and in whom an abdominal abscess is suspected. The condition is relatively benign.


Localization of metastatic adrenal carcinoma utilizing 67Ga-citrate. Soft tissue metastases from left adrenal cortical carcinoma in a 30-year-old white man were localized on a gallium scintigram six weeks following left adrenalectomy.


Pseudo-Budd-Chiari syndrome.

Pseudo-Budd-Chiari syndrome. A patient with clinical, laboratory, radiographic and scintigraphic findings resembling the Budd-Chiari syndrome is described. However, at autopsy there was no thrombotic occlusion of any of the intrahepatic veins. The right hepatic vein was completely constricted by the hypertrophied left lobe of the liver, and the left hepatic vein was narrowed. We have referred to this clinical entity as the pseudo-Budd-Chiari syndrome. It represents a potentially treatable form of the Budd-Chiari syndrome.


A dural calcification presenting as a solitary lesion on radionuclide bone scan. Y.S. is an 80-year-old white woman with metastatic adenocarcinoma. A bone scintisurvey demonstrated a solitary lesion in the right frontal calvarium. Skull x-rays revealed it to be a dural calcification.


Radionuclide imaging of Meckel's diverticulum in children. Fifty-eight children were studied for the presence of Meckel's diverticulum by scintigraphy with 99mTc-pertechnetate. Meckel's diverticulum was found at surgery in 6 of 6 patients with positive radionuclide studies and in 2 of 48 patients with negative studies. Four studies could not be interpreted because of widespread intestinal activity. Using the criteria described in this paper, false-positive readings did not occur.


A review of carotid cavernous fistula including diagnosis and evaluation by nuclear medicine angiography. The various causes and differential diagnosis of carotid cavernous fistula are discussed as well as the description of the use of radionuclide angiography in the diagnosis and evaluation of patients with carotid cavernous fistulas. Radionuclide angiography has proven extremely useful in the diagnosis and follow-up of patients with carotid cavernous fistulas. The procedure is of maximum benefit in situations where repeat studies are required at frequent intervals. Five cases are described in which the nuclear medicine technique was instrumental in primary diagnosis and follow-up.


Bacteremia in 28 ambulatory children: relationship to pneumonitis and meningitis. Bacteremia with known pathogens was documented in 28 acutely ill, febrile outpatients during a 29-month period. All of the children were previously healthy and were initially managed as outpatients. Eight patients presented with no identifiable focus of infection. Twenty patients had either otitis media or pneumonitis. An association between otitis media and bacteremia with H. influenzae type b was noted in 5 patients. Bacterial meningitis occurred subsequently in 7 patients (25%); 1 death occurred in this group. The blood culture, as an outpatient procedure, was helpful in establishing a bacterial etiology in selected children with either high fever (with or without otitis media), febrile seizures, or pneumonia. In addition, the positive blood culture was a vital aid in identifying the young child at risk for meningitis.


Recurrent abdominal pain in children: a retrospective survey of 119 patients. The clinical pattern of 119 children with recurrent abdominal pain, located most commonly in the periumbilical region, revealed no distinct features. The most common associated symptoms were pallor, tiredness and anorexia. The most important socioenvironmental and behavioral factors were marital turmoil in 44%, school activity in 32%, and perfectionism in 30%. Laboratory and radiologic and fiberoptic endoscopic studies were uniformly unremarkable. Counseling on a continuing basis helped 105 of these children.


Appraising children for mental retardation: the usefulness and limitations of IQ testing. As a result of their unique relationship with families, pediatricians are often faced with the difficult task of counseling the parents of a mentally retarded child. For this reason it is important that he understand the nature of the tools used to evaluate the retarded. Since the IQ test is still the most commonly used tool to assess presence or absence of retardation, this paper has briefly reviewed the concepts of intelligence, the IQ, and their interrelationships and their usefulness when evaluating the mentally retarded child.


Relationship between diazepam dose, plasma level, age, and central nervous system depression. Patients undergoing elective cardioversion for treatment of arrhythmias were premedicated with diazepam. The dose was individualized to achieve a degree of central nervous system CNS) depression characterized by response to painful but not vocal stimulation. Promptly following each cardioversion, blood was drawn and the plasma diazepam concentration was measured by gas chromatography. The plasma levels varied as widely as the diazepam doses so that there was no fixed plasma level of diazepam associated with the degree of CNS depression produced in these patients. However, both the dose of diazepam and the resulting plasma level were inversely correlated to age, indicating that age is a critical factor in the use of diazepam for cardioversion premedication; elderly are more sensitive to the depressant effects of this drug than the young.


Failure of hydrocortisone to alter acutely antipyrine disposition. The disposition of intravenously administered antipyrine in single doses of 40 mg/kg was studied in 3 dogs at 7:00 A.M. and 3 wk later at 7:00 P.M. Our purpose was to determine whether hydrocortisone differentially affected antipyrine disposition according to a circadian pattern. After each intravenous dose of antipyrine, saline was infused for 3 hr followed by intravenous hydrocortisone (2 mg/15 kg loading dose; 2 mg/15 mg/hr infusion for 3 hr). This regimen of hydrocortisone failed at either 7:00 A.M. or 7:00 P.M. to alter acutely antipyrine decay curves. Furthermore, in 4 normal male volunteers, no inflection in the salivary antipyrine decay curve occurred when hydrocortisone was injected 8 hr after antipyrine. In the human volunteers an intravenous injection of 3 mg was followed immediately by an additional 6 hr of continuous hydrocortisone infusion at 3 mg/hr. These experiments show that hydrocortisone alters the pharmacokinetics of previously administered antipyrine in neither dogs nor man.


Rise in serum and urine creatinine after phenacemide. Three patients under treatment with phenacemide for uncontrollable psychomotor epilepsy were found to have greatly increased serum creatinine levels in the absence of elevated blood urea nitrogen (BUN) values or any other evidence of renal disease. Serum creatinine returned promptly to normal after omission of the phenacemide and rose quickly again on resumption. Experiments in rabbits and rats fully reproduced these clinical observations. In vivo and in vitro studies with the drug and its metabolites excluded these as a cause for a spurious analytical finding. Rabbits given phenacemide have a fall in serum and urine creatine, while the corresponding creatine values rise. With the use of a creatininase degradation procedure, it could be proved that the markedly elevated serum level and the increased excretion consist of the creatinine and not of any other substance. An effect of phenacemide on the conversion rate of creatinine to creatinine in the body is a speculative possibility.


Theophylline disposition in obesity.

Theophylline disposition in obesity. Theophylline disposition was examined in 14 obese subjects and 57 normal subjects. A single oral dose of aminophylline solution was given and serum and saliva samples were collected over several hours and assayed by high-pressure liquid chromatography. The apparent volume of distribution (Vd) and body clearance (ClB) were analyzed for total body weight (TBW) and ideal body weight (IBW). The Vd averaged 0.482 (SD = 0.084) L/kg TBW in normals vs 0.382 (0.069) L/kg TBW and 0.77 (0.189) L/kg IBW in obese subjects. The ClB averaged 63.0 (28.5) ml/hr/kg IBW in normals compared to 32.8 (11.1) ml/hr/kg TBW and 64.1 (20.8) ml/hr/kg IBW in obese subjects. Similar Vd values between the two groups when TBW is used indicates that loading dose is best calculated based on TBW. Similar ClB based on IBW in normal and obese subjects indicates that IBW should be used to calculate maintenance doses for theophylline. Mean half-lives were longer in obese subjects than in normals, 8.6 (2.0) and 6.0 (2.1) hr, respectively, suggesting that obese patients may need less frequent dosing.


Effect of charcoal-broiled beef on antipyrine and theophylline metabolism. Eight healthy volunteers were sequentially fed a control diet, a charcoal-broiled beef--containing diet, and the control diet a second time. The mean plasma half-lives (t1/2) of antipyrine and theophylline were each decreased by 22% after the subjects were fed the charcoal-broiled beed--containing diet. The main plasma t1/2s for these drugs returned to control values when the subjects were fed the control diet for a second time. Considerable individuality occurred in the responsiveness of the subjects to the charcoal-broiled beef--containing diet. The decreases in antipyrine plasma t1/2s among the 8 subjects ranged from 5% to 39%, and the decreases in theophylling t1/2s ranged from 0% to 42%.


Effect of lithium on plasma chlorpromazine levels. The interaction of lithium and chlorpromazine (CPZ) was studied in healthy volunteers in a randomized crossover study. Each subject ingested two doses of CPZ (100 mg) as the liquid concentrate: (1) without concurrent lithium therapy and (2) after a 7-day treatment with lithium carbonate (900 mg/day). When CPZ was administered with lithium, peak plasma CPZ levels were 40.3% (mean) lower than those without lithium (p = 0.006), and the area under the CPZ plasma concentration time curve was 26.6% smaller (p = 0.08). The time to reach peak plasma CPZ levels was similar in both groups. All subjects slept for 4 to 6 hr after oral CPZ and had a maximum fall in both systolic (8 to 32 mg Hg) and diastolic (5 to 23 mg Hg) blood pressure at the time of peak plasma CPZ concentration. This lithium-CPZ interaction may explain the low plasma CPZ levels reported previously in psychiatric patients taking both lithium and CPZ.


Ticrynafen, a uricosuric antihypertensive diuretic. Ticrynafen, a diuretic-uricosuric also effective as an antihypertensive, was compared in single doses with several other diuretics. Over an 8-hr period, a 250- mg dose exerted natriuretic activity comparable to that of 25 mg of chlorthalidone and 50 mg of ethacrynic acid; a 500-mg dose was comparable to 50 mg chlorthalidone and 50 mg hydrochlorothiazide. Ticrynafen combined with furosemide had an additive effect, whereas a combination with hydrochlorothiazide was not additive. In both doses ticrynafen was a uricosuric and this effect was maintained when given with furosemide and hydrochlorothiazide, both of which individually were slightly antiuricosuric. Ticrynafen may be useful in patients requiring a diuretic in whom it is desirable to avoid hyperuricemia.


Tetracycline absorption in elderly patients with achlorhydria. Five elderly achlorhydric patients and five controls took 250 mg tetracycline as a capsule or as an oral solution. Venous blood samples drawn during the 12-hr period following administration and urine collected for 72 hr post-dosing were assayed fluorometrically for tetracycline. There were no differences between the two groups in either rate or extent of tetracycline absorption. The mean apparent first-order rate constant (ka) for absorption of drug from capsules was 0.58 +/- 0.17 hr-1 for patients and 0.65 +/- 0.21 hr-1 for controls. The mean extent of absorption for capsule dosage forms relative to an oral solution was 1.0 +/- 0.20 for patients and 1.0 +/- 0.24 for controls. Concurrent administration of 2 gm of sodium bicarbonate to 2 of the normal subjects resulted in no impairment of either the rate or extent of tetracycline absorption from capsules, suggesting that the effect of elevated gastric pH on tetracycline bioavailability may relate to formulation.


Cefamandole kinetics during cardiopulmonary bypass. The kinetics of cefamandole during cardiac surgery was studied in 16 adult patients given a single intravenous infusion of 20 mg/kg at the time of anesthesia induction. Five normal volunteers who received the same dose served as controls. Cardiopulmonary bypass (CPB) was found to signficantly increase the half-life (t 1/2) of cefamandole. The mean t 1/2 during CPB (113.2 min) was longer than the terminal t 1/2 in normal volunteers (52.0 min; p less than 0.005). Throughout CPB (maximum, 3,7 hr), cefamandole plasma levels were maintained above the minimum inhibitory concentration for those organisms most likely to cause postoperative infections. We conclude that if 20 mg/kg of cefamandole is given within an hour of the beginning of cardiovascular surgery, a supplemental dose is not needed until the patient has been on CPB for at least four hours.