Pericytes and perivascular microglial cells in the basal forebrain of the neonatal rabbit.

Three types of pericytes outline the vascular bed in Golgi preparations of the newborn rabbit brain. Elongate cells (Type I) are restricted to capillaries, elements resembling smooth muscle cells (Type II) surround vessels of intermediate size, and large flat forms (Type III) cover the surface of arterioles and venules. Electron microscopy shows all types to be located within a well defined perivascular basement membrane. It also reveals the presence of filaments in the cytoplasm of some pericytes resembling the myofilaments of smooth muscle cells. It suggests the possibility that some pericytes are capable of contraction and may participate in regulating blood flow in small vessels. Microglia cells bear no resemblance to pericytes in terms of their shape, distribution or staining characteristics. Microglia cells are located outside the vascular basement membrane (external basal lamina) in the brain parenchyma, and they vary in form according to their location and the character of the surrounding extracellular space. This study does not support the hypothesis that microglia cells arise from pericytes but indicates that they originate either by in situ division or from hematogenous elements that enter the brain by crossing the vessel wall.


Early effects of nerve growth factor on adrenergic neurons: an electron microscopic morphometric study of the rat superior cervical ganglion.

Nerve cells of the superior cervical ganglion of young rats (20 g body weight) were investigated electron microscopically 6 h, 24 h, 48 h and 5 days after subcutaneous injection of nerve growth factor (10 mug/g body weight every 24 h). By means of a planimetric method with high accuracy significant changes of the Nissl substance and the Golgi apparatus could be demonstrated as early as 6 h after injection. Within the Nissl bodies both the density of bound ribosomes on the cisternae of the rough endoplasmic reticulum and the density of free ribosomes and polysomes decreased in a given field. This finding reflects a rearrangement of the Nissl substance and a spreading over larger areas of the cytoplasm, indicating an activation of the ribosomal system. The Golgi apparatus, in particular its outer part, increases in volume with time of nerve growth factor treatment. On the other hand, the total cell volume does not show significant changes before 48 h of nerve growth factor treatment. At this time an increase in the cytoplasmic volume can be seen, whereas the nuclear volume remains unchanged. The possibility of correlations of the present findings with data from biochemical studies done under similar experimental conditions is discussed.


Data on protein synthesis of deafferented hypothalamic arcuate neurons.

Protein synthesizing activity of the rat hypothalamic arcuate nucleus following partial or total deafferentation of the medial basal hypothalamus was studied by light and electron microscopic autoradiography when administering tritiated leucine into the lateral ventricle. There were significantly more grains over the arcuate nucleus 21 days after disconnection of this hypothalamic region than over the intact nucleus. Isolation of a temporal cortical region induced similar changes in the isolated area, although this effect was not so pronounced as in the arcuate region. Data suggest that the protein synthesizing activity of arcuate neurons increases significantly after interruption of neural connections of the medial basal hypothalamus. It is assumed that the effect is primarily due to transneuronal alteration and/or interruption of inhibitory afferents.


Location of sequences on the adenovirus genome coding for the 5.5S RNA.

The origin of a low molecular weight virus-associated RNA (VA-RNA) was mapped by hybridization of VA-RNA to specific fragments of adenovirus type 2 DNA, obtained after cleavage with three different restriction endonucleases. VA-RNA was found to hybridize exculsively to the l-strand [strand with low buoyant density in CsCl when complexed with poly(U,G)] of a segment of the viral DNA which is located between positions 0.27 and 0.32 on the unit map of the adenovirus type 2 genome.


Methylated constituents of heterogeneous nuclear RNA: presence in blocked 5' terminal structures.

A substantial portion of the hnRNA of mouse L cells contains internal residues of N6-methyl adenylate and blocked 5' terminal sequences which are apparently of the type m7G5' ppp5' YmpZp..., in which 7-methyl guanosine is joined by a 5'-5' pyrophosphate linkage to a 2'-0-methylated residue, Ym. These sequences are indistinguishable from those comprising one of the two classes of blocked 5' sequences found in mRNA, and are quite distinct from those comprising the other class. The remarkable similarity in 5' terminal methylated sequences of hnRNA and a major fraction of mRNA appears to extend even to the relative occurrence of each of the four 2'-0-methylated species in position Ym.


Detection in HeLa cell extracts of a 7-methyl guanosine specific enzyme activity that cleaves m7GpppNm.

Extracts prepared from HeLa cells contain an enzymatic activity which cleaves m7G(5')ppp(5')Gm to m7pG and ppGm. The activity exhibits a high degree of substrate specificity and does not cleave G(5')ppp(5')G or the ring opened derivative of m7GpppGm which has lost the positive charge from the N7 position of m7G. m7GpppGm as the 5' terminal structure of intact reovirus mRNA is resistant to attack by the pyrophosphatase activity, but becomes partially sensitive in the 5' terminal fragment consisting of 7-10 nucleotides derived from the same mRNA by T1 RNAase digestion. m7G(5')ppp(5')GmpCp is completely sensitive to cleavage resulting in the release of m7pG without generation of m7GpppGm as an intermediate. These results establish the existence of a 7-methyl guanosine specific pyrophosphatase activity in HeLa cells.


DNA sequence organization in the mollusc Aplysia californica.

The sequence organization of the DNA of the mollusc Aplysia californica has been examined by a combination of techniques. Close-spaced interspersion of repetitive and single copy sequences occurs throughout the majority of the genome. Detailed examination of the DNA of this protostome reveals great similarities to the pattern observed in the two deuterostome organisms previously examined in detail in this laboratory, Xenopus laevis and Strongylocentrotus purpuratus. Labeled and unlabeled Aplysia DNA were prepared from developing embryos and sheared to a fragment length of 400 nucleotides. The kinetics of reassociation were studied by means of hydroxyapatite chromatography, single-strand-specific S1 nuclease, and optical methods of assay. Aplysia DNA of this fragment length contains at least five resolvable kinetic fractions. One classification of these fractions, listed with their reassociation rate constants (l M-1 sec-1) is: single copy (0.00057), slow (0.047), fast (2.58), very fast (4000), and foldback (greater than 10(5)). Sequence arrangement was deduced from: the kinetics of reassociation of DNA fragments of length 400 or 2000 nucleotides; the hyperchromicity of reassociated fragments containing duplex regions; the size of duplex regions resistant to S1 nuclease; and the reassociation of labeled fragments of various lengths with short driver fragments. More than 80% of the single copy DNA sequences are interspersed with repetitive sequences. The maximum spacing of the repeats is about 2000 nucleotides, and the average less than 1000. The very fast fraction does not show interspersion with single copy sequences or with other kinetic fractions. The foldback fraction sequences are fairly widely interspersed. The slow fraction sequences are interspersed with the fast fraction, and possibly also with the single copy DNA. The fast fraction is the dominant interspersed repetitive fraction. Its sequences are adjacent to the great majority of the single copy sequences and have an average length of about 300 nucleotides.


A rapid rise in cell variants during the senescence of populations of human fibroblasts.

An attempt has been made to measure the frequency of mutations throughout the lifespan of human fibroblast strain MRC-5. A novel procedure has been used which involves staining individual cells for high levels of glucose-6-phosphate dehydrogenase. Evidence is presented that this phenotype is due to mutation. The frequency of variants was scored from passage 16 until the final phase of senescence (passage 60). There is an exponential increase of stained cells throughout this period. The results are in agreement with the general error theory, which proposes that aging is due to a breakdown in the fidelity of information transfer between macromolecules.


Histones H2a, H2b, H3, and H4 form a tetrameric complex in solutions of high salt.

In 2 M NaCl, histones H2b, H2a, H3, and H4 form a heterotypic tetrameric complex made up of one chain of each histone. This complex has been analyzed by hydrodynamic techniques. It is indistinguishable from histones in chromatin by its resistance to trypsin, pattern of reactivity with 125I. and ability to form specific crosslinked products after treatment with formaldehyde. It is proposed that this complex is responsible for protecting the small DNA fragments produced by exhausting nuclease digestion of nuclei and that on the average two of these complexes protect the larger 180-200 base pair unit produced by partial treatment of nuclei with nuclease.


Single-channel autoanalyzer adpated for multiple tests without manifold changes.

A different approach to continuous-flow analysis is described, in which the initial reagent concentration is adjusted to fit a prefixed manifold while still providing optimum concentrations of the reactants in the mixing coils. A single-channel AutoAnalyzer so designed can perform multiple tests without the need to change manifolds. The system was assembled from a Technicon Sampler II and Pump II, a gilford 300 N spectrophotometer, and a Varian recorder. Results for calcium, uric acid, glucose, phosphorus, chloride, urea nitrogen, and carbon dioxide, analyzed on this instrument at a speed of 60 samples/h, compare favorably with those obtained with the AutoAnalyzer 12/60 and 6/60. The instrument is not restricted to certain methodologies and, in addition, can be used manually or for kinetic reactions.


Determination of Na+ and K+ in urine with ion-selective electrodes in an automated analyzer.

We applied an automatic potentiometric electrolyte analyzer (STAT/ION) to the routine determination of Na+ and K+ in urine samples, and found a high correlation with results obtained by flame photometry. The electrodes were selective and no obvious interferences were encountered in the limited number of samples available in this study.


Manual and semi-automated procedures for measurements of triglycerides in serum.

We describe manual and semi-automated procedures for serum triglyceride determinations, in which lipids are partitioned between a water/isopropanol phase and a nonane phase. More than 99% of the triglyceride is extracted into the nonane phase, as determined by recovery of 3H-labeled triolein. Studies with 14C-labeled lecithin demonstrate that less than 1.3% is extracted into the nonane phase at concentrations up to 2.5 g/liter. A novel feature of the method is that glycerol can be liberated from triglyceride by sodium hydroxide at room temperature in less than 5 min. Glycerol is oxidized by periodate in 1-2 min at 25 degrees C; the formaldehyde produced is reacted with 2,4-pentanedione to yield 3,5-diacetyl-1,3-dihydrolutidine. The manual procedure requires less than 20 min; the semi-automated method requires 7 min from sampling to readout. The procedure may be run at 30-40 samples/h, with stable baseline and less than 2.0% carryover. Both methods are linear to 0.50 g (5.6 mol) of triolein per liter. Analytical recoveries at several concentrations ranged from 97-101% (mean, 100%).


Measurement of spectral bandwidth, as exemplified with the Beckman "Enzyme Analyzer System TR spectrophotometer".

This paper describes simple methods for determining spectral bandwidth by measurement and by calculation. We measured the spectral bandwidth of the monochromator from the Beckman Enzyme Analyzer TR, and found it to be 3.5-4.0 nm (av 3.8) by two different methods. We visually estimated it to be 4 nm. Using the specifications for the diffraction grafting, focal length, and fixed slit width, we calculated the theoretical spectral bandwidth to be 3.6 nm.


Correlation of selected serum constituents: 1. Inter-individual variation and analytical error.

The intra-subject correlations of three clinically meaningful combinations of serum constituents--(a) potassium, calcium, and albumin; (b) urea, creatinine, and uric acid; and (c) aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase--were studied in 11 healthy men. Duplicate serum samples were obtained at 800 h, 1100 h, and 1400 h on five different days. All assays were performed on the AutoChemist Multichannel Analyzer. Correlation coefficients differed significantly among the subjects for the following six pairs of serum constituents: urea and creatinine, urea and uric acid, creatinine and uric acid, aspartate aminotransferase and lactate dehydrogenase, aspartate aminotransferase and alkaline phosphatase, and lactate dehydrogenase and alkaline phosphatase. Nonbiological positive correlation between analytical errors (i.e., errors of two different assays performed on the same specimen) was demonstrated for two of the pairs: potassium and calcium, and aspartate aminotransferase and lactate dehydrogenase. The error correlations of these two pairs of constituents comprised a significant component of the observed intra-subject correlations. Probable reasons for these analytical error correlations are discussed.


Chromatographic and electrophoretic separation of creatine kinase isoenzymes compared.

We compared two techniques for separating and evaluating serum creatine kinase isoenzymes--fluorometric agarose electrophoresis and Sephadex chromatography--in 50 patients, 25 of whom had confirmed acute myocardial infarction. In every case isoenzyme MB (heart isoenzyme) was detected with equal sensitivity by either procedure. Evidently, only the presence or absence of MB is clinically significant; none of the 25 patients without infarction had detectable MB activity in their serum. Columns connected to a continuous-flow sample line for analyses of the eluting stream without further modification produced satisfactory results.


Simple, highly selective screening method for barbiturates in urine.

I present a new, simple colorimetric method for detecting and estimating barbiturates in urine. After the barbiturates are extracted with ether, an aliquot of the washed ether phase is added to the color reagent (a bivalent mercury/dithizone chelate in chloroform). On addition of diluted pyridine and shaking, a pinkish-violet color appears if a barbiturate is present. The overall sensitivity of the above method was evaluated by probit analysis in the case of sodium phenobarbital. The concentration of sodium phenobarbital in urine detectable at least 99% of the time was 6.72 mg/liter, with 95% confidence limits of 5.37 to 10.36 mg/liter. Sodium phenobarbital, 10 mg/liter, can be detected in the presence of phenytoin (50 mg/liter), glutethimide (100 mg/liter), or bemegride (100 mg/liter). The whole procedure requires less than 10 min. An excretion study illustrates application of the procedure.


New manual and automated method for determining activity of creatine kinase isoenzyme MB, by use of dithiothreitol: clinical applications.

The method is based on the selective activating capacity of dithiothreitol on creatine kinase isoenzyme MB, after isoenzyme MM is activated by glutathione. Isolated isoenzymes MM and MB of human and canine origin were assayed individually and in mixtures of known activities. When glutathione was present in the assay medium the activity of each isoenzyme could be measured individually, but glutathione did not activate isoenzyme MB if it was present in a mixture with MM. Dithiothreitol, added to the serum before assay, activated the isoenzyme MB in the mixture. Values for MB activities obtained for isolated isoenzyme MB and for the isoenzyme mixture after dithiothreitol was added averaged 110 and 111 U/liter, respectively (r = 0.998; y = 1.007 x + 0.298; n = 10). In the serum of 40 patients with documented acute transmural myocardial infarction, the mean proportion of isoenzyme MB activity measured in this way was 5.5% (coefficient of variation, 7.7%). Isoenzyme MB activities measured by use of dithiothreitol compared well with those obtained by conventional electrophoresis/spectrophotometry (r = 0.998; y = 1.09x -0.65) and spectrofluorometry (r = 0.996; y = 1.10 x + 0.80). The assay of MB activity by the dithiothreitol method was automated, by use of an Abbott Bichromatic Analyser and a Calbiochem Super-Stat Pack Kit. In 60 isoenzyme MB determinations the manual and automated method correlated well (r = 0.990; y = 1.0x -1.36). The simplicity of isoenzyme MB determination by use of dithiothreitol and its ease of automation allow routine monitoring of the isoenzyme activity in patients with ischemic heart disease.


Improved method for enzymatic determination of serum triglycerides.

I describe an enzymatic method for determing serum triglycerides (triacylglycerols). The triglycerides are hydrolyzed by a mixture of lipase and esterase. The glycerol released is determined by kinetic fixed-time analysis, with use of glycerol kinase, pyruvate kinase, and lactate dehydrogenase. Through addition of the competitive inhibitor ATP the Michaelis constant of pyruvate kinase is apparently increased, considerably extending the linearity of the assay. There is no need for serum blanks or reagent blanks. The method has been adapted to a centrifugal analyzer (the ENI GEMSAEC). It yields satisfactory results with regard to precision, accuracy, and insensitivity to interferences.


Specificity of oxidation of bile-salt hydroxyl groups by crude extracts of Pseudomonas testosteroni (ATCC 11996) used in determining bile salts.

Recent experimental evidence suggests that, presumably as a recent of mutation, crude extracts of Pseudomonas testosteroni (ATCC 11996) no contain amounts of 7alpha- and 12alpha-hydroxysteroid dehydrogenate activity that invalidate the results of bile-salt determinations. To confirm or deny this, we studied the specificity of hydroxysteroid dehydrogenase contained in crude extracts of currently available samples of this bacterium in the oxidation of bile-salt hydroxyl groups. The dehydrogenases in these extracts specifically oxidized 3alpha-hydroxyl groups of cholate, chenodeoxycholate, and deoxycholate anions. No significant amount of 12alpha- or 7alpha-hydroxysteriod dehydrogenase activity was detected. Currently available crude extracts of Pseudomonas testosteroni (ATCC 11996) are therefore suitable for bile-salt quantification.


Fluorometric determination of "albumin-titratable bilirubin" in the jaundiced neonate.

We report a fluorometric technique for determination of albumin-titratable bilirubin in the jaundiced neonate. Although bilirubin alone has very little native fluorescence, considerable emission is observed in the presence of albumin under acid conditions. Analysis of the plasma sample alone and in the presence of excess human serum albumin solution appears to reflect the bilirubin tightly bound to albumin and the total serum bilirubin, respectively. The difference between these two values has been designated as "albumin-titratable bilirubin". Where the concentration of albumin-titratable bilirubin is considerable, a typical saturation effect is observed. In samples where the circulating bilirubin is strongly bound to endogenous alumin, no change in fluorescence is seen when exogenous albumin is added. Results correlate well with the clinical picture.


Parallel radioimmunoassay for plasma cortisol and 11-deoxycortisol.

We describe a direct, rapid, and specific procedure for the parallel radioimmunoassay for cortisol and 11-deoxycortisol in plasma. The plasma sample is used directly, after heat inactivation of the natural cortisol-binding protein. The radioimmunoassay utilizes antibodies generated in rabbits by steroids congugated at their 3-oxo position to thyroglobulin. Ammonium sulfate is used to separate bound and free steroids. Our cortisol antibody and an 11-deoxycortisol antibody obtained elsewhere cross reacted negligibly with each other or with other steroids that might be present in plasma. Radioimmunoassays were therefore developed for both steroids in only 1.25 mul of plasma. The intra- and inter-assay coefficients of variation for both steroids were less than 10%, with a sensitivyt of 4 mug/liter. Steroid values obtained by a competitive protein binding method were consistently higher than those of the present method, suggesting that the former is measuring total corticosteroids. This simple approach requires only 4 h for the specific measurement of both cortisol and 11-deoxycortisol in 20 samples of plasma.


Patients as their own controls: use of the computer to identify "laboratory error".

I describe a system of quality control based on computer detection of changes in individual patient test results. This system, called "delta check," was used to follow all the tests performed by the clinical chemistry laboratory in a 1200-bed hospital. Analysis of 22 months' experience indicates that specimen misidentification is a serious problem in the clinical chemistry laboratory. Over a nine-month period, errors were most frequent in the results for total thyroxine, total calcium, and total protein. Instances of laboratory error detectable by the delta check system are not detected by other currently used methods of quality control. This system therefore appears to be a valuable asset to the clinical laboratory.


Therapeutic monitoring of anticonvulsant drugs: gas-chromatographic simultaneous determination of primidone, phenylethylmalonamide, carbamazepine, and diphenylhydantoin.

We describe a sensitive and precise gas-chromatographic method in which benzylmalonate methylester monoamide is used as the internal standard for the simultaneous determination of primidone, phenylethylmalonamide, carbamazepine, and diphenylhydantoin. The trimethylsilyl derivatives of the anticonvulsants are well separated from each other and from normal serum constituents. The lower limit of detection for each drug is 0.5 mg/liter when 1 ml of serum is analyzed. Within-run precision (CV), established by analysis of 10 replicates, was as follows: primidone (5.4 mg/liter), 2.6%; phenylethylmalonamide (5.5 mg/liter), diphenylhydantoin (6.6 mg/liter), 3.8%; and carbamazepine (10.4 mg/liter), 3.2%. Fifty specimens were analyzed for primidone and 35 for diphenylhydantoin by a standard gas-chromatographic method involving on-column methylation and by the procedure we have developed. The mean value observed for primidone with the on-column alkylation procedure was 9.3 mg/liter and with our procedure was 9.6 mg/liter. When values for our assay were regressed against values for the standard method, the slope of the least-squares line was 0.936, the intercept was 1.00 mg/liter, and r was 0.939. The mean values observed for diphenylhydantoin by on-column methylation and with our procedure were both 12.6 mg/liter. When values for our assay were regressed against the standard method, the slope of the least-squares line was 0.944, the intercept was 0.3 mg/liter, and r was 0.988.


Device for more economical standby operation of continuous-flow analyzers.

To decrease the reagent-consumption rate of continuous-flow analyzers, I constructed a device that allows standby operation. The device, when actuated by switching off the sampler, decreases the effective pumping rate to less than 1/15 normal. The bubble pattern remains virtually undisturbed, and the system can be immediately restarted for emergency use. During five months of use in our laboratory with a Technicon platelet counter, the device was decreased reagent consumption by 60%, while allowing 24-hour-a-day operation. There have been no analytical errors traceable to the device, and no mechanical problems have arisen. I describe the use of the device in a continuous-flow system for determination of creatinine.


Laboratory diagnosis of Bence Jones proteinuria in a patient with plasma cell leukemia.

Kappa Bence Jones proteinuria was found by immunoelectrophoretic techniques in a patient with plasma cell leukemia, who presented with no M-proteins either in serum or urine. However, a significant decrease in normal immunoglobulins was observed. On microscopic examination of kidney sections obtained a autopsy, protein casts were seen in the distal tubules. Bence Jones protein was not detected by the conventional heat test.


A rapid gas-liquid chromatographic determination of serum levels of phenobarbital and diphenyllhydantoin.

This report describes a simple gas-liquid chromatographic method for the simultaneous determination of phenobarbital and diphenylhydantoin in serum or plasma. The procedure involves a simple extraction with an isobutylmethyl ketone/n-hexane mixture, on-column ethylation with a methanolic solution of tetraethylammonium hydroxide, and analysis on a flame ionisation chromatograph. This method offers advantages of accuracy, sensitivity and rapidity. No interference from other constituents of blood was found. This reliable technique is well adapted to the routine monitoring of epileptic patients.


The use of microfilters as an alternative to centrifugation in radioimmunoassay.

A microfilter was designed, together with a mechanical filtration apparatus for the separation of "antibody-bound" and "free" antigen in radioimmunoassay. A comparison of the results obtained using both filtration and centrifugation was carried out and the optimum incubation times, reaction conditions and washing volume for use with the microfilter were studied. The use of microfilters in radioimmunoassay gave reproducible results and offered a convenient means of automating the separation procedure.


Validation of methods for determination of urinary estriol during pregnancy using mass fragmentography.

A specific and accurate method for determination of urinary estriol during pregnancy is described. After acid hydrolysis of 1 ml urine, a fixed amount of [2,4-2H2] estriol (usually 15 mug) is added and the mixture is extracted with diethyl ether. The extracted estriol is converted into the tri-trimethylsily derivative and the amount of unlabeled estriol is determined from the ratio between the recordings at m/e 504 and m/e 506 obtained after analysis with a gas chromatograph-mass spectrometer equipped with an MID (multiple ion detector). The two ions used correspond to the molecular peak in the mass spectrum of unlabeled and (2,4-2H2)-labeled tri-trimethylsilyl derivative, respectively. The relative standard deviation of the method was about 6%. The method was compared with a photometric method using the Kober reaction and the gas liquid chromatographic method used in routine analysis. There was a good correlation in both cases and the regression coefficient was 1.5 and 1.3, respectively.


A sensitive non-isotopic assay for monoamine oxidase activity in human blood platelets.

A sensitive and specific procedure for measuring monoamine oxidase (MAO) activity in human platelets is described. Serotonin is used as substrate and formed 5-hydroxyindoleacetic acid (5-HIAA) is separated by a double microcolumn technique on Sephadex G-10 and Amberlite CG-50 and measured fluorimetrically. MAO activities were 5.11 +/- 1.32 (mean +/- S.D.) nmol/mg protein/hour in male and 7.85 +/- 1.58 in female healthy adults (p less than 0.001). MAO activity measured in 32 depressed patients was in a range of 3.20-10.62 nmol/mg protein/hour, the value not differing from that in the normal subjects. No significant difference was established between three subtypes of depression, in bipolar, unipolar and involutional patients, while significantly higher values were evident in female than in male patients (p less than 0.001).


Elimination of antipyrine from saliva as a measure of metabolism in man.

The salivary half-life of antipyrine was used as a convenient procedure for estimating the relative rates of drug metabolism in man. The concentration ratio of antipyrine in plasma and saliva was one over a 24-hr period following the oral or parenteral administration of the drug to man and rat. Phenobarbital, a known stimulator of drug metabolism in animals and man, increased markedly the elimination of antipyrine from saliva of rats, while SKF-525A, a potent inhibitor of drug metabolism, prolonged the elimination of antipyrine from rat saliva. In addition, the known sex difference in the metabolism of drugs in the rat was detected by measuring the elimination rate of antipyrine from saliva of male and female rats. The clinical application of the procedure indicated that a group of epileptic patients treated with anticonvulsants for more than 2 mo had a mean antipyrine salivary half-life of 4 hr, whereas a mean half-life of 13 hr was found in a group of normal volunteers. The results show that the elimination rate of antipyrine from saliva is a useful index of drug metabolism in animals and man.


Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine.

In normal male subjects, the half-lives of antipyrine, aminopyrine, or phenacetin were not significantly different from the half-lives of each drug in saliva. Apparent volumes of distribution (aVd) in plasma and saliva differed by the extent to which each drug has been reported to bind to plasma proteins. Thus, the aVd of antipyrine in plasma and saliva was similar; there were significant differences in aVd for aminopyrine; even greater differences were observed for penacetin. The expression (see article) equals the fraction of the drug bound to plasma proteins. Rates of appearance in the urine of metabolites of antipyrine and aminopyrine were measured. General equations were used to show the relationship between half-life for elimination of the parent drug from the body and rate of excretion of metabolites. There were significant correlations between the half-life for elimination of antipyrine from the body and the half-life for production of 4-OH antipyrine (r equal 0.90), as well as between the plasma half-life of aminopyrine and the half-life of 4-aminoantipyrine (r equal 0.95). No significant correlation was observed in the same individual between the plasma half-lives of antipyrine and phenacetin (r equal 0.05, p greater than 0.05), of aminopyrine and phenacetin (r equal 0.11, p greater than 0.05), or of antipyrine and aminopyrine (r equal 0.50, p greater than 0.05).


Interactions of levodopa with inhibitors of monoamine oxidase and L-aromatic amino acid decarboxylase.

Drug interactions between levodopa, tranylcypromine, and carbidopa have been studied in 4 patients with idiopathic parkinsonism. Pressor responses were induced by a combination of levodopa and tranylcypromine. These hypertensive reactions were inhibited by carbidopa, indicating that they are mediated at the periphery. Very small doses of levodopa induced an improvement in parkinsonism when patients were concomitantly taking carbidopa and tranylcypromine, but adverse reactions were prominent.


Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion.

In contrast to the tachycardia and unchanged or increased blood pressure seen after single doses, prolonged delta-9-tetrahydrocannabinol (THC) ingestion produced significant heart rate slowing and blood pressure lowering in hospitalized volunteers. Impaired circulatory responses to standing, exercise, Valsalva maneuver, and cold pressor testing suggest a state of sympathetic insufficiency. Marked weight gain was observed in all subjects, which has been shown to be related to fluid retention and plasma volume expansion. Tolerance developed to orthostatic hypotension, possibly related to plasma volume expansion, but did not develop to the supine hypotensive effects. Nearly complete tolerance developed to the tachycardia and psychological effects produced by smoked marijuana while ingesting THC. Electrocardiographic changes were minimal despite the large cumulative dose of THC. The hypothesis that THC has a biphasic effect on the sympathetic nervous system in man, producing excitation with single doses and inhibition with prolonged administration, is discussed.


First-pass metabolism of nortriptyline in man.

The kinetics of nortriptyline were studied after oral and intravenous (iv) administration of test doses of 50 mg 14C-nortriptyline. The systemic availability of orally administered nortriptyline varied from 0.46 to 0.59 in 6 subjects. The decrease in availability was due to metabolism after administration. Systemic clearance varied from 0.31 to 0.66 L/min. From these measurements indirect estimates of the hepatic blood flow could be made, and a variation from 0.6 to 1.5 L/min was found. Quantitative measurements of first-pass metabolism could also be obtained from urinary metabolite excretion data when the kinetics of metabolite formation and elimination were taken into account. From the second or third day after the test dose, the urinary excretion rate of total radioactivity declined monoexponentially with half-lives closely corresponding to the plasma half-lives of unchanged nortriptyline. Analysis of the data from the iv test according to a 2-compartment open model showed that there was a close correlation between the rate constant of distribution from central to peripheral compartment (k12) and the elimination rate constant in the central compartment (kel). Still, there was some variation in the kel/k12-ratio, and this variation corresponded to the variation of the estimated hepatic blood flow.


Commentary: a physiological approach to hepatic drug clearance.

A physiological approach has been developed recognizing that hepatic blood flow, the activity of the overall elimination process (intrinsic clearance), drug binding in the blood, and the anatomical arrangement of the hepatic circulation are the major biological determinants of hepatic drug clearance. This approach permits quantitative prediction of both the unbound and total drug concentration/time relationships in the blood after intravenous and oral administration, and any changes that may occur as a result of alterations in the above biological parameters. These considerations have led to a classification of drug metabolism based on the hepatic extraction ratio. The proposed classification allows prediction and interpretation of the effects of individual variations in drug-metabolizing activity, route of administration, pharmacokinetic interactions, and disease states on hepatic drug elimination.


Effect of intravenous diazepam on renal function.

The effect of intravenous diazepam on glomerular filtration rate (inulin clearance) and effective renal plasma flow (PAH clearance) was investigated in 6 children and 12 anesthetized rabbits. A transient decrease in inulin and PAH clearances was observed in 6 children given 4 mg of diazepam intravenously, without measurable change in blood pressure. A similar renal effect was observed in anesthetized rabbits, together with a transient drop in systemic arterial pressure. Continuous infusion of diazepam (5 mg/kg/hr) did not affect renal function in rabbits. We suggest that this effect of diazepam should be borne in mind when the drug is administered to patients undergoing renal clearance studies or to patients with preexistent renal insufficiency.


Total body potassium and 24-hour creatinine excretion in healthy males.

Total body potassium may be predicted from height, weight, and age by TBKmmol = 30.83 Hcm + 18.05 Wkg - 11 (ageyr - 20) - 3034. This equation, based on measurements of 31 men, has been compared with others in the literature. Prediction of 24-hr creatinine (CR), excretion derived from 33 control adults whose excretion rates gave a coefficient of variation less than 13%, may be made from the equation: CRgm = 0.0143 Hcm + 0.00975 Wkg - 0.00734 (ageyr -20) -1.391. For 31 chronic schizophrenics, the corresponding equation CRgm = 0.0122 Hcm + 0.0145 Wkg - 1.611 contained no age correction. The relationship between CR and TBK is expressed by CRgm = 0.000403 TBKmmol + 0.278. Discussion of significance of these equations in the light of extensive literature suggests that about half of the error variance in predicting CR may be explained by the lack of suitable data on somatotype and much of the residual variance, including the day-to-day variation in CR, relate to factors altering basal O2 consumption. The predictors given should prove generally satisfactory for many metabolic and drug studies.


Antipyrine metabolism in man: influence of age, alcohol, caffeine, and smoking.

Age has been shown to influence drug metabolism but effects of aging could be due to other variables that influence metabolism and differ with age. Plasma half-life and metabolic clearance rate of antipyrine were studied in 307 healthy male subjects, aged 18 to 92. Half-life was 16.5% longer and metabolic clearance rate was 18.5% less in a group of the older than in the younger subjects. Both caffeine and cigarette use were positively correlated with the rate of antipyrine metabolism. Multiple regression analysis showed that the effect of smoking was partially responsible for the age differences in antipyrine metabolism. Smoking explained 12% of the variance in metabolic clearance rate and age explained 3%. Our results suggest that studies attempting to quantify the effects of aging on drug metabolism must also take into account other factors that differ with age.


Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery.

The pharmacokinetics of hexobarbital were studied in 13 patients with acute hepatitis. Hexobarbital sodium was administered by zero order intravenous (iv) infusion, and plasma concentrations were determined regularly by gas chromatography. For each patient the data were fitted according to 2-compartment kinetics. The results were compared to those obtained for 14 healthy volunteers. The elimination half-life of hexobarbital was 490 +/- 186 min in the hepatitis patients and 261 +/- 69 min in the control group. Clearance was significantly reduced in the hepatitis group, whereas the volume of distribution at steady state was not significantly altered. For some patients the initial distribution volume was reduced. In 6 patients the experiment with hexobarbital was repeated after apparent recovery from hepatitis as judged by normal transaminase and bilirubin levels. Generally the half-life of hexobarbital was shorter and the clearance value was higher than during the acute illness, but the values had not yet returned to normal. Clinical recovery from liver disease is not accompanied by corresponding recovery of drug-metabolizing capability.


Biopharmaceutic influences on the anticholinergic effects of propantheline.

With reduction of salivary flow rates as an index of anticholinergic response, 3 subjects manifested demonstrable effects shortly after ingestion of 15-mg doses of propantheline in conventional tablets. Ingestion of this dose i-mediately after a standardized breakfast substantially reduced the anticholinergic effects. In 1 subject, a dose-response relationship was noted after 15 mg and 30 mg doses under both fasting and fed conditions, but at each dose level the influence of food was clear. Administration of a 30-mg dose of propantheline in a commercially available "prolonged-acting" tablet induced little if any anticholinergic effects; in 2 subjects, marginal but fleeting indications of salivary suppression were noted about 4 hr after ingestion, while no effects were observed in the third subject (even after 2 "prolonged-acting" tablets).


In vitro and in vivo transport of lithium by human erythrocytes.

An in vitro system that can be used to measure both uptake and efflux of lithium by erythrocytes (RBCs) is described. Using this system, RBC lithium accumulation in vitro was compared with in vivo RBC lithium concentrations observed in 6 normal volunteers. A significant correlation was demonstrated between in vitro RBC lithium accumulation after 48-hr incubation and in vivo RBC lithium concentration at 24, 48, 72, and 96 hr following the beginning of lithium ingestion. In addition, when efflux of lithium from RBCs in vitro was studied, a significant correlation was observed between residual lithium in RBCs and in vitro RBC lithium accumulation. Finally, it has been demonstrated that storage of blood in ice for 5 hr prior to incubation with lithium results in increased RBC lithium accumulation. A potential role for this in vitro incubation system as a model for in vivo RBC lithium accumulation is suggested.


Pharmacokinetics of ampicillin in cirrhosis.

Ampicillin pharmacokinetics was studied in 9 cirrhotic patients and in 8 healthy subjects to assess liver disease-related differences in distribution, elimination, and bioavailability of ampicillin. Plasma, urine, and ascites fluid samples were analyzed microbiologically. After intravenous doses, the cirrhotic patients have lower initial plasma concentrations of ampicillin because of the larger volume of distribution. Such patients usually have diminished renal function, which, because renal tubular secretion is the main route of excretion of ampicillin, causes prolonged retention of ampicillin. Metabolic-biliary clearance of ampicillin, normally accounting for removal of only 10% of the dose in normal subjects, is three times as great in cirrhotic patients. Peak ascites fluid concentrations of ampicillin ranged from 2 to 7 mcg/ml after 600 mg iv doses, and very slow clearance of ampicillin from the peritoneal cavity results in persistence in this compartment. Though absorption of ampicillin from capsules was often erratic, its bioavailability was similar in normal and cirrhotic subjects. These findings suggest that the usual course of ampicillin therapy of infections should not be altered in cirrhotic patients. On the other hand, reduction in dosage may be called for when there is renal impairment.


A computer program for the graphical and iterative fitting of probability density functions to biological data.

A tutorially-assisted, interactive program, written for a Digital Equipment Corporation LAB-11 minicomputer (PDP-11/20, is described which allows a user to fit (with or without automatic estimation of initial parameter values), by a method of nonlinear least squres, any one of seven different types of probability density functions (p.d.f.'s) to an empirical frequency distribution; the latter of which may be input to the program or formed by the program whenever it is furnished a series of times between events. The iteratively-obtained, "best fit" p.d.f. is displayed on a two color, point-plot display against the background of a point-plot histogram. By selecting any one of nine output modes, the user is allowed: (1) to view histograms successively on the point-plot display, (2) to generate selected p.d.f.'s (3) to "force" p.d.f.'s having known parameters through the histogram data, (4) to obtain Chi-square (x2) and Kolmogorov-Smionov estimates of the goodness of fit to the data, and (5) to apply a special test [Williams and Kloot, 1953] in order to determine whether the least squares estimates of two candidate models are statistically different. The resident driver program and the four overlayable program segments are written in standard FORTRAN IV; except for two plot routines, which are written in PDP-11 assembly language.


A computer analysis of electrophoresis and ultracentrifugation patterns.

A program DIANA is designed to fit the scanning curves of electrophoresis and ultracentrifugation patterns with 10-15 overlapping peaks by a sum of Gaussian-like distribitions. The parameters of the distributions are adjusted by minimizing x, using a problem oriented minimizing procedure. The number of molecular components as well as starting values of the positions and the widths of the peaks must be choosen as input for each type of pattern. Programs are written in FORTRAN IV.


Smiss, stoichiometric matrix inversion for steady state metabolic networks.

A program is described for the reduction of the stoichiometric matrices associated with steady state metabolic networks. The program generates a set of independent and dependent reactions and gives the dependent reactions as functions of the independent reactions. The program can also be used to generate all possible alternative sets of independent reactions.


Statistical analysis and graphical representation the temporal and distributive properties of urodynamic data.

A collection of programs are described to analyze and display urodynamic data on a digital plotter. Utilizing a small programmable calculator, routines have been written to characterize the temporal and distributive properties of experimentally observed ureteral peristalses and associated urine output. The encoding pricipals used are designed to optimally use limited calculator memory.


A subroutine to represent tridimensional surfaces on a printer.

To get a better idea of the shape of a function, it is often desirable to represent it by a relief map. The representation of tridimensional surfaces is generally obtained with a plotter, tracing the level curves step by step. We are describing here a subrouting allowing the diagrammatic representation of surfaces directly with a line pinter using a blackening whose intensity is proportional to the values of the function.


Operant conditioning and behavioral analyses using a minicomputer.

An operant conditioning and data analysis software system was developed for use on a PDP-12A minicomputer. The operant software functions in quasi time-sharing fashion to control and acquire data from any peripheral device that operates in the binary mode. In addition to independently running different experiments in near simultaneous fashion, the program also provides information on the current status of each experiment using a cathode ray-tube display. Response data from each experimental subject is stored on magnetic tape and analyzed, off-line, by the data analysis portion of the software system. A discussion of the operation of this system is given for one possible application: visual discrimination training.


A minicomputer interface for realtime operations: an application to operant conditioning.

A PDP-12 interface was designed, constructed, and tested for realtime imput and output of binary information. Within limits this interface can be used with any peripheral device which operates in the binary mode. In addition to its generality of application the interface features include ease of expansion and low cost. A description of its design and operation is give here is terms of a typical application: the control of behavioral equipment (i.e. "Skinner Boxes") for operant conditioning.


"Individual" versus conjoint therapy.

The pragmatic test of whether a troubled couple should be treated by an approach oriented toward intrapsychic problems or by an approach with an interpersonal focus lies in the couple's perception of their difficulties. If intrapsychic difficulties are ego-syntonic and experienced primarily at an interpersonal level, that is the level at which treatment must be done. To the extent that each of the marital partners has a differing goal for treatment, different levels of treatment, including individual therapy for both, must be available after an adequate trial of dealing with the couple as a unit.


Technique of fluphenazine decanoate therapy in acute schizophrenic illnesses.

F.D. can be safely used as the phenothiazine of first choice in the management of acute schizophrenic illness, either alone or in combination with other neuroleptics if necessary for additional sedation. Usually 2 - 5 ccs im are needed to effect remission. Striopallidal symptoms are the major problem but these are usually manageable. The advantages of this regime are discussed.


Prognostic significance of episodic low amplitude or relatively isoelectric EEG patterns.

Electroencephalograms demonstrating episodes of relative iso-electric activity in 14 comatose patients are divided into three patterns. The first, Type I, showed brief low amplitude or relatively iso-electric episodes intermixed with slow activity. The second, Type II, showed epileptogenic activity with episodes of relative iso-electricity. The third, Type III, showed burst suppression in which iso-electric intervals were of greater duration than periodic slow activity. All patients expired, indicating grave prognostic implications for all three patterns.


A total community approach to the treatment of alcoholism.

A review of psychopathology and withdrawal in alcoholics is presented. The use of disulfiram, milieu and half-way houses in the treatment of alcoholic patients is described. The role of the Community Mental Health Center is outlined. An extensive description of Palm Beach County's approach to the treatment of alcoholism is then explained. This heterogeneous county offers facilities for all types of patients, from the lowest to highest socioeconomic backgrounds. Detoxification in the Palm Beach Community Mental Health Center is fully described. The half-way houses, Alcoholics Anonymous programs, and other outpatient and inpatient treatment facilities are depicted.


Seizures following burns of the skin. III. Electroencephalographic recordings.

1. EEGs were recorded on 40 burned (acute) patients during their hospitalization. Abnormal records were seen in 88% of the 49 records, all showing slow waves and nearly 10% with epileptiform activity. EEG abnormality seems related to the combination of total body surface burned and time after burn and is maximal not immediately after the burn, but within 3-11 days after the trauma when hyperventilation, hypopotassemia and deaths tend to occur. 2. EEGs were also recorded on 27 (chronic) patients, 17 with seizures and 10 others with cognitive-behavior disorders. All showed an abnormal EEG. Patients with seizures showed slow waves in 82% of cases, often diffuse, usually more marked than those seen in the cognitive-behavior disorders; 41% of patients with seizures showed epiliptiform activity. Patients with cognitive-behavior disorders showed slow waves abnormalities, usually mild in degree of severity; positive spikes were found in patients specifically with a behavior disorder.


Stimulant drug treatment of hyperactive adolescents.

The characteristics and classroom behavior changes of hyperactive (HA) school children treated with stimulants during the years, 1969-1974, were evaluated in relation to the age of the child. Fourteen children who began taking stimulants before age 8 were compared to 11 who were initiated on stimulant treatment at age 13-16. Next, 13 children who continued on stimulants into their teens were studied to compare their pre-teen with their teenage drug response. The major findings were: 1) The therapeutic response of stimulants for hyperactivity did not significantly change from age 6 to age 16. 2) Pre-treatment teacher ratings indicated that as a group, teenage HA children were as inattentive as younger HA children, but less aggressive and overactive. 3) The mean dose of stimulant medication to achieve a successful classroom response for school age HA children did not significantly increase with age. 4) Parental resistances to stimulants were not related to the age of the HA child, but behavioral resistances by the child increased significantly during the teens. 5) There were no reports of abuse of stimulants by HA teenagers.


Latent tetany and anxiety, marginal magnesium deficit, and normocalcemia.

The identification of marginal magnesium deficit, such as we have detected in a patient with anxiety, depression, and psychomatic complaints, is a difficult diagnostic problem. Electromyography of a limb, rendered acutely ischemic either just before or after hyperventilation, can elicit latent tetany in this condition, as well as in calcium deficiency. We have demonstrated iterative electrical activity in our patient, whose magnesium deficit is attributable to renal wasting of magnesium. We have elicited similar patterns in several other patients, who had marginally low serum magnesium and who also exhibited weakness, anxiety, and psychosomatic disorders. This preliminary report suggests the need for further consideration of the possibility that chronic magnesium-deficit may contribute to the syndrome of latent tetany, psychosomatic complaints, and weakness.


[Prevention of postoperative thrombo-embolism using a new principle of drug treatment (author's transl)].

Slowing of venous return is, in addition to endothelial damage and hypercoagulability, one of the decisive factors in the development of thrombi. This is especially so in operated patients with loss of vessel tone caused by general anaesthesia. The radiofibrinogen test was used on a group of 106 patients to check whether the administration of dihydroergotamine, which produces vasoconstriction particularly of the venous channels, can bring about a reduction in the incidence of postoperative thrombo-embolism. There was a statistically (variance analysis) highly significant difference in the average thrombosis rate between treated (8.8%) and untreated (34.7%) patients. In patients especially at risk, the rate was more than three times as high in the untreated group (39.5% and 12.9%, respectively). In low-risk patients the rate actually dropped to zero (from 20%).


[Pacemaker implantation for heart failure with bradycardia (author's transl)].

The long-term effect of pacemakers in the management of bradycardic heart failure with or without syncope was tested on 337 patients. The cumulative survival rate of patients with Adams-Stokes attacks without heart failure (group I) was 91% at the end of one year, 73% at the end of three and 35% at the end of eight years. Among patients with Adams-Stokes attacks and accompanying heart failure (group II) 81% survived one year, 64% three and 46% five years, but only 25% eight years. Among patients in whom heart failure was the only indication for pacemaker implantation (group III), 70% were still alive after one year, 56% after three and 17% after five years. Related to the severity of heart failure before and after pacemaker implantation, most of the patients of group II (mild or moderately severe failure) had definite improvement, while of those in group III (mainly severe failure) only about half had less cardiac failure. In patients with severe heart failure and bradycardia (without syncope) long-term results are not likely to be very good, as regards both duration of survival and physical capacity.


[Controlled study of the therapeutic effect of B vitamins and an anabolic steroid in  chronic hepatitis (author's transl)].

In 66 patients with chronic active hepatitis and chronic fatty liver hepatitis of predominantly alcoholic aetiology the effect of B vitamins and the anabolic steroid clostebol (Steranabol) was tested during an eight-week period, using 12-biochemical parameters of liver function, histological findings and the activity of 14 enzymes. In chronic active hepatitis there was no demonstrable difference in effect between the treated and untreated subjects. In those with chronic fatty liver hepatitis, the marked greater therapeutic effect among the untreated group during hospitalization is thought to have been due largely to an accompanying reduction of alcohol intake.


[Eosinophilic leukaemia with chloroacetate-esterase-positive granules in a child (author's transl)].

Eosinophilic leukaemia was diagnosed in a 13-year-old boy with clinical and haematological signs of acute leukaemia. A positive naphthol-AS-D-chloroacetate esterase reaction was present in 93% of bone marrow eosinophils. This confirms earlier findings for this sub-group of leukaemia in adultsmcharcot-Leyden's crystals were found in bone marrow, and the eosinophils were further characterized by other cytochemical and electronmicroscopic studies. Only short remission periods were achieved, the patient dying 53 weeks after diagnosis. Attacks of cardiac arrhythmias, thought to be due to adriamycin treatment, were probably related to thrombi in the coronary arteries as a result of disseminated intravascular coagulation. It is thought that eosinophilic leukaemia with a positive naphthol-AS-D-chloroacetate esterase reaction is a variant of acute myeloid leukaemia.


[Acute bilateral pulmonary infiltration as a complication of cytostatic treatment (author's transl)].

In three patients on cytostatic drugs acute bilaterally symmetrical pulmonary infiltrates developed. Bacterial, viral or mycotic infections were excluded. The histological findings in the lungs of two had died were those of nonspecific alveolitis. Clinical and radiological findings, as well as the rapid regression of the infiltrates after stopping the cytostatic drugs in the third patient and the marked similarity of the X-ray picture to some similar cases reported in the literature, suggest that these infiltrates resulted from an acute allergic reaction to the cytostatic drugs.


[Failure to partial synchronization with hydroxyurea to improve results of chemotherapy of solid neurosarcoma in the rat (author's transl)].

Partial synchronization of the slow-growing cell of solid neurosarcoma in the rat can be achieved by blocking DNA synthesis with hydroxyurea. Possible augmentation after synchronization of the therapeutic effects achieved with various cytostatics was tested. The substances were administered to tumour-bearing rats at various times after synchronization (at the transition from G1 to S phase; at maximal DNA synthesis; at the transition from the S to the G2 phases; at mitosis) and therapeutic effects on tumour gs. Cyclophosphamide and adriamycin reduced tumour size, the effect being dose-dependent. No differences were noted between synchronized and non-synchronized cells. Hydroxyurea and vincristine had significantly less effect on the tumour cells, this minimal effect not being enhanced by synchronization. The reported results were obtained in tests on 360 rats and are statistically significant (double variance analysis).


[Clinical course and prognosis of acute myocardial infarction in the elderly (author's transl)].

71 of 840 patients admitted to an intensive care unit (I.C.U.) between 1970 and 1974 because of acute myocardial infarction were aged over 80 years. Age was thus an important determinant of infarction and the death-rate rose steeply with age, the hospital death-rate being 61% in those over 80 but only 8.4% in those under 50 years. The high incidence and severity of haemodynamic complications (pulmonary oedema, generalized heart failure, cardiogenic shock) were the main cause of the high death-rate. Supraventricular arrhythmias (atrial flutter and fibrillation) were frequent. Early treatment in an I.C.U. improved prognosis even in the elderly patient, by control of conduction disturbances and other arrhythmias but also by early recognition and treatment of haemodynamic complications.


[Cardiomyopathy in uncomplicated systemic lupus erythematosus (author's transl)].

Haemodynamic functions, myocardial contractility, and coronary blood flow were measured in five young women with systemic lupus erythematosus. There had been no signs of cardiac involvement. Left and right heart catherterisation excluded abnormal pressure gradients and valvar regurgitation. But left ventricular end-diastolic pressures were considerably raised while cardiac output, stroke volume, ejection fraction, and left ventricular compliance were decreased. Isovolumic indices of myocardial contractility were altered, corresponding to a decreased contractile state of the myocardium. Coronary blood flow was moderately increased at rest, but pharmacologically induced coronary vascular reserve was markedly reduced. It is concluded that in young women with this disease there may be, in the absence of clinical signs of cardiac involvement, haemodynamic abnormalities which must be ascribed to the consequences of a lupus cardiomyopathy.


[Pharmacokinetics and clinical observations of sisomicin, a newly developed aminoglycoside derivative (author's transl)].

In a randomized study of 12 healthy subjects the pharmacokinetics of gentamicin, sisomicin and tobramycin were determined after a one-hour infusion of each drug (1.0 mg/kg body-weight) four weeks apart. There were no pharmacokinetic differences of therapeutic significance between the three drugs. The mean serum concentrations at the end of infusion were 3.85 mug/ml for gentamicin and 4.66 mug/ml for sisomicin, falling to 0.12 and 0.26 mug/ml, respectively, after eight hours. The biological half-life varied between 96 and 122 min and the apparent volumes of distribution corresponded closely tothe size of the extracellular space. The antibacterial effectiveness, tolerance and modes of application were studied in 24 patients, most of them with urinary infection, at a dosage of 1.0 mg per kg body-weight two to three times daily. Good clinical results were achieved in 15, satisfactory ones in three, and in 16 the causative bacteria were eradicated. Sisomicin was well tolerated, except for minor and reversible renal (2 patients), hepatic (3 patients), and hearing (1 patient) disturbances.


[Stimulation thresholds of implanted cardiac pacemakers (author's transl)].

The Vario-pacemaker EM 169 makes it possible, without additional equipment, to determine stimulation thresholds after implantation. A study on 149 patients with implanted pacemakers demonstrated characteristic temporal changes in stimulation threshold: starting with a mean value of 0.57 +/- 0.18 V on implantation, a maximal value of 1.93 +/- 0.66 V to 2.00 +/- 0.58 V was reached between the eighth and fourteenth days. The threshold remained constant at this level for a time and then oscillated downwards from the third month onward to values of about 1.55 to 1.70 V. However, when the electrode was dislodged or dislocated, there was in most instances an increased threshold and, during the same test, variations in threshold values. In general, electrode dislocation could be diagnosed in time with the vario-principle, before failure of stimulation at maximal voltage of 5.2 V. In 17 of 140 cases of implantation (12%) the electrode position had to be revised: in 13 electrode dislodgement was diagnosed even before failure of stimulation at full voltage of 5.2 V. The reported results suggest that occurrence of an exit block is always due to electrode dislodgement. In addition, it is clear retrospectively that in most cases of dislocation primary fixation of the electrode in the trabeculations of the right ventricle had been unsatisfactory.


Diaminobenzidine an electron donor to photosystem 1 and to photosystem 2 in chloroplasts.

1. 3,3'-Diaminobenzidine was shown to serve as an electron donor to photosystem 1 in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea. In Tris-treated chloroplasts diaminobenzidine serves as an electron donor to photosystem 1 and to photosystem 2; the latter is sensitive to 3-(3,4-dichlorophenyl)-1,1-dimethylurea. 2. Addition of diaminobenzidine to Tris-treated chloroplasts causes an increase in fluorescence yield. 3. Diaminobenzidine-dependent electron transport mediated by photosystem 2 is coupled to synthesis of ATP even in the absence of an electron acceptor. This phosphorylation which is presumably supported by cyclic electron flow, is sensitive to 3-(3,4-dichlorophenyl)-1,1-dimethylurea. 4. Diaminobenzidine-dependent ATP formation, in Tris-treated chloroplasts exhibits the red-drop phenomenon. 5. The diaminobenzidine-induced cyclic photophosphorylation (mediated by photosystem 2) is resistant to a large extent to KCN-treatment which is known to inhibit reactions catalyzed by photosystem 1. On the other hand ATP formation supported by electron transport from diaminobenzidine to methyl viologen [in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea] is largely inhibited by KCN-treatment. This observation suggests that there are two coupling sites of ATP formation, one catalyzed by diaminobenzidine as a donor to photosystem 1 (in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea), and the other supported by diaminobenzidine which acts both as a donor to photosystem 2 (in Tris-treated chloroplasts) and as an acceptor (in its oxidized form) from a carrier located between the two photosystems.


Lens glycoproteins: biosynthesis in cultured epithelial cells of bovine lens.

1. Radioactivity from [3H]glucosamine is rapidly incorporated into cellular fractions of lens epithelial cells cultured in vitro. The incorporated isotope appears largely in glycoproteins of the cell surface that are exposed to trypsin and are released into a soluble form by proteolysis of intact cells. Glycoproteins are also secreted by cultured cells and can be recovered in the culture fluids. Sodium dodecysulphate-polyacrylamide gell electrophoresis shows that a range of glycoproteins with apparent molecular weights from approximately 14000 to 120000 are present. The relationships of these glycoproteins to collagen and the non-collagenous glycoproteins of lens basement membranes are discussed. 2. A plasma membrane fraction obtained from non-trypsinised lens epithelial cells contains one major glycoprotein of apparent molecular weight 120000. A major non-glycosylated polypeptide of molecular weight about 38000 detectable by Bloemendal et al. (1972) in plasma membranes of differentiated lens fibre cells was not prominent in lens epithelial cell membranes. 3. Examination of lens basement membranes extracted in various ways failed to reveal major glycoproteins of low molecular weight. Higher molecular weight glycoproteins, some of them related to collagen, were present.


Purification and studies on some properties of the 4-aminobutyrate : 2-oxoglutarate transaminase from rat brain.

Using various chromatographic procedures, 4-aminobutyrate : 2-oxoglutarate transaminase from rat brain has been purified 2400 times with respect to the initial brain homogenate. The purified protein, which has a specific activity of 10 mumol times min -1, x mg-1 gave a single band by acrylamide gel electrophoresis and isoelectric focusing. It has a molecular weight of 105000 +/- 5000 and an isoelectric point of 6.8. In the presence of 0.1% sodium dodecylsulphate, a single protein band is seen on polyacrylamide gel, corresponding to a molecular weight of 57000 +/- 5000. N-terminal analysis reveals two chains with the same N-terminal amino acid, thus the enzyme may be considered as a dimer consisting of two identical subunits. The pH optimum for enzyme activity is 8.5. Studies of the enzymic reaction show that the general mechanism is of the ping-pong bi-bi model. The Km for 2-oxoglutarate at saturating 4-aminobutyrate extrapolated to saturating 2-oxoglutarate concentration is 4 mM. 2-Oxoglutarate competitively inhibits the enzyme with respect to 4-aminobutyrate, with a Ki of 1.8 times 10(-4) M. The same phenomenon is seen for the reverse reaction where the Ki is 6.6 times 10(-4) M for succinic semi-aldehyde.


Studies on new intracellular proteases in various organs of rat. 1. Purification and comparison of their properties.

1. Specific proteases which inactivate the apo-proteins of many pyridoxal enzymes were found in skeletal muscle, liver and small intestine of rats. The protease from these three organs were purified and their properties were compared. 2. The purified proteases from liver and skeletal muscle appeared homogeneous on acrylamide gel electrophoresis. Two different proteases were separated from small intestine. A homogeneous, crystalline enzyme was obtained from the muscle layer while enzyme from the mucosa was partially purified. 3. They showed substrate specificity for pyridoxal enzymes. Their pH optima were in an alkaline region. They showed activity with the substrate of chymotrypsin, N-acetyl-L-tyrosine ethyl ester, but not with that of trypsin, p-toluenesulfonyl-L-arginine ethyl ester. They were inhibited by pyridoxal phosphate or pyridoxamine phosphate and seryl residues were involved in their active center. 4. The four enzymes differed in the following characters: (a) molecular weights; (b) patterns of elution from a CM-Sephadex column; (c) rates of inactivation of substrate enzymes; (d) rates of cleavage of N-acetyl-L-tyrosine ethyl ester; (e) reactivities with antiserum against the enzyme from the muscle layer of small intestine; (f) specific activities. 5. The amino acid composition and effect of chemical modifications of the crystalline enzyme from the muscle layer of small intestine were examined to elucidate its active sites and mode of action. Serine and histidine residues were found to be essential for protease activity. A tyrosine residue was also necessary for activity. Modifications of its sulfhydryl group, amino residues and carboxyl group had no effect on its activity.


Studies on new intracellular proteases in various organs of rat. 2. Mode of limited proteolysis.

1. The mechanism of proteolysis of ornithine transaminase apoenzyme II by group-specific protease and the relation between the confirmations of ornithine transaminase and its susceptibility to group-specific protease were studied to elucidate the mode of action of the protease. 2. Differences in the conformations of ornithine transaminase apoenzyme II, molecular weight 67000, and ornithine transaminase holoenzyme, molecular weight 140000, were shown by studies on difference spectra produced by various concentrations of ethylene glycol. Increase of the titratable sulfhydryl groups on resolution of the coenzyme from ornithine transaminase also supports this finding. These results are consistent with the facts that the apoenzyme was sensitive to group-specific protease, while the holoenzyme was not. 3. Kinetics studies showed that ornithine transaminase apoenzyme II was degraded by limited proteolysis. Reaction of the native enzyme with group-specific protease resulted in a nick in the enzyme molecule with formation of one homogeneous large product and small peptides. The large product was not degraded further. The large product was indistinguishable from native ornithine transaminase apoenzyme II in various properties including its elution volume on gel filtration, its mobility on disc electrophoresis, its antigenicity, its estimated number of exposed tryptophan residues, and its titratable number of sulfhydryl groups. But unlike the apoenzyme the product did not show tetramerization with coenzyme or catalytic activity, although it retained the ability to bind with coenzyme and had the same number of bound pyridoxal phosphate as the native ornithine transaminase molecule. Thus, native ornithine transaminase apoenzyme II was degraded by limited proteolysis. Unfolded enzyme, denatured by 8 M urea, was degraded extensively. 4. The initial step of intracellular proteins degradation is discussed on the basis of these results.


Studies on new intracellular proteases in various organs of rat. 3. Control of group-specific protease under physiological conditions.

1. To study the role of group-specific protease in enzyme degradation, alternation of its activity under various physiological conditions was examined. 2. Studies on the distribution of group-specific protease in various organs of rats showed high activity in skeletal muscle and the muscle layer of small intestine, and rather low activity in liver. The activity varied in different muscles, but red muscle tended to have higher activity than white muscle. Activity was much lower in the muscles of the stomach and colon than in those of the small intestine. 3. Group-specific protease in skeletal muscle increased under various dietary conditions (starvation, protein-free diet or high protein diet), but the activities in the muscle layer of the small intestine and liver were not greatly influenced by dietary conditions. None of the hormones tested (i.e. hydrocortisone, glucagon, insulin, growth hormone and estrogen) influenced the activity of group-specific protease in liver. 4. The level of group-specific protease in skeletal muscle was increased markedly fifteen days after denervation, with a reciprocal decrease in the level of muscle phosphorylase, which is a good substrate of the protease. 5. Liver protease activity appeared in the late suckling period. The activity in skeletal muscle was high at the time of birth and attained the adult level 3 weeks after birth. The activity in the muscle layer of the small intestine did not change after birth. Thus the mechanism for evoking these three specific proteases during development are apparently different. The activity of liver protease began to decrease approximately 12 h after partial hepatectomy and reached a minimum after about 72 h. Recovery of the protease activity was very slow and activity had not returned to the normal value 7 days after the operation. This observation seems to be consistent with the fact that there is little or no protease activity in liver in the neonatal period.


The covalent structure of collagen: amino-acid sequence of the cyanogen-bromide peptides alpha1-CB2, alpha1-CB4 and alpha1-CB5 from calf-skin collagen.

The amino acid sequence of 120 residues in the N-terminal region of the alpha1-chain of calf skin collagen (comprising the cyanogen-bromide-derived peptides alpha1-CB2, alpha1-CB4 and alpha1-CB5) has been determined by automated Edman degradation. The lysyl residue in position 87 is completely hydroxylated, while those in positions 99 and 108 partially hydroxylated. Two substitutions are found with respect to the homologous region of the alpha1-chain from rat skin collagen. Positions 101 and 102 of calf skin collagen are occupied by Asp-Ala, in rat skin collagen by Asn-Thr. The extensive homology in this region is remarkable and is not found in other regions of the alpha1 and alpha2-chain.


First-generation effects on second-generation fertility.

The number of children born to the second generation is shown to be inversely related to the predicted income of the first generation (father's father) and to the number of siblings in the second generation. This is true even when second-generation characteristics are taken account of. This long-term effect may be the result of parental influences on the tastes, opportunities or genes of their children. They do get an empirical expression because of the imperfect and partial measurement of second-generation characteristics.


Do statements about desired family size predict fertility? The case of Taiwan, 1967-1970.

The predictive accuracy of respondents' statements about their future fertility is examined, using interview data from a longitudinal study conducted in Taiwan. Two measures of preference are found to be highly intercorrelated; and regardless of which one is used, Taiwanese women are shown to predict their subsequent fertility at least as well as U.S. women. The preference measures are also predictive of rates of contraceptive use and abortion. While demographic and social characteristics are correlated with fertility in expected directions, statements about wanting more children prove to be highly predictive of subsequent fertility for both modern and less advanced segments of the population.


Socioeconomic status, value orientations, and fertility behavior in India.

This paper examines the role assumed by value orientations in the explanation of fertility behavior. Specifically the concern is with the extent to which value orientations intervene between, or mediate, the relationship between socioeconomic status and fertility behavior. The relationships between socioeconomic status, four types of value orientations and three aspects of fertility behavior are examined among males in India. In most instances value orientations provide neither the sole nor the partial interpretations of the relationship between socioeconomic status and fertility. The results of this investigation suggest once again the inadequacy of value orientations as predictors of fertility behavior.


Emigration and fertility decline: the case of Barbados.

This paper examines the role of emigration in the recent fertility declines which have occurred on the island of Barbados. Barbados with a history of over two centuries of out-migration has experienced in the period 1951-1970 very significant migration loss. In the period 1960-1970 and up to the present fertility has been declining. An important question is what part has this net migration loss of 32,600 had on the reduction of the crude birth rate from 33.6 in 1960 or from 31.5 in 1956 to 20.5 in 1970? Using officially published net migration loss figures and supplementing them with data on Barbadians living overseas, we calculated the crude birth rates which would have occurred had there been no migration loss. We also calculated the numbers of births to be expected if certain age-specific fertility rates were maintained and compared these with the births to residents plus the calculated births to Barbadians overseas. We conclude that in both cases emigration is a very significant contributor to the fertility declines which have occurred and are still underway.


Birth trajectory under changing fertility conditions.

An initially stable population of women is assumed to shift its reproductive behavior to a different level either abruptly or in a prescribed gradual fashion. A closed-form solution which is exact up to about 30 years after the reproductive adjustment is found for the resulting birth trajectory. Exact expressions are also found for the long-time asymptotic behavior of both the birth trajectory and the total population size when the shift in reproductive behavior is to bare replacement level. Accurate approximations to these asymptotic results are then derived and used to illustrate why a growing population continues to grow even after shifting to bare replacement reproductive behavior.


Open and closed birth intervals for once-married spouse-present white women.

Using the 1970 1/1,000 Public Use Sample of the U.S. population, the relationships of the closed and open birth intervals with parity and mother's age, with parity and marital duration, and with children ever born/marital duration and mother's age are analyzed. These findings both replicate and expand on Srinivasan's earlier research on the open interval. The open interval is more sensitive as an index of marital fertility when marital duration and parity are controlled than when mother's age and parity are controlled.


Standardization of cumulative failure rates.

A method is proposed for standardizing life table cumulative failure rates for various cohorts so that they are adjusted to the distribution of exposure by age group for a particular cohort. An approximate standard error for the standardized cumulative failure rate is presented. Application of the methodology is illustrated by a numerical example.


Contraceptive practice required to meet a prescribed crude birth rate target: a proposed macro-model (TABRAP) and hypothetical illustrations.

TABRAP (TArget Birth Rate Acceptor Program) is a computer programmed model that provides a direct solution to the problem of determining the total annual numbers of contraceptive acceptors required to achieve a prescribed crude birth rate target path. Applied to an initial population for which age structure, the fertility schedule, and expected trends in life expectancy and age-specific proportions of females married are known, TABRAP incorporates the following factors: age at acceptance, with acceptors drawn from currently married nonusers; age-method-specific attrition rates of users; a potential fertility schedule of acceptors that allows for aging and sterility; and allowance both for postpartum anovulation and nine months for gestation to time properly the averted births. TABRAP generates annual data on acceptors, couple-years of use, births averted and age-specific fertility rates that meet the crude birth rate target. Resulting changes in population size, age structure and crude vital rates, also yielded, are invariant with respect to acceptor age and method mix. Assuming a target to reduce the crude birth rate from 45 to 30 in ten years, TABRAP is illustrated for seven mixes of acceptor age-method combinations applied to a population approximately that of Thailand, circa 1965.


Residential preferences and population distribution.

Public opinion research has revealed decided preferences for living in rural areas and small towns, and proponents of population deconcentration have interpreted this as support for their policies. This study, based on a national sample, yielded similar results, but when we introduced the additional possibility of a preference for proximity to a larger city, then the rural areas preferred were found, for most respondents, to be those within the commuting range of a metropolitan central city. Although persons wishing to live near large cities were found to be looking for the same qualities of living sought by those who prefer a more remote location, these findings are not, in general, consistent with the argument that public preferences support strategies of population dispersal into nonmetropolitan areas. Instead they indicate that most of those who wish to live in a different location favor the peripheral metropolitan ring areas that have, in fact, been growing rapidly by in-migration.


Living arrangements of widows in the United States and Israel, 1960 and 1961.

One of the neglected areas in the study of the social structure of the family is that of widowhood, the last stage in the family life cycle. A study of living arrangements of the widowed provides an opportunity to examine the kinship solidarity of a society and to point up in bold relief the influence of a variety of factors that contribute to the residential patterns of the widowed. The data in this study were drawn from the 1960 Census of the United States and the 1961 Census of Israel, the latest which offer comparable data. Five ethnic-religious groups are examined in Israel and eight in the United States. Goode and others have stated that family modernization is a universal trend, and this is borne out by the results of this study. The small family system shows that age and children ever born are the most important predictors of living alone among the widowed in both countries. Otherwise, among the 13 ethnic-religious and ethnic-racial groups there is a general similarity of the importance of the variables in the total prediction scheme.


Simultaneity bias in migration models: an empirical examination.

A number of migration studies have attempted to explain migration that occurred over a given time interval by means of variables defined for the end of the period and/or variables relating to changes that occurred over the period. Since migration may influence end-of-period levels of explanatory variables by influencing the behavior of these variables over the period of migration, simultaneous-equations bias may be inherent in the parameter estimates of the many single-equation, multiple-regression analyses. This study constitutes an empirical examination of qualitative differences in the parameter estimates of five different types of migration models estimated for two different time periods, 1960 and 1970.


The demography of the Kuwaiti population of Kuwait.

Kuwait has experienced a dramatic rise in national income since 1945, and its material standard of living is as high as that of any country in the world. The national population (Kuwaitis) is a stable and almost closed population comprising 45 percent of the total population of the state. The Kuwaitis, readily separable from the immigrant population, both de facto and de jure, have a very low level of mortality but retain their traditionally high level of fertility. It is suggested that this largely unaltered pattern of fertility is a function of the peculiar form of economic development to which Kuwait has been subjected and of the strongly pro-natalist pressures associated with Arabic Islam.


A biophysicist's view of ovum transport.

Experimental evidence justifying the selection of primary variables in ovum isthmic transport is evaluated. Peristaltic pumping alone cannot account for the observed ovum motions, however, the theory of pressure forcing of pellets through narrow tubes when combined with the dynamic and motile properties of the mucosal and muscular layers of the isthmus, appears capable of modeling the physiological mechanism. In this model the hormonally dependent tubal compliance is a controlling element of transport rate. The contractile activity statistically distributed both spatially and temporally, provides a persistent though irregular directionality to the movement.


Feeding ecology and nutrition of an eastern gorilla group in the Mt. Kahuzi Region (République du Zaïre).

An eastern gorilla group of the Mt. Kahuzi region (République du Zaïre) was studied over 15 months. Its migration route was determined, and the various biotopes it visited are described. A record was made of its main food plants, and of the plant parts eaten. For nine important food plants the protein content, the concentration of the individual amino acids and the water content were measured for the plant parts eaten and for those not eaten. For some of these plant parts the Na, K, Ca and Mg content were also determined. No general correlation between food selection and one or several of these factors could be found. The development and value of a traditionally determined mixed diet is discussed.


Family mental health maintenance: a new approach to primary prevention.

The authors describe an approach to primary prevention in which indirect services are redefined to include community services aimed at promoting mental health and preventing emotional and mental disorders. At the Peninsula Hospital Community Mental Health Center such services are family-focused and include consultation, education, collaboration with other agencies, and early intervention with children and families with special needs. The authors describe some of the programs that have been developed and discuss how mental health Centers can conceivably, under contract, develop such community services for health maintenance organizations and other prepayment plans that provide comprehensive health maintenance and medical care.


Psychiatric consultation and teaching in a home for the aged.

An outpatient psychiatric department of a medical center was organized as a community psychiatry team to provide direct services, consultation and education, and preventive programs for high-risk groups. By successfully handling requests for service from a home for the aged, the team established a consultative relationship and then a six-month teaching program centered on problems presented by the home's staff in group sessions. Results included a drop in requests for direct service, the establishment of group programs for residents, and an increase in the home's willingness to accept and deal with disturbed behavior without resort to hospitalization.


Measuring consumer satisfaction in a mental health center.

In this age of consumerism, the degree of patient satisfaction should be considered when evaluating mental health services, according to the authors. They attempted to measure consumer satisfaction of mental health center patients by correlating it with various demographic and therapeutic parameters such as length of treatment, age, socioeconomic status, and previous expectations. One surprising finding was that patients treated by the approach least popular with the therapists, extended intake, rated the services higher than those treated by approaches considered more acceptable.


Factors determining effective psychiatric outpatient treatment for Mexican-Americans.

A mental health center offering outpatient services to Mexican-Americans should be centrally located in the Mexican-American community, should have a bicultural and bilingual staff, and should have an informal atmosphere with a minimum number of bureaucratic procedures. The center's services must be publicized in a way that minimizes the stigmatization of mental illness, promotes preventive care, and indicates that staff understand Mexican-Americans' problems. La Frontera, a mental health outpatient clinic serving the Tucson area, operates under those guidelines. Clinic records in March 1973 showed that Mexican-Americans accounted for 61 per cent of the active cases.


Emergency services: status categorization is dynamic.

If hospitals do not categorize themselves, it is very possible that categorization of emergency capabilities will be imposed by some local, state, or federal agency, probably using the rigid guidelines. The use of status categorization could be an alternative method of evaluating hospital emergency capabilities, especially when consideration is given to the ability to handle medical problems and to the shifting capabilities at different times of the day and night. Ignoring the problem or downgrading the rigid guidelines to include all hospitals are ineffective.


Chromosomal damage in chronic alcohol users.

First in vitro mitoses were analysed from the peripheral leukocytes of 22 chronic alcohol users and of 18 controls. The frequency of exchange aberrations of the chromatid and chromosome type were significantly higher in the alcohol as compared with the control group. The results indicate an indirect or direct mutagenic activity of alcohol in vivo.


The rate of sister chromatid exchanges parallel to spontaneous chromosome breakage in Fanconi's anemia and to trenimon-induced aberrations in human lymphocytes and fibroblasts.

The incidence of structural chromosome aberrations and the rate of sister chromatid exchanges (SCE) was investigated in lymphocyte cultures from a patient with typical Fanconi's anemia and his parents. The rate of SCEs was found to be normal. In experiments with the alkylating agent Trenimon the SCE rates proved to be a sensitive indicator for the induction of structural aberrations: in presence of an induced aberration rate half as high as the spontaneous rate in the Fanconi's anemia case, the rate of SCEs was found to be quintupled. Dose-effect relationships for the induction of SCE rates by Trenimon were studied over a wide dose range in lymphocyte and fibroblast cultures. The results reflect the same difference in sensitivity earlier observed in the induction of structural chromosome aberrations, fibroblasts being far more sensitive.


Power of assaying inbreeding through sampling of phenotypes and mating types.

Power of detecting inbreeding coefficient through a phenotype or mating type bioassay is evaluated as a function of sample size and level of inbreeding. Efficiency of a mating bioassay over a phenotypic one is then defined as the ratio of the two power functions for a given sample size while surveying the same population (i.e., with the same F). Empirical analysis of this efficiency function indicates that efficiency depends largely on n and F apart from the gene frequencies at the locus.


Partial trisomy 9q: a new syndrome.

Two unrelated patients with a strikingly similar phenotype (low birth weight and poor thriving; mental retardation; dolichocephaly; beaked nose; deeply set eyes; prominent maxilla and receding small chin; long fingers with a peculiar clench) were partially trisomic for two different segments of 9q. The segment found to be trisomic in both patients is small and corresponds to the q31q32 region. This new syndrome is compared to observations of trisomy 9 reported in the literature.


Prenatal diagnosis of trisomy 9.

A male karyotype with trisomy 9 (47,XY,+9) was identified in amniotic fluid cells from a 40-year-old pregnant woman. After termination of the pregnancy by saline abortion, the cytogenetic diagnosis was confirmed in a cell line grown from placental tissue. Microscopic and gross pathological findings in the fetus were compared to 1 case with trisomy 9 and 3 with trisomy 9 mosaicism reported in the literature. A distinct clinical syndrome appears to be associated with this rare autosomal trisomy.


Enrichment of memory cells carrying receptors for a protein antigen (HSA). II. Improved enrichment technique, using BSA density gradient separation.

Mice primed to human serum albumin (HSA) by means of an HSA--sheep red cell conjugate, developed a high level of memory to HSA, with little concomitant antibody production ('pure priming'). The proportion of HSA-specific antigen-binding cells was determined in the spleens of the primed mice by means of a rosette technique, using an HSA-donkey red cell conjugate. The specificity of the rosette-forming cells (RFC) was confirmed by the ability of soluble HSA to inhibit rosette formation. Highly enriched rosette suspensions (up to 40-fold enrichment) were prepared by bovine serum albumin density gradient centrifugation. The enriched suspensions could transfer adoptively memory to HSA, whereas the rosette-depleted fractions were totally inactive. It was thus confirmed that memory cells are included in the antigen-binding cells. A detectable level of memory could be transferred with 3000 rosettes. RFC similarly isolated from spleens of non-primed mice could also transfer a low level of responsiveness to HSA, but only when large numbers (70,000) were injected, together with primed, RFC-depleted spleen cells.


The labelling of peripheral blood lymphocytes of the mouse with [3H]thymidine.

The labelling of lymphocytes in the peripheral blood of mice following a single injection of [3H]thymidine was studied in autoradiographs exposed for 185 days before processing. The proportion of labelled cells was found to be greater than could be accounted for by new lymphocyte production. In addition, stimulation by sheep red cells 2 hours after giving [3H]thymidine resulted in the appearance of more labelled lymphocytes in the blood, but the greatest differences from control mice occurred relatively late in the immune response after cell proliferation in the responding lymphoid organ had reverted to control levels. The results are discussed on the basis that they indicate synthesis of DNA and reutilization of label by lymphocytes, which then circulate in the blood, these processes possibly occurring in the bone marrow and lymphoid tissues.


Immunological capacity of the chicken embryo. I. Relationship between the maturation of lymphoid tissues and the occurrence of cell-mediated immunity in the developing chicken embryo.

In an investigation of the ontogeny of lymphoid tissue in chick embryos to relate maturation of lymphocytes with immunological competence, the numbers and sizes of lymphocytes were determined in the thymus, bursa of Fabricius, spleen, femoral marrow and peripheral blood of embryos from the 12th to 21st day of incubation, and in 6-day-old chicks. Results showed the thymus to be the first fully developed and most active lymphocytopoietic organ, followed by the bursa. The bone marrow was not lymphocytopoietic; the spleen and bone marrow were mainly granulocytopoietic and erythropoietic; some morphological differences between thymic and bursal lymphocytes were shown by light microscopy. It appears that in embryos and young chicks the lymphocytes are derived from the thymus and bursa, but not the bone marrow. In tests of immunological competency, cells of the thymus, bursa, spleen, bone marrow and peripheral blood from 12--21-day-old embryos and 6-day-old chicks were transferred to chorioallantoic membranes of 12-day-old recipient embryos. There were distinct differences between the ability of various lymphoid tissues to induce formation of chorioallantoic pocks or splenic enlargement. The thymus, spleen and peripheral blood elicited both lymphocytic pocks and splenomegaly, the bursa elicited splenomegaly only, and the bone marrow was ineffective. The bone marrow, however, induced formation of nonlymphocytic pocks. It is concluded that the immunological activity of the chicken embryo is primarily effected by the thymus and bursa and that cell-mediated immunity appears in the 2nd week of incubation.


Human chorionic gonadotropin. Its inhibitory effect on cell-mediated immunity in vivo and in vitro.

An inhibitory effect of human chorionic gonadotropin (HCG) on delayed hypersensitivity skin test responses in guinea-pigs given 4000 i.u. of HCG intraperitoneally, 1--7 days prior to skin testing, is presented. The effect of HCG on skin test responses lasted for at least 3 weeks. Inhibition of lymphocyte response to PHA or PPD in the HCG-treated guinea-pigs was also observed. Guinea-pig peripheral blood lymphocyte response to mitogen or antigen is unequivocally inhibited by HCG in vitro. The effect of this hormone is not due to direct cytotoxicity, and its inhibitory effect seems to be dose related. These observations support the hypothesis that the HCG and possibly other placental hormones might play an important role in protecting the foetus against maternal rejection.


Correlation of anaphylactic bronchoconstriction with circulating reaginic antibody level and active cutaneous anaphylaxis in the rat.

The interrelationships of anaphylactic bronchoconstriction, active cutaneous anaphylaxis and circulating reaginic antibody level in rats sensitized with Nippostrongylus brasiliensis have been studied. The mean rise in bronchial reactivity during the 5-week sensitization period was correlated with the rise in circulating reaginic antibody level in groups of rats, although weak bronchial reactivity was observed before circulating reagin was demonstrable. In individual animals bronchial reactivity did not significantly correlate with circulating reaginic antibody level or cutaneous reactivity. Bronchial and cutaneous reactivity on challenge may be transferred to non-sensitized rats by passive sensitization with reaginic serum. It is concluded that the ability of a tissue to respond to antigen challenge is multifactorial and may not be reliably predicted from a knowledge of circulating reaginic antibody level or the response of another tissue in the same animal.