Differences of cerebral lateralization among schizophrenic and depressed patients.

Conjugate lateral eye movements (LEMs) have been used as a measure of contralateral frontal hemisphere activation when individuals carry out reflective tasks. In a previous study, schizophrenics were noted to produce significantly more R-LEMs than controls suggesting that they use the left hemisphere in general more often than controls when initiating thought. More specifically, schizophrenics initiated thought on spatial emotional material in their left hemisphere more often than normals. In an effort to replicate these findings, the present study contrasted a new sample of 13 schizophrenics first with the original schizophrenic sample, and then with 13 psychotic depressives, and the original controls. In addition, other group comparisons are reported. The data obtained replicate the original findings of increased R-LEM (i.e., increased left hemisphere activity) and the excessive processing of spatial and to a lesser extent emotional material in the left hemisphere of schizophrenics. Psychotic depressives were found to initiate reflective tasks more often in their right hemisphere than either schizophrenic or the original sample of normal controls. Significant group differences among schizophrenics, normal controls, and psychotically depressed patients were obtained. The data are consistent with emerging concepts of a left hemisphere locus of disturbance in schizophrenia and right hemisphere disturbances in affective disorders.


Callosal transfer and left-hand anomia in schizophrenia.

The theory of callosal failure in schizophrenia is examined using the test for left-hand anomia. It is argued that if the corpus callosum is affected in schizophrenia with consequent difficulty of transmission between the two sides of the brain, a greater number of left-hand errors should be found in producing the names of objects held by that hand because the speech area of the left hemisphere is no longer available for the description of the perceptions of the left hand. The findings support this view and they confirm the communication failures of the brain related to callosal disturbance.


A preliminary study of the effect of pyridoxine administration in a subgroup of hyperkinetic children: a double-blind crossover comparison with methylphenidate.

A small sample of six patients with the putative "hyperkinetic syndrome" participated in a research protocol comparing administration of pyridoxine, methylphenidate, and placeboes. The children had had low whole blood serotonin levels and a history of previous responsiveness to methylphenidate. The results of the double-blind clinical evaluation showed trends suggesting that both pyridoxine and methylphenidate were more effective than placebo in suppressing the symptoms of hyperkinesis. Pyridoxine elevated whole-blood serotonin levels, methylphenidate did not. Clinical and laboratory evidence indicated that the pyridoxine effects persisted after the 3-week period when the vitamin had been given in this experimental design.


Memory complaint after electroconvulsive therapy: assessment with a new self-rating instrument.

Memory complaints before bilateral electroconvulsive therapy (ECT), 1 week after ECT, and 6 months after ECT were assessed in 35 patients using a newly developed self-rating scale. Memory complaints that occurred 1 week after ECT differed quantitatively and qualitatively from memory complaints that occurred before ECT. Six months later, memory complaints qualitatively resembled the complaints reported 1 week after ECT and differed sharply from those reported before ECT. It was suggested that a patient's impression of his memory is altered by bilateral ECT and that this altered impression persists in gradually diminishing form for at least 6 months after a typical course of treatment. Since the self-rating instrument used here appeared to differentiate between memory complaints associated with depression (before ECT) and memory complaints associated with amnesia (1 week after ECT), this instrument may be useful in a variety of settings where there is interest in human memory function.


Degeneration and regeneration of motor neurons in psychotic patients.

The pattern of distribution of intramuscular nerve twigs was studied in muscle biopsies of peroneus brevis muscle from 62 schizophrenic and affective psychotic patients, and 8 normal control volunteers. Using methylene blue staining, the incidence of abnormally increased collateral branching was significantly greater in the patient population compared with normal controls. Paranoid psychotic patients had significantly higher values for branching than did non-paranoid schizophrenics. Abnormal branching was also correlated with excessive percentages of small angular muscle fibers. There was a significant relationship between increased branching and a positive family history of psychosis. The findings are suggestive of a process of neuronal degeneration followed by compensatory regeneration in some psychotic patients.


Lithium-induced hypothyroidism and thyroiditis.

Patients with a preexisting thyroiditis may be particularly susceptible to a rapid onset of lithium-induced hypothyroidism. The evidence for this hypothesis is reviewed and a case report illustrating this phenomena is presented.


Hyponatremic seizures in psychiatric patients.

Thirty-four cases of hyponatremic seizures occurring in psychiatric patients as a result of self-induced water intoxication are reviewed. Clinical and pathophysiological correlates of the condition are outlined.


A factor-analytic examination of the unitary OR concept.

Recent studies have generated a four-system structure proposed as a replacement for Sokolov's unitary OR concept. This conceptualisation developed from a logical consideration of stimulus--response relationships based upon mean response magnitudes over subjects, and paid no attention to individual response types. It is conceivable that no individual subject exhibited responses compatible with such a formulation. This paper addressed that problem by using factor analysis as a means of descriptively summarising the data of each subject, and examining its compatibility with both unitary and four-system structures. Of 72 subjects, none exhibited a factor structure compatible with Sokolov's unitary concept, while 70 exhibited structures compatible with the four-system structure. These results support the validity of the structure proposed to replace the unitary OR.


Plasma glucose and lactic acid alterations in response to a stressful exam.

Changes in lactic acid and plasma glucose levels as a function of examination stress were measured using a 'pinprick' blood sampling method. Blood samples were obtained from 12 subjects at each of four times, one week prior to the exam, within 15 min pre-exam, within 15 min post-exam, and three weeks after the exam. Glucose was significantly elevated pre-exam over control times and decreased significantly from before to after the exam. Lactic acid was significantly elevated pre-exam over control times and increased significantly before to after the exam. It is suggested that changes in the levels of these metabolites in the blood are indicative of stress levels. Self-ratings of 'nervousness' were not significantly correlated with either pre-exam glucose or pre-exam lactic acid.


The influence of visual information on habituation of the electrodermal and the visual orienting reaction.

In this study the influence of the information value of visual stimuli on habituation of the visual orienting reaction (VOR) and the skin conductance reaction (SCR) was investigated. 28 subjects received two blocks of 14 trials. Half the subjects received the higher information condition first and then the lower information, the other half received the conditions in the reversed order. Subjects fixated the stimuli with the higher information value longer than the stimuli with the lower information value during the 14 trials and habituated slower. This effect of information was absent in the second block and VOR habituation was also faster in this block. There was no difference in SCR amplitudes nor in SCR habituation scores between the two information conditions, neither in block 1 nor in block 2. The results of this study are discussed in relation with a two-stage model of the OR.


The discrimination of blood pressure fluctuations.

Two studies are described in which volunteers were trained to distinguish between displays contingent on or independent of blood pressure fluctuations. The latter were monitored with pulse transit time (TT). In Experiment 1, subjects were required to choose between TV displays that either reflected instantaneous TT or variations recorded a few minutes earlier in the session. Accurate discrimination was rapidly acquired. In Study 2, the choice was between signals dependent on TT or interbeat interval. Only one out of six subjects was successful. In both cases, associations between display fluctuations and respiratory activity were employed by subjects for distinguishing signal origin. The use of contingency discrimination strategies for assessing cardiovascular perception is discussed.


The terminal CNV and stimulus discriminability in motor and sensory tasks.

Slow EEG potentials were recorded during the foreperiod of a signal detection task which involved different levels of discrimination difficulty. The subject was required to react to S2 as quickly as possible or to delay his response by 1 s. It was found that the contingent negative variation (CNV) was attenuated when no speeded response was required and that larger amplitudes preceded the easy rather than the difficult discrimination. In addition, no differences were found between correct and incorrect detections. On these grounds it is concluded that the CNV is not positively correlated with perceptual sensitivity.


The return to sleep.

Six young adult subjects were awakened five to eight times per night from stage 2 sleep in a standardized manner for a series of at least 11 non-consecutive nights. After adaptation to the procedure, subjects received placebo, pentobarbital, or flurazepam on two random nights and caffeine on one night. The latency of the return to sleep after each awakening was measured. On placebo nights a characteristic U-shaped curve of latency as a function of time of night was found. Latencies were long shortly after sleep onset but decreased rapidly to about 50 sec before beginning an approximately linear logarithmic increase throughout the rest of the night. The drugs characteristically altered this time course. Pentobarbital decreased latencies in the first half of the night. Flurazepam decreased latencies throughout the night. Caffeine increased latencies during the first half of the night.


Lambda waves associated with offset of saccades: a subject with large lambda waves.

The temporal relationship between the lambda wave and the saccade was investigated in a subject with large amplitude lambda waves. The peak latency of the lambda wave from onset of the saccade was increased in proportion to increase of the saccade duration while the latency from offset was constant. The result showed that the lambda wave was associated with offset of the saccade rather than onset of it. It is suggested that the lambda wave might be the evoked response elicited by the afferent inflow beginning a fixation.


Statistical methods for classification of human chromosomes.

The basic technical facts of human cytogenetics and the laboratory methods employed in chromosome research are explained in simple terms. The main variables used to describe chromosome images are defined and discussed. Three discriminant analysis models for chromosome classification are developed: one in which each chromosome is classified in isolation, a modification in which the cell, if normal, contains 2 chromosomes of each of the 23 kinds, and a final one in which the cell is the unit of analysis instead of the chromosome. Suggestions are made to reduce the calculations involved and to take into account missing chromosomes. The problem of detection and classification of aberrative chromosomes is studied, also in relation to multiple cell analysis. Finally four relevant problems are briefly discussed: selection of metaphase spreads, selection of variables, uncertain reference classification and measurement of performance.


Some models of genetic selection.

This paper begins with a description of the classical theory of viability selection in which probabilities that individuals of various genotypes survive are in proportions that do not change with time and are independent of population structure. Salient features of viability selection with one and two loci are reviewed. This theory is intimately connected with the usual theory of mass selection in quantitative genetics. It is well known that the mean of the relative viabilities does not necessarily increase if there is viability selection at more than one locus. It also turns out that if there is selection for fecundity with one locus, the mean fecundity may steadily decrease or oscillate rather than increase. This and the fact that a Hardy-Weinberg structure may no longer exist at any stage of life may have a bearing on predicting progress from artificial selection on reproductive characters. Classical viability selection theory does not completely describe natural selection. Other possibilities are discussed. Among these is the density and frequency dependent selection induced when the population lives in a limited habitat. Implications in quantitative genetics are discussed.


General right censoring and its impact on the analysis of survival data.

This paper concerns general right censoring and some of the difficulties it creates in the analysis of survival data. A general formulation of censored-survival processes leads to the partition of all models into those based on noninformative and informative censoring. Nearly all statistical methods for censored data assume that censoring is noninformative. Topics considered within this class include: the relationships between three models for noninformative censoring, the use of likelihood methods for inferences about the distribution of survival time, the effects of censoring on the K-sample problem, and the effects of censoring on model testing. Also considered are several topics which relate to informative censoring models. These include: problems of nonidentifiability that can be encountered when attempting to assess a set of data for the type of censoring in effect, the consequences of falsely assuming that censoring is noninformative, and classes of informative censoring models.


Dose response problems in carcinogenesis.

The estimation of risks from exposure to carcinogens is an important problem from the viewpoint of protection of human health. It also poses some very difficult dose-response problems. Two dose-response models may fit experimental data about equally well and yet predict responses that differ by many orders of magnitude at low doses. Mechanisms of carcinogenesis are not sufficiently understood so that the shape of the dose-response curve at low doses can be satisfactorily predicted. Mathematical theories of carcinogenesis and statistical procedures can be of use with dose-reponse problems such as this and, in addition, can lead to a better understanding of the mechanisms of carcinogenesis. In this paper, mathematical dose-response models of carcinogenesis are considered as well as various proposed dose-response procedures for estimating carcinogenic risks at low doses. Areas are suggested in which further work may be useful. These areas include experimental design problems, statistical procedures for use with time-to-occurrence data, and mathematical models that incorporate such biological features as pharmacokinetics of carcinogens, synergistic effects, DNA repair, susceptible subpopulations, and immune reactions.


Allocation of patients to treatment in clinical trials.

This article is intended as a practical guide to the various methods of patient assignment in clinical trials. Topics discussed include a critical appraisal of non-randomized studies, methods of restricted randomization such as random permuted blocks and the biased coin technique, the extent to which stratification is necessary and the methods available, the possible benefits of randomization with a greater proportion of patients on a new treatment, factorial designs, crossover designs, randomized consent designs and adaptive assignment procedures. With all this diversity of approach it needs to be remembered that the effective implementation and reliability of a relatively straightforward randomization scheme may be more important than attempting theoretical optimality with more complex designs.


Inferences about linkage disequilibrium.

Existing theory for inferences about linkage disequilibrium is restricted to a measure defined on gametic frequencies. Unless gametic frequencies are directly observable, they are inferred from genotypic frequencies under the assumption of random union of gametes. Primary emphasis in this paper is given to genotypic data, and disequilibrium coefficients are defined for all subsets of two or more of the four genes, two at each of two loci, carried by an individual. Linkage disequilibrium coefficients are defined for genes within and between gametes, and methods of estimating and testing these coefficients are given for gametic data. For genotypic data, when coupling and repulsion double heterozygotes cannot be distinguished. Burrows' composite measure of linkage disequilibrium is discussed. In particular, the estimate for this measure and hypothesis tests based on it are compared to the usual maximum likelihood estimate of gametic linkage disequilibrium, and corresponding likelihood ratio or contingency chi-square tests. General use of the composite measure, whether or not random union of gametes is an appropriate assumption, is recommended. Attention is given to small samples, where the non-normality of gene frequencies will have greatest effect on methods of inference based on normal theory. Even tools such as Fisher's z-transformation for the correlation of gene frequencies are found to perform quite satisfactorily.


Hazard rate models with covariates.

Many problems, particularly in medical research, concern the relationship between certain covariates and the time to occurrence of an event. The hazard or failure rate function provides a conceptually simple representation of time to occurrence data that readily adapts to include such generalizations as competing risks and covariates that vary with time. Two partially parametric models for the hazard function are considered. These are the proportional hazards model of Cox (1972) and the class of log-linear or accelerated failure time models. A synthesis of the literature on estimation from these models under prospective sampling indicates that, although important advances have occurred during the past decade, further effort is warranted on such topics as distribution theory, tests of fit, robustness, and the full utilization of a methodology that permits non-standard features. It is further argued that a good deal of fruitful research could be done on applying the same models under a variety of other sampling schemes. A discussion of estimation from case-control studies illustrates this point.


The uses of epidemic models.

This paper is concerned with models formulated to describe the spread of infectious diseases through a community. Some standard epidemic models are introduced and an overview of their uses is provided. The paper includes a discussion of the advantages of simple models over complex ones and the advantages of stochastic models over deterministic ones. The role that epidemic models can play in helping us to understand the spread of diseases and to plan control policies for diseases is explained. The paper also contains a review of some major insights gained from a study of epidemic models and from statistical analyses of disease data using epidemic models. Some explicit suggestions for future research projects are made.


Multifactorial genetic models for quantitative traits in humans.

Quantitative traits measured in human families can be analyzed to partition the total population variance into genetic and environmental components, or to elucidate the genetic mechanism involved. We review the estimation of variance components directly from human pedigree data, or in the form of path coefficients from correlations between pairs of relatives. To elucidate genetic mechanisms, a mixed model that allows for segregation at a major locus, a polygenic effect and a sibling environmental correlation is described for nuclear families. In each case appropriate likelihoods are derived as a basis, using numerical maximum likelihood methods, for parameter estimation and hypothesis testing. A general model is then described that allows for several familial sources of environmental variation, assortative mating, and both major gene and polygenic effects; and an algorithm for calculating the likelihood of a pedigree under this model is indicated. Finally, some of the remaining problems in this area of biometric analysis are pointed out.


Biocomputational methodology an adjunct to theory and applications.

The role of "methodology", as distinguished from "theory" and "application", is discussed and illustrated. It is argued that research in the biomedical sciences is moving towards a degree of complexity different in both kind and extent from that usually encountered in other disciplines. Certain biocomputational methodology can be viewed as a bridge between the data forms commonly encountered in biomedicine, and the statistical and computational machinery which had previously been developed to deal with physical science information. Examples are given of three promising research subareas, all of which concern methods for dealing with highly complex forms of health and medical data.


First passage times as environmental safety indicators: carboxyhemoglobin from cigarette smoke.

The concentration of carbon monoxide in the blood of a cigarette smoker varies in response to the frequency and dose of CO delivered by the cigarettes he smokes and by the rate at which CO washes out of his blood. Moments of first passage times or exit times above a nominal threshold can be calculated using a stochastic differential equation that takes into account certain random variations in smoking intervals. CO doses, and washout rate. Almost any additional source of variation decreases in length of time a smoker may expect to smoke until a threshold value is exceeded. In particular the methodology proposed by Gori (1976) and Gori and Lynch (1978) for constant intervals, doses and rate may greatly overestimate the length of the "low-risk" interval for carbon monoxide concentration. One possible modification that may reduce CO hazards is to smoke less from each cigarette, even when this may be partially compensated by increased frequency of smoking.


A multiple testing procedure for clinical trials.

A multiple testing procedure is proposed for comparing two treatments when response to treatment is both dichotomous (i.e., success or failure) and immediate. The proposed test statistic for each test is the usual (Pearson) chi-square statistic based on all data collected to that point. The maximum number (N) of tests and the number (m1 + m2) of observations collected between successive tests is fixed in advance. The overall size of the procedure is shown to be controlled with virtually the same accuracy as the single sample chi-square test based on N(m1 + m2) observations. The power is also found to be virtually the same. However, by affording the opportunity to terminate early when one treatment performs markedly better than the other, the multiple testing procedure may eliminate the ethical dilemmas that often accompany clinical trials.


The application of robust calibration to radioimmunoassay.

The minute concentrations of many biochemically and clinically important substances are currently estimated by radioimmunoassay (RIA). Traditionally, the most popular approaches to the statistical analysis of RIA data have been to linearize the data through transformation and fit the calibration curve using least squares or to directly fit a nonlinear calibration curve using least squares. Estimates of the hormone concentration in patients are then obtained using this curve. Unfortunately, the transformation is frequently unsuccessful in linearizing the data. Furthermore, the least squares fit can lead to erroneous results in both approaches since the many sources of error which exist in the RIA process often result in outlier observations. In this paper, an approach to the analysis of RIA data which incorporates robust estimation methods is described. An algorithm is presented for obtaining the M-estimates of nonlinear calibration curves. The curves to be fitted are modified hyperbolae based on 12 to 16 observations. A procedure, based on the application of the Bonferroni Inequality, is presented for obtaining tolerance-like interval estimates of the concentration of the hormone of interest in the patients. Results of simulations are cited to support the method of construction of confidence bands for the fitted calibration curve. Data obtained from the Veteran's Hospital, Buffalo, New York are used to illustrate the application of the algorithm which is presented.


Longitudinal analysis of the dynamics and risk of coronary heart disease in the Framingham Study.

Statistical methods designed specifically for the analysis of chronic disease incidence and progression in longitudinal studies are presented. These method model the risk of acute phases of chronic disease separately from the temporal change in risk variables. This could be accomplished because, under a specific biological model of the disease mechanism, the problems of estimating the risk of an acute event and of predicting the change in risk variables are independent. Specifically, a quadratic equation relating risk variable values to chronic disease risk and a system of linear equations predicting future risk variable values from present values may beestimated separately. Taken together, they utilize the full information available in a longitudinal study on the temporal dimension of chronic disease progression. In addition, the model is found to possess a number of attractive statistical and theoretical properties. These methods are applied to longitudinal data from the Framingham Study on coronary heart disease (CHD) in males. A quadratic function relating the risk of a CHD event to selected risk variables (age, and the natural logarithms of serum cholesterol, uric acid, diastolic blood pressure and pulse pressure) was estimated from measurements made at four points equally spaced in time (two years) with a further morbidity follow-up at a fifth point. The risk function was found to predict CHD risk accurately. It showed that, apart from the linear effects of the risk variables, cohort effects, quadratic effects and interaction effects were important predictors of CHD risk. The linear regression equations used to predict future risk variable values showed that there was an intricate network of cross-temporal associations. Study of the two types of equations jointly show that putative risk variables could affect the risk of CHD incidence both directly, by being associated with higher levels of risk, and indirectly, by causing other risk variable values to change with time. The results led us to identify several different roles that risk variables might play in CHD incidence.


Analysis of life tables with grouping and withdrawals.

A number of individuals is observed at the beginning of a period. At the end of the period the number is surviving, the number who have died and the number who have withdrawn are noted. From these three numbers it is required to estimate the death rate for the period. All relevant quantities are supposed independent and identically distributed for the individuals. The likelihood is calculated and found to depend on two parameters, other than the death rate, and to be unidenttifiable so that no consistent estimators exist. For large numbers, the posterior distribution of the death rate is approximated by a normal distribution whose mean is the root of a quadratic equation and whose variance is the sum of two terms; the first is proportional to the reciprocal of the number of individuals, as usually happens with a consistent estimator; the second does not tend to zero and depends on initial opinions about one of the nuisance parameters. The paper is a simple exercise in the routine use of coherent, Bayesian methodology. Numerical calucations illustrate the results.


Testing hypotheses in case-control studies--equivalence of Mantel-Haenszel statistics and logit score tests.

The two approaches in common use for the analysis of case-control studies are cross-classification by confounding variables, and modeling the logarithm of the odds ratio as a function of exposure and confounding variables. We show here that score statistics derived from the likelihood function in the latter approach are identical to the Mantel-Haenszel test statistics appropriate for the former approach. This identity holds in the most general situation considered, testing for marginal homogeneity in mK tables. This equivalence is demonstrated by a permutational argument which leads to a general likelihood expression in which the exposure variable may be a vector of discrete and/or continuous variables and in which more than two comparison groups may be considered. This likelihood can be used in analyzing studies in which there are multiple controls for each case or in which several disease categories are being compared. The possibility of including continuous variables makes this likelihood useful in situations that cannot be treated using the Mantel-Haenszel cross-classification approach.


Detecting systematic errors in multi-clinic observational data.

In multi-clinic studies it is hard to maintain a uniformly high quality of measurement and coding. Systematic errors almost always occur, in spite of the best of intentions and the most rigid protocols. It is the statistician's responsibility to plan for the detection of these errors, as well as to try to avoid them and not be misled by them. The practice of examining the univariate and multivariate sample frequency distributions of the variables under study, with an eye open for anything that looks puzzling, can be very helpful in detecting and trying to correct systematic errors that would bias the analysis. Examples are given from a 21-clinic study on pregnancy and child development.


Protein amino acid analysis by an isotope ratio gas chromatography mass spectrometry computer technique.

A method for quantitative analysis of protein amino acids by a gas chromatography mass spectrometry computer system is described. Amino acids were analysed as their N-trifluoroacetyl n-butyl ester derivatives. Isotope ratio determination was used as the quantitating technique via multiple internal standards. The exact composition of a deuterated amino acid mixture was determined against a standard amino acid calibration mixture and in turn the protein amino acid composition was determined against the deuterated amino acid mixture. The amount of protein taken for analysis was 100 micrograms and the procedure, excluding hydrolysis, could be performed with 2 1/2 hours. The introduction of the internal standards prior to protein hydrolysis provides a method with good precision (mean coefficient of variation less than 5%). The method, tested on insulin, gave results which agreed well with the known composition of the protein and with simultaneous analysis on ion exchangers.


Determination of carprofen in blood by gas chromatography chemical ionization mass spectrometry.

A gas chromatographic chemical ionization mass spectrometric assay has been developed to measure carprofen in blood. The method features the addition of either a structural or stable isotope analog internal standard to plasma prior to a simple benzene extraction at pH 4.5. The residue, after removal of the benzene, is methylated with ethereal diazomethane. Following evaporation of the methylating solvents, a portion of the reconstituted residue is analyzed by gas chromatography mass spectrometry. The mass spectrometer is set to monitor in the gas chromatographic effluent the [MH]+ ions of carprofen methyl ester and the methyl ester of the internal standard generated by isobutane chemical ionization. Assay sensitivity is 5 pmol ml-1. When 200 pmol ml-1 samples are analyzed using a stable isotope analog as the internal standard, the precision and accuracy are both 4%. Using a structural analog as the internal standard, the assay was neither as precise nor as accurate.


Simultaneous quantitative estimates of several isotopically labelled substances in the picogram range with selected ion monitoring.

The use of a model developed by the authors for the simultaneous quantitative determination of several isotopically labelled substances of the same chemical structure is described in detail for a two substance system. A computational flow chart is included. An example using natural estradiol and 4-[14C] labelled estradiol with manifold deuterated estradiol as an internal standard is presented. The basis of the model is discussed.


Isolation and structural analysis by mass analysed ion kinetic energy spectroscopy of diverse sidechains from steroids of similar tetracyclic carbon skeletons.

The technique of mass analysed ion kinetic energy spectroscopy has been applied to the structural determination of five different substituent sidechains from five steroids of similar ring anatomy. A mass spectrometer of reversed geometry, which permits ion selection according to its mass-to-charge ratio before the ions enter the electric sector, was used to isolate the ion corresponding to the mass of each particular sidechain. Subsequent mass analysed ion kinetic energy spectra of the selected ion demonstrated daughter ions whose compositions were compatible with the structures of the model compounds. This ability to determine the structure of a specific portion of a large molecule and to permit differentiation of minor structural features in a series of compounds, whose major framework is similar, adds a new dimension to the powerful mass analysed ion kinetic energy spectroscopy technique for structural analysis of complex biological molecules.


Characterization of ethyl substituted fatty acids from lamb subcutaneous triacylglycerols by combined gas chromatography mass spectrometry.

Mid-chain ethyl substituted fatty acids with chain lengths ranging from 10 to 16 carbon atoms were identified in a concentrate of branched chain fatty acids isolated from the triacylglycerol fatty acids of the subcutaneous adipose tissue of barley-fed lambs. The acids were identified by gas chromatography in combination with mass spectrometry and their mass spectral features are discussed.


A microprocessor controlled mass spectrometer for the fully automated purification and isotopic analysis of breath carbon dioxide.

Breath tests that measure the oxidative utilization of 13C labeled substrates have been shown to be clinically useful, but have failed to gain wide acceptance because of the slow and costly isotopic analysis of the breath samples. Therefore we have developed a fully automated, microprocessor controlled CO2 purification and isotopic analysis system. The breath CO2 is cryogenically purified by passage through cold traps of -94 degrees C and -196 degrees to condense water and CO2, respectively. The CO2 is intorduced into a dual inlet, peak-stepping mass spectrometer and analyzed for isotopic content by comparison with a known standard. Thirty samples can be analyzed without operator intervention. Analysis time average 14 minutes per sample, and the analysis has a precision of 0.3% which corresponds to 3 parts excess 13C per 10(6) parts CO2. The speed of analysis is comparable with scintillation counting and permits next day reporting of clinical breath test results. The precision is sufficient for clinical applications as it is less than 0.7% isotopic variation in basal breath CO2.


Thermolysis chemical ionization of a complex polar lipid.

Vaporization of a ornithine-containing polar lipid from Thiobacillus thiooxidans has been accomplished by thermolysis in a chemical ionization source. The thermolysis has been shown to be more extensive than previously thought. It occurs in at least two steps, the first being dehydration of the ornithine to produce a substituted piperidone. This fragment undergoes a facile elimination to produce two neutral lipid components: a long chain fatty acid and piperidone-containing fatty amide. The results demonstrate the utility of chemical ionization for developing an understanding of a thermolysis process.


Ion cluster techniques in drug metabolism: an example of the use of mixtures of the [12C]:[14C] isotopic forms of the synthetic prostaglandin cloprostenol ('Estrumate') to facilitate metabolite identification.

The synthetic prostaglandin analogue cloprostenol has been prepared radiolabelled with 14C. The isotopic abundance of 14C at position C-15 was greater than 90% of the theoretical maximum. We have utilizted the high abundance of the 14C isotope for metabolism studies by preparing mixtures of [12C]:[14C]cloprostenol such that fragments detected by mass spectrometry contained characteristic isotope clusters analogous to those often obtained using stable isotopes.


Analog-digital molecular cell computer.

The living cell is controlled by a molecular stochastic computer of parallel-successive action. MCC may be equivalent to the universal computer. MCC operates with molecule-words (DNA, RNA, proteins) according to the programme recorded in DNA and RNA. Operations are produced by molecular devices (RNA- and DNA-polymerases, ligases, proteinases and so on). Molecular devices operating with molecule-words are recorded on molecules themselves, and they are read off by ribosomes. Therefore the programme of the reorganization of the programme itself may be recorded on the molecule-words. MCC operates with molecular words having definite addresses. The words and the operators collide by Brownian movement and combine if the molecular surface of address segment is complementary and properly oriented. It is possible to reproduce not only the programmes but also the operators of MCC. The molecular computer operates with word-molecules according to the programme, recorded in DNA, with the aim of predicting an outer situation in the next time-moment and selecting of a correct answer by synthesis of suitable proteins and other substances and also by macroscopic motion. Each step of directed calculation is needed of the consumption of minimally necessary portion of free energy and search is due to the Brownian movement without free energy loss. Cyclic nucleotides are intraneuron membrane potential controlling systems which can be described as molecular diffusional analog computers, well fitted to solve mathematical physics equations if there are high frequency generators and regulators of cyclic nucleotides sources and sinks. It is suggested that molecular proton channels in an electric field are such generators of 10(11)-10(12) Hz. Biophysics cannot use the ordinary laws of physics and must take into account the influence on the phenomena to be studied, not only of a measurement but also of a calculation process in the real device predicting the future.


An automaton analogue of unicellularity.

There is presented in outline form an abstract model of a cell in an evolutionary context. The design is based on an elaboration of John Holland's one-dimensional, abstract universe recently posed for the study of the emergence of self-replicating systems. Eight new ingredients constitute the elaboration. They suggest how compartmentation of a set of "molecules" in a one-dimensional universe can be achieved and how a suitable, compartmentalized set of molecules can replicate in a manner analogous to real cell replication, i.e., there is segregation and semi-conservative replication of the genetic material, and there is division of the compartment through the construction of an "inner membrane". The approach to self-replication of a spatially delimited entity exemplified by this design differs from the abstract models of replication of the von Neumann or Laing type. In these the replicating entity constructs a copy external to itself and does not undergo any essential replacement of any of its parts. Also, while in these models the concern is primarily with questions of the "logical" type, our design has in mind features identifiable with both energy and information considerations. Thus, the rules which define the underlying "physics and chemistry" imply that the self-replicating entity is a dissipative structure. A constant flux of energy is required to maintain the system far from thermodynamic equilibrium in order to account for multiple steady states, and hence dynamic structure.


Bootstrapping on the adaptive landscape.

Different versions of a gene or of a multigenic system may be essentially equivalent so far as the specific function of the structures which they code for or control is concerned, but very different with respect to their amenability to evolution. The structural features which increase evolutionary amenability are a disadvantage to the organism in terms of energy. Nevertheless, they accumulate in the course of evolution as a consequence of hitchhiking along with the desirable traits whose evolution they make possible. This is the bootstrap principle of evolutionary adaptability. In terms of the adaptive landscape bootstrapping corresponds to populations evolving in such a way that they occupy regions of the landscape which are more amenable to evolutionary hill climbing. The bootstrapping idea has implications for structure-function relations in a number of complex biological information processing systems, including biochemical systems, the immune system, and the brain. Bootstrapping is also discussed in connection with the origin of information processing (the origin of life) and in connection with possible designs for macromolecular computing systems.


Recursive evolution.

In evolutionary systems in which the units (individuals) are generated by a morphogenetic process, unbiased "mosaic type" mutability of the phenotype is not possible (Waddington's principle). The question is whether this unavoidable "channeling" can itself be made plastic through provision of alternative morphogeneses possessing differing "hot spots." If so, plasticity would not only be reestablished, but be established at a higher level. Plasticity itself would be plastic. The property of ultrasplasticity is evolutionarily necessary and stable, but perhaps not possible. Ultraplastic systems form a subclass of "temporal brains" as described in deductive biology. Many of their properties have yet to be discovered.


Machines as organisms: an exploration of the relevance of recent results.

The capacity of machines to exhibit organism-like behavior is examined. Some known results on machine description, self-description, construction and self-construction, are reviewed. The basic mechanism of machines and the ways in which they can be combined to form more complex biological-like systems are put forth as a source of explanatory mechanisms in biology. The proven properties can be employed in the design of machines which can repair themselves, and can exhibit a behavior distinguishing between machines which are or are not structurally similar to themselves. It is then argued that in an appropriate setting of variation and competition, such behavior would arise without explicit design.


Dissipation-error tradeoff in proofreading.

Chemical proofreading systems, of the kind believed responsible for the extremely high fidelity of DNA replication, achieve minimum error probability (equal to the product of the error probabilities of the writing and proofreading stages) only in the limit of infinite energy dissipation. However, a considerable degree of proofreading can be obtained in less strongly driven systems, dissipation only 0.1-1 kT/step.


Multilayer immobilized-enzyme filter reactors: urease bound to nylon fabric filters.

Urease was bound to commercially available nonwoven nylon fabric filters. Multilayer immobilized-enzyme filter reactors were constructed by packing varying numbers of urease-nylon filters in a column. Owing to the relatively open structure and high mechanical strength of the filter fabric, compaction and pressure drop effects were minimal. The reactors could be operated in a wide range of substrate concentrations and flow rates under conditions where mass-transfer limitations could be neglected. The kinetic behavior of the immobilized-enzyme filter reactors could be described by a linear form of the integrated Michaelis-Menten equation using a model based on the sequential action of the enzyme filters.


[New evidence of depression of depolarization of primary afferents with ammonium ions].

Perfusion of the central canal of the lumbar segment of the spinal cord with artificial cerebrospinal fluid (CSF) supplemented with ammonium ions induced in cats depression of slow negative electrotonic potentials of dorsal roots (PDR). PDR depression developed simultaneously with postsynaptic depression of the inhibition of monosynaptic reflexes, however it was not related to the depression of mono- or polysynaptic reflex discharges. Further perfusion of the central canal with normal CSF resulted in a complete restoration of the PDR as well as inhibition of control reflexes. It is suggested that PDR depression with ammonium ions could be the result of the blocking of the chloric pump acting the afferent terminals and creating electromotive power for outward transmembranous chloric current producing depolarization of the afferent fibres.


[Brain stem and very late reflex response of the vasoconstrictor neurons to impulses of somatic A-afferents].

In decerebrated unanesthetized cats single stimuli to the tibial nerve A-afferents apart from the late response, a discharge with a latency of 60--140 ms, elicited another discharge, a "very late" response (VLR) with a latency of about 0.35 s. This response was easily detectable, in almost all experiments in "mesencephalic" animals, but in different pontine sections including the ponto-bulbar junction and most rostral parts of the medulla oblongata, it was seen only in one out of 18 animals. At slightly more caudal sections of the brain stem (in "bolfar" animals) VLR was seen in 10 out of 11 animals. Thus, in the region of the ponto-bulbar junction there exist structures that tonically suppress the activity of the VLR generating system. It was shown that the activity of this system is augmented by summation processes of two types, developing in long (seconds) and short (milliseconds) time periods.


[Milk protein digestion and lysosomal proteinases of the ileal mucosa in young rats].

The proteolytic activity of lysosomal and pancreatic proteinases was studied in the chyme and tissue homogenates of the jejunum and ileum of 12- and 30-day rats in order to elucidate whether lysosomal proteinases of the mucous membrane of the ileum participate in cavitary digestion. During milk feeding the proteolytic activity of acid (lysosomal) proteinases in the ileum was 3 times greater than in the jejunum, which has been demonstrated both for the mucous membrane and the contents of these parts of the small intestine. In rats on definitive nutrition the activity of acid proteinases from the jejunum and ileum remained almost unchanged both in the mucous membrane and in the contents. The data obtained also indicate that pancreatic proteinase absorbed from the chyme of the small intestine may participate in parietal digestion.


[Effect of beta-phenylethylamine on evoked potentials of the neostriatum of rats].

The effect of intraperitoneal (70 mg/kg) and local (39 ug) administration of beta-phenylethylamine (beta-PEA) on evoked potentials (EP) in the caudate nucleus upon stimulation of substantia nigra zona compacta (SNC) and frontal cortex in rats has been studied. beta-PEA, glutamate and haloperidol were injected into the caudate nucleus by means of a system consisting of a pushpull cannule and an electrode for simultaneous registration of EP. Specificity in the effect of the drugs on EP in response to stimulation of the cortex and substantia nigra was revealed. The intraperitoneal injection of beta-PEA induced, comparatively to the application, more rapid and potent decrease in the amplitude of the component (N2-P2) as a result of the substantia nigra stimulation and slightly influenced the EP amplitude in stimulation of the frontal cortex. It was established using haloperidol that the component (N2-P2) of EP in response to the substantia nigra stimulation is of dopaminergic neuron function in the nigro-neostrital system of the rat brain.


[Non-uniformity of the ventilation-perfusion ratio in the lungs, and arterial hypoxemia].

The general analysis of the relationships between the extent of nonuniformity of ventilation-perfusion ratios and blood flow through poorly ventilated protions of the lungs on the one hand and arterial hypoxemia on the other one has been performed. Quantitative evidence on the onset of arterial hypoxemia in disturbances of ventilation-perfusion ratios are obtained.


[Insulin sensitivity of isolated muscle tissue of rats with manifest alloxan diabetes of different duration].

Insulin sensitivity of muscle tissue was assessed in 20 control rats and 27 rats with alloxan diabetes from the extent of its effect on C14-glucose incorporation by the diaphragmatic muscular glycogen. In diabetes of 5--8-day standing insulin sensitivity of muscle tissue remained unchanged. In alloxan diabetes of 22--24-day duration insulin sensitivity of muscle tissue diminished. With prolongation of decompensated alloxan diabetes up to 5--8 months a further decrease in incorporation of labelled glucose by the diaphragmatic glycogen was recorded. The data obtained indicate that metabolic disturbances inherent in diabetes mellitus lead to a decrease in insulin sensitivity of muscle tissue.


[Endogenous production of prostaglandins E and F2-alpha in cerebral and extracerebral vessels of cats and its change under the effect of noradrenaline].

The quantitative determination of prostaglandins (PG) E and F2 alpha has been carried out in isolated cerebral and extracerebral vessels of cats. It has been found that the basal production of PG predominates in cerebral vessels, the content of PGF2 alpha prevailing compared to PGE. The incubation of isolated vessels with noradrenaline causes a decrease in production of vasopressor PGF2 alpha with a simultaneous considerable increase in the content of vasodepressor PGE. The changes indicated are especially clearly seen in the cerebral vessels. It is suggested that the level of endogenic production of PG in the cerebral vessels may play an important role in the local regulation of the vascular tone, while the disbalance of their dynamic correlation may be responsible for cerebrovascular abnormalities.


[Formation of hematopoietic colonies of the donor type in the bone marrow of irradiated chickens after transplantation of the cells of the yolk sac and hindlimb of the quail embryo].

The ability of yolk sac and primary bone marrow cells of the quail to form hemopoietic colonies at 6 hours of incubation (i. e. before establishment of circulation) was studied in the bone marrow of 3-week sublethally irradiated chickens. The experiments were based on the possibility of differentiating between quail and chicken cells from the natural cell marker (Pheulgen-positive nucleolus). The number of hemopoietic colonies produced by cells transplanted from the primary bone marrow was three times greater than that consequent on transplantation of yolk sac cells. With the given dose of irradiation the bone marrow shows about 75% exogenous (quail) and 25% endogenous (chicken) hemopoietic colonies.


[Study of the nature and mechanism of biosynthesis of nonspecific immunoglobulins].

Mice were immunized with Vi-antigen. Spleen cells, removed at different time after immunization, were cultivated in Eagle medium, containing glycine-14C. The biosynthesis of antibodies to Vi-antigens, autoantibodies to mouse IgG and antigen-dependent non-specific immunoglobulins (NigG) were determined by means of specific immunosorbents. Immunization of mice with Vi-antigen resulted in a sharp increase in antigen-dependent NIgG formation. Thus, this protein biosynthesis takes place not only during immunization with thymus-dependent antigens, but also in response to the thymus-independent antigen. It is shown that the synthesized antigen-dependent NIgG were not autoantibodies to self mouse IgG.


[Possible role of DNAse I in the development of experimental leukemia].

An increase in the DNAase 1 activity in the serum and an increase in the DNAase inhibitor activity in the spleen in the development of virus Friend leukemia were demonstrated. Increased activity of the inhibitor in the spleen was also revealed after intravenous injection of exogenous DNAase 1 into mice. A potential role of serum DNAase 1 in the development of experimental leukemia is discussed.


[Cells with fragmented nuclei in ascites hepatoma 22A and their participation in proliferation].

The number of cells with fragmented nuclei (FN) (mainly, multilobate) increased with aging of ascites hepatoma 22A (AH22A) as follows: 15 +/- 9.3% in the 6-day AH22A, 196 +/- 53% in the 14-day tumor and 453 +/- 51% in the delayed (18-day) AH22A. The basic way of FN formation was amitotic. About 150 and 170% of cells with FN in the 14- and 18-day AH22A were at the reversible resting R1 stage (or at the very long G1 period, more than 4 days). The rest of the cells, 50 and 230%, respectively, quit the mitotic cycle irreversibly and apparently undergo the involution that is faster during passage-stimulated division.


[Effect of a carcinogen on the electric activity of the rat stomach].

Acute experiments on rats showed that the intragastric administration of an aqueous solution of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) elicited depression of the electrical activity of the gastric wall manifested by a decrease in the amplitude and frequency of the basic electrical rhythm and by its complete stopping in most cases. MNNG abolished the excitatory reaction caused both by the vagal electric stimulation and administration of carbacholine, but there persists an inhibitory reaction elicited both by the vagal stimulation and infusion of ATP.


[Characteristics of wound healing after laser-CO2 injury].

The studies of the laser-CO2 ray injury to the liver, kidneys and lung tissues showed the absence of the pronounced leukocytic infiltration in the tissues adjacent to the damaged ones. The lack of inflammatory alterations during the healing indicates that the resorption of the damaged tissues, accompanied by inflammation, and the tissue element proliferation are relatively autonomic processes, not forming an entire pathogenetic reparation chain.


[Effect of prostaglandin F2-alpha on the course of pregnancy and 17-beta-estradiol concentration in blood plasma of mice].

The effect of prostaglandin F2 alpha (at a dose of 2 mg/kg, per each stage of development) on the mouse preimplantation development and 17 beta-estradiol concentration in the blood plasma was studied. Prostaglandin F2 alpha caused inhibition of mitoses in the embryo and decreased the percentage of embryos liberated from zona pellucida. Meanwhile blood plasma showed diminution of 17 beta-estradiol level as a result of administering prostaglandin F2 alpha. In physiological conditions a significant rise in 17 beta-estradiol level was recorded at the stage of blastocyst liberated from zona pellucida.


[Detection of heterogenicity of the lymphoid populations by measuring the diameter of the cells and cell nuclei].

Some parameters of distribution according to the lymphoid cell and its nuclei size in the peripheral blood, bone marrow, thymus and spleen of healthy rats were studied. A comparative assay revealed population homogeneity for the thymus and bone marrow lymphocytes as well as their mean diameter differences. Mixing of these cell types markedly changed the distribution parameters of newly formed population, as shown on the model of the bone marrow lymphoid reaction caused by migration of thymic lymphocytes after 5-fluorouracil use. Preliminary thymectomy excluded migration and homogeneity of the bone marrow lymphocyte size remained unchanged.


[Effect of transplantation of thymus, bone marrow and spleen cells on the regenerative processes in pathologically changed liver].

In tests on CBAXC57BL mice with experimental hepatitis, induced by carbon tetrachloride, the transplantation of cells from the lymphoid organs of healthy donors intensified the repairing process in the recipient pathologically changed liver. The most pronounced normalization was seen in the liver of the animals given thymocytes which suggests a deficit of these cells in experimental toxic hepatitis and indicates a definite role of the thymus in the repairing processes of the damaged liver.


[Electron-microscopic and electron-autoradiographic characteristics of embryonal lung cells in organ cultures].

Cells of the mouse embryonal lung at early stages of organotypical cultivation were studied by electron microscopy and autoradiography. The electron autoradiography technique allowed the fate of poorly differentiated cells to be elucidated.


[Ultrastructural-morphometric study of cardiac myocytes in the cell culture].

Ultrastructural-morphometric studies of the right and left heart ventricles of 4-day young rat were carried out during 7-day cultivation to examine morphologic and sterologic parameters of mitochondria and myofibrils. The morphometric data demonstrated a recurrent character of mitochondria and myofibril structural changes. The changes occurred should not be regarded as structural cell differentiations but rather as adaptation to the cultivation conditions.


[Functional morphology of the hypothalamo-neurohypophyseal system and juxtaglomerular apparatus in acute vascular insufficiency].

The functional morphology of the hypothalamic neurohypophyseal system (HNHS) and juxtaglomerular apparatus (JGA) were studied in 50 male cate. A rising secretory activity in HNHS and JGA, accompanied by accumulation of hormone-containing granules, was seen in acute vascular insufficiency caused both by the injection of a ganglion-blocking agent and by bloodletting. This factor is qualified by the authors as a specific sign of hypotonic stress, consisting in incomplete use of HNHS and JGA adaptive capacity in acute pressor hormone deficit.


Deficiency of factor Xa-factor Va binding sites on the platelets of a patient with a bleeding disorder.

Factor V (Va) is essential for binding of factor Xa to the surface of platelets. After thrombin treatment, normal platelets release at least five times more factor Va activity than is required for maximal factor Xa binding. The concentration of factor V activity obtained after thrombin stimulation of 10(7) normal platelets is sufficient to allow half-maximal factor Xa binding to 10(8) platelets (10% normal, 90% factor-V deficient). Therefore, factor Va activity is not limiting in platelet-surface factor Xa binding and prothrombin activation in normal platelets; some other components limit the number of binding sites. We report studies of a patient (M.S.) with a moderate to severe bleeding abnormality whose platelets are deficient in the platelet-surface component required for the factor Va-factor Xa binding. The patient's platelet factor Va activity released after thrombin treatment is normal, but factor Xa binding is 20%-25% of control values at saturation. Abnormal prothrombin consumption in a patient with normal plasma coagulation factors and platelet function suggests a disorder in platelet-surface thrombin formation.


Successful transfusion of platelets cryopreserved for more than 3 years.

To determine the duration of storage for cryopreserved platelets, 14 transfusions of random-donor, pooled platelets, stored in the vapor phase of liquid nitrogen for a mean period of 1157 days (range 1060-1240), were analyzed. Twelve of these transfusions were compared in a paired fashion with fresh, random-donor, pooled platelets given within a few days to the same thrombocytopenic recipients. Platelets had been frozen using 5% dimethylsulfoxide as a cryoprotective agent either at a controlled rate of -1 degrees C/min to -80 degrees C or by simply placing them in the vapor phase (-120 degrees C) of a liquid nitrogen freezer. The mean freeze-thaw loss for the 14 transfusions was 22%, and the mean corrected 1-hr increment in platelet count was 12,600/microliter. In the 12 paired observations, the mean corrected 1-hr increment for frozen platelets was 11,800/microliter and 25,900 for fresh platelets, giving a frozen/fresh recovery of 46%. Random donor platelets can be cryopreserved by these methods for greater than 3 yr with satisfactory post-transfusion increments. This suggests that a reservoir of frozen platelets, either random-donor for emergency transfusion or of known HLA-type for transfusion to alloimmunized patients, can be established and stored for at least 3 yr.


Activated clotting factors in factor IX concentrates.

The precise quantitation of activated factors in human factor IX concentrates has been accomplished with the use of recently developed, specific assays for factors IXa, Xa, and thrombin. The assay for factor IXa, which measures the initial rate of 3H-factor-X activation, was shown to be specific for factor IXa in the concentrates. Activated factor IX concentrates contained 1.0-2.3 microgram/ml of factor IXa; whereas the assays of unactivated concentrates were negative (less than 0.2 microgram/ml). The assays of factor Xa and thrombin, which measure the initial rate of p-nitroaniline release from S-2222 and S-2238, respectively, showed similar small amounts of factor Xa (4-34 ng/ml) and thrombin (12-76 ng/ml) in the activated and unactivated concentrates. The nonactivated partial thromboplastin time of the concentrates correlated significantly with the factor IXa content, but not with factor Xa or thrombin. Antithrombin III antigen in 3 of 4 concentrates was several-fold higher than antithrombin III activity, suggesting the presence of antithrombin III complexed with activated factors. These results support the hypothesis that the degree of activation of factor IX concentrates is related primarily to the concentration of factor IXa, which may be responsible for the thrombogenicity of these concentrates in some clinical settings.


Human erythroid burst-promoting activity produced by phytohemagglutinin-stimulated, radioresistant peripheral blood mononuclear cells.

The regulation of erythroid burst-colony formation was studied in cultures of human peripheral blood mononuclear cells. Numbers of erythropoietin-stimulated colonies obtainable from the cells in response to various treatments were compared. One-day preincubation of the cells with phytohemagglutinin (PHA) doubled the yield of colonies. Irradiation of the cells with 3000 rad eliminated their ability to form erythroid bursts, but did not impair the ability of PHA-treated cells to enhance burst formation when added to a fresh batch of cells. This was due to a humoral factor, since media conditioned by PHA-treated washed cells were as effective as the cells themselves. When cells were separated into subpopulations by an adherence procedure and according to their ability to form rosettes with sheep red blood cells, it was found that the PHA-dependent burst-promoting activity released into the medium originated in a nonadherent, nonrosetting (T-cell depleted) cell population.


Hereditary dyserythropoiesis with abnormal membrane folate transport.

Dyserythropoiesis, which morphologically and serologically resembles congenital dyserythropoietic anemia type III but is not accompanied by anemia, is described in a young man. In addition to striking gigantism and multinuclearity of erythroid precursors, electron microscopy revealed widening of nuclear pores, nuclear clefts, and cytoplasmic inclusions. Membrane transport of 5-methyltetrahydrofolate by the patient's red cells was markedly reduced; total uptake, uptake velocity, and maximal velocity of uptake were all significantly less than in controls. In contrast, red cell uptake of pteroylglutamic acid was normal. Bone marrow cells in culture also showed decreased 5-methyltetrahydrofolate uptake, as well as very low thymidine incorporation. Because folate uptake by mitogen-stimulated lymphocytes was normal, the defect apparently does not involve all cell lines. These results suggest that a specific membrane defect, affecting the carrier system for reduced folate compounds, is present in this patient's erythrocytes, and perhaps, their bone marrow precursors.


The G gamma:A gamma composition of fetal hemoglobin in fetuses and newborns.

To determine whether the G gamma:A gamma HbF switch is coordinated in development with the HbF:HbA switch, hemoglobin F Gly/Ala (G gamma:A gamma) heterogeneity was evaluated by electrophoresis on polyacrylamide gels. The mean G gamma was 70% in 19 newborns, similar to the published value of 73% obtained by amino acid analysis of the gamma CG-3 peptide. In 29 fetuses at 18-20-wk gestation, G gamma was 71%. The values were similar in normal fetuses and newborns and in those with hemoglobinopathies. The synthetic ratio of 3H-leucine-labeled G gamma:A gamma was identical to the ratio found in the globin protein accumulated by 20 wk. The proportion of G gamma was also identical in 6 paired samples, at 20-wk gestation and at birth. Thus, G gamma production does not decline with respect to A gamma in utero at the time of onset of the HbF:HbA switch.


Human myeloid precursors forming colonies in diffusion chambers expresses the Ia-like antigen.

Normal human bone marrow contains cells capable of forming myeloid colonies (CFU-DG) in fibrin clots in diffusion chambers placed in the peritoneal cavity of cyclophosphamide-treated mice. Evidence has accumulated indicating that these colony-forming cells represent an earlier stem cell than the granulocyte-monocyte precursor cell (CFU-C) assayed in soft agar. We provide data showing that these stem cells express the "Ia-like" or DR antigen. In the presence of rabbit Ia antiserum at a titer of 1:300, all CFU-DG were inhibited. Cytotoxicity was complement-dependent. Data are also presented that suggest that the megakaryocyte stem cell also expresses the Ia antigen.


Blood kinetics and in vivo chemotaxis of transfused neutrophils: effect of colllection method, donor corticosteroid treatment, and short-term storage.

To evaluate effect of collection technique and short-term storage on in vivo cell function, neutrophils were collected from 53 normal subjects by phlebotomy (PB), intermittent flow centrifugation (IFC), or filtration leukopheresis (FL), stored 0 or 1 day, labeled with 32P-diisopropylfluorophosphate, reinfused into the donor, and blood kinetics and/or skin chamber accumulation of labeled cells measured. The blood kinetics of unstored PB and IFC cells were similar; the kinetics of unstored FL cells were markedly abnormal. The percent of infused neutrophils localizing to the skin chamber was 0.1, 0.06, and 0.006 for unstored PB, IFC, and FL cells, respectively. One-day storage substantially decreased chamber accumulation of infused neutrophils. Donor steroid pretreatment had no effect on chamber results. Thus, in vivo chemotactic ability of IFC neutrophils is slightly impaired, whereas that of FL cells is severely impaired. One-day storage of either cell concentrate causes further cell damage.


Comparison of fibrinogen association with normal and thrombasthenic platelets on exposure to ADP or chymotrypsin.

Although 125I-fibrinogen becomes associated with washed platelets from normal human subjects during ADP-induced shape change and aggregation, 125I-fibrinogen did not become associated with washed plateletes from a thrombasthenic subject during ADP-induced shape change and the platelets did not aggregate. Platelets from control and thrombasthenic subjects were treated with chymotrypsin, which is known to degrade platelet membrane glycoproteins. More 125I-fibrinogen became associated with chymotrypsin-pretreated platelets from normal subejcts than with untreated platelets, and fibrinogen caused the enzyme-treated platelets to aggregate. 125I-fibrinogen did not become associated with chymotrypsin-pretreated thromobasthenic platelets, and fibrinogen did not aggregate them. Thus, there appears to be a defect in thrombasthenic platelets that prevents the association of fibrinogen with them.


Normal range of blood colony-forming cells (CFU-C) in humans: influence of experimental conditions, age, sex, and diurnal variations.

Blood colony-forming cells (CFU-C) and colony-stimulating activity obtained from feeder layers of peripheral blood leucocytes (leucocyte CSA) have been studies in 69 normal subjects by means of semisolid agar culture system. Groups of normal volunteers were selected according to sex and age (20 to 45 and older than 60 years) and the results compared. The mean number of circulating CFU-C was significantly lower  in young women (20-45 years old) than in males over 60 years of age, but no differences were found among the other age and sex groups. Leucocyte CSA did not significantly differ among these groups. In 5 young males the blood CFU-C did not show significant variations at 8 AM and at 4 PM of the same day. When the study was repeated in 18 subjects at longer time intervals, the number of colonies showed a maximum fivefold variation. The amount of plasma and polymorphonuclear granulocytes present in our culture system did not inhibit the colony growth. In most cases, double layer cultures grow a higher number of colonies than single layer, but feeder layers of some normal subject seem to inhibit the colony growth.


Lazy leukocyte syndrome.

A-35-year-old woman with a long-lasting history of neutropenia and recurrent infections was found to have defective neutrophil chemotaxis, random motility, and in vivo migration. Although the bone marrow granulocyte reserve was normal, the patient failed to release an appropriate amount of granulocytes after injection of etiocholanolone. These features are characteristic of the so-called "Lazy leukocyte syndrome". The clinical presentation of the five cases of this syndrome so far reported and its pathophysiological aspects are discussed.


[In vitro studies of whole blood and buffycoat-free packed cells in CPD-adenine with 1.5-fold glucose concentration and 0.4 mm adenine (author's transl)].

We studied a new CPD-adenine preservative with 1.5-fold of usual glucose concentration and 0.4 mM adenine during 6 weeks of storage in whole blood and buffycoat-free packed cells. Measurements of ATP and glucose indicated no necessity for increasing the glucose concentration in the standard CPD-adenine.


[Detection of development of resistance in the short-term test (author's transl].

By treatment of the mouse leukemia L 1210 with cytosinarabinoside (120 mg/kg per week) a tumour cell line was developed which was resistant to this cytostatic agent. It is possible, using the short-term test, to follow the development of resistance to cytosinarabinoside.


Effect of milk on mercury absorption and gut retention in rats.

The retention of 203Hg was studied six days after a single oral or intraperitoneal administration to six week old female albino rats fed rat's diet or milk. After oral administration rats on milk diet had a two times higher retention of mercury in the gut-free carcass and a 23 times higher retention in the gut than animals on rat's diet. Changes in diet had very little influence on mercury retention after intraperitoneal administration. The higher gut and carcass rentions of mercury in animals on milk diet could be prevented or reduced by transferring rats from milk diet to rat's diet several days after an oral dose of mercury. These results might be relevant for interpreting high gut and carcass retention after oral administration of some metals in suckling and changes which occur at weaning.


Disturbances in pulmonary mechanics during serotonin perfusion.

The effect of i.v. perfused serotonin (75 microgram.kg-1.min-1) on bronchomotor tone was assessed in dogs by mechanical studies, with the result in an increase in total lung resistance. The increased residual volume (RV), closing capacity (CC) and slope of phase III (nitrogen single-breath washout) as well as the reduction of the helium response at low lung volumes suggest a peripheral action of the drug. Because of the large increase in total lung resistance and the decreased dead space (VD), bronchoconstriction of large airways must also be present. Vagal tone inhibition is incomplete whether by volume history or bilateral vagotomy and could be limited mainly to a segment which is situated between the equal pressure point and the most peripheral airways: maximal flows during partial expiratory flow-volume manoeuvres (PEFV) are lower than during maximal expiratory flow-volume manoeuvres (MEFV) and the volume of isoflow is higher in PEFV than in MEFV manoeuvers, suggesting that full inspiration reduces the bronchoconstriction induced by serotonin. On the other hand, the bilateral vagotomy did not reverse CC, RV, slope of phase III or VD back to control values. Isoproterenol i.v. injection improved all physiological measurements almost to the level of control values: beta-adrenergic stimulating drugs seem to inhibit completely serotonin induced bronchospasm, at all levels of the bronchial tree.


The effects of long-term oxygen therapy on the EEG in patients with chronic stable ventilatory failure.

A homogeneous sample of 14 patients with advanced chronic bronchitis and emphysema complicated by secondary polycythaemia and pulmonary hypertension was examined. Eight patients who were receiving long-term oxygen therapy (LTO2) for 15-20 h in the 24 h day showed a significantly faster, that is more normal, frequency of the dominant EEG activity and a higher level of arterial oxygenation when breathing air than six similar patients not receiving LTO2. Acute administration of oxygen (2 1/min) for 15 min did not change the EEG pattern in either group of patients. The frequency of the dominant EEG activity in all 14 patients showed a significant positive correlation with the arterial oxygen saturation and negative correlation with the level of polycythaemia. Occurrence of intermixed EEG show activity theta and delta was positively correlated both with hypoxaemia and hypercapnia. The results suggest that the LTO2 in patients with chronic ventilatory failure has a beneficial effect on cerebral function as measured by EEG.


Lung function abnormalities in cystic fibrosis and changes during growth.

Static lung volumes (VC, TLC, FRC, RV), elastic recoil pressure of the lungs (Pst(1) at 100, 90, and 60% of TLC), static lung compliance [Cst(1)], specific airway conductance at FRC level (Gaw/TGVex), forced expiratory volume in the first second (FEV1), maximal expiratory flows (Vmax.) at 25 and 50% of VC and at 60% of TLC, and "upstream" airway conductance (Gus) at 60% of TLC were studied in 28 patients with cystic fibrosis, 5 to 25 years old, over a period of 1 to 5 years. The data were compared individually with normal values, related to body height in the form of regression equations and expressed in percentage of predicted values. From the indices assessing airway function, Vmax. at low lung volumes, Gus at 60% TLC, RV and RV/TLC were the functional parameters most consistently abnormal. Among the indices characterizing lung elasticity, Pst(1) at 60% TLC was the most abnormal. Generally, the values of the majority of lung function indices [VC, TLC, FRC, Pst(1)] declined during growth. Vmax. at all lung volumes and Gus at 60% TLC did not deteriorate with growth probably due to the great abnormality of these parameters already in young patients. It was also observed that lung function did not change significantly over a period of 1 to 5 years corresponding to a 10 cm increase in body height. However, over that period, lung function improved in some of the subjects, did not change in over 50% of the cases and deteriorated in the others.


[Proteins and enzymes in normal human bronchial washing fluids (author's transl)].

Six normal subjects, two of whom were heavy smokers, underwent broncho-alveolar and bronchial washings. The aim of our work was to compare the biochemical composition of these fluids. Quantitative measurements of total protein, IgG AND IgA were made, the percentage of IgA 7S among the IgA population was established, an immunoelectrophoretic study was carried out, and glycosidase and protease activities were determined. In a given subject, the bronchial washing always showed more IgA, 11S and more concentrated glycosidase activities than the broncho-alveolar washing; the latter had higher values for IgG and protease activities, the most important being chymotrypsin-like activity. In both fluids, IgA 11S represented the main part of IgA population.


Effect of CO2 on the systemic and coronary circulations and on coronary sinus blood gas tensions.

The responses to hypocapnia and to hypercapnia of both the systemic and the coronary circulations have been studied in the dog during intermittent positive pressure ventilation under halothane anaesthesia. In the absence of significant variations of myocardial contractility, the reduction of cardiac output, because of hypocapnia, was determined by the increase of systemic vascular resistance, while the increase of cardiac output because of hypercapnia was determined by an increase of heart rate without change of stroke volume. The alterations of coronary blood flow (reduction following hypocapnia, augmentation following hypercapnia) were considerably larger than the changes of cardiac output and of myocardial oxygen consumption. Such disparity between oxygen supply and demand, together with the effect of pH and PCO2 on the oxyhaemoglobin dissociation curve led to a marked reduction of coronary sinus PO2 in response to hypocapnia and a marked increase of coronary sinus PO2 in response to hypercapnia. The data suggests that PCO2 (or respiratory alterations of pH) may have a direct effect on the regulation of coronary blood flow. The low coronary sinus PO2 observed at hypocapnia may suggest the risk of myocardial ischaemia.


Pulmonary function in systemic lupus erythematosus patients without respiratory symptoms.

Pulmonary function was studied in 22 patients with systemic lupus erythematosus without pulmonary clinical symptoms. The most striking features were: a) a restrictive functional pattern with hyperinflation, characterized by a decreased vital capacity and increased residual volume; b) alteration of the elastic properties of the lung, with increased pulmonary elastance; c) impairment of the alveolar-capillary gas transfer capacity, with very significant changes of the CO diffusion and arterio-alveolar gradients for O2 and CO2. No marked differences were found in functional disturbance among patients in the active or inactive phase of the disease.


Primary alveolar hypoventilation (Ondine's curse syndrome) in an infant without external arcuate nucleus. Case report.

A five month old boy suffered from primary alveolar hypoventilation, with attacks of apnea during sleep (Ondine's curse syndrome). The ventilation did not increase when PACO2 was increased. However, it decreased during hyperoxia. This indicates a strong peripheral chemoreceptor drive and a dysfunction of the central chemoreception. The infant died from circulatory failure following an aspiration pneumonia. Autopsy revealed the absence of the external arcuate nucleus, which may be involved in the central chemocreception.


[A rotative control plate for separation of inspired and expired gases (author's transl)].

Some drawbacks of the valve chamber are well known: high flow gas resistance, sensitivity to position and to condensation of water vapour, vibrations of the valve especially at high flow rate. To avoid these defects a rotative control valve separating inhaled and exhaled gases is described. A rotative plate shuts off one of two large ports and separates expired and inspired gases. The rotation of the plate is controlled by a sensor signal, which may be delivered by a pneumotachograph and switches on and off the electrical supply of the motor. The major characteristics of this valve are: its small dead space (11 cm3), a negligible error in the volumes which are to be displaced through either of the two ports, a total insensitivity to water condensation, a very low flow resistance and an insensitivity to position and displacement. This device may be adapted to infants and neonates.


[Measurement of binary diffusion coefficients of oxygen and another gas (author's transl)].

Diffusion coefficients between oxygen and seven other gases (air, N2, He, Ne, Ar, CO2, SF6) have been measured using a set-up derived from Loschmidt's tube. Measurements have been made continously with an electrochemical cell sensitive to oxygen. The causes of errors are reviewed. The influence of gravity is discussed.


[Study of mucins of two sinus mucoceles (author's transl)].

Glycoproteins were isolated in the contents of two sinus mucoceles by ionic exchange and gel filtration chromatography. These glycoproteins are of the mucin-type and characterized by their richness in carbohydrate, a low amino acid content with a strong proportion of hydroxy amino acids. However, they differ largely by their peptide axis, the length of the carbohydrate chain and their acidity, which is in relation with the presence of sialic acid residue and of sulfate groups. The least acidic mucins are the richest in sialic acid residue and in threonine but have the shortest carbohydrate chains while the most acidic are rich in sulfate, richer in serine and have longer carbohydrate chains. The wall of these two mucoceles has only one type of cell capable of synthetizing the glycoproteins: the epithelium goblet cells revealed by the PAS and the alcian blue at different pH. Glandular formations have never been found in the chorion.


Muscimol antagonism of morphine analgesia in rats.

1 Muscimol, a gamma-aminobutyric acid (GABA) receptor agonist, when injected intraventricularly antagonizes the antinociceptive effect of morphine given either subcutaneously or intraventricularly. The antagonistic effect of muscimol on morphine analgesia appears to be linearly related. 2 This finding provides support for the view that a GABA-ergic system is involved in morphine analgesia.


Electrophysiological actions of mexiletine (Kö1173) on canine Purkinje fibres and ventricular muscle.

1 The effects of mexiletine (Kö1173) were investigated in canine isolated cardiac Purkinje fibres and ventricular muscle with microelectrodes. Some Purkinje fibres were depolarized by mechanical stretch to induce spontaneous activity with slow upstroke velocity. The preparations were stimulated at rates of 1, 2, 3 and 4 Hz. The drug concentrations tested were 0.4, 2 and 10 mug/ml in Tyrode solution (KCl = 5.4 mM).2 The ;therapeutic' drug concentration (2 mug/ml) shortened action potential duration and effective refractory period of Purkinje fibres, the effect being pronounced at lower stimulation rates. In ventricular fibres, action potential duration changes were not consistent while the effective refractory period was prolonged.3 In depolarized Purkinje fibres showing automatic activity, the drug (0.4 or 2 mug/ml) depressed phase 4 depolarization and reduced the firing rate without changing maximum diastolic potential. However, when depolarized Purkinje fibres were electrically driven at a constant rate, the maximum diastolic potential became more negative with a concomitant decrease of pacemaker slope and increase of maximum rate of rise (V(max)) of action potentials.4 Moderate (2 mug/ml) to high (10 mug/ml) concentrations of the drug depressed V(max) in Purkinje fibres stimulated at 2 Hz by 12 and 42% respectively and depressed ;membrane responsiveness'. The decrease in V(max) depended upon the stimulation rate, being minimum at the lowest (1 Hz) and maximum at the highest (4 Hz) stimulation rate.5 The drug (2 mug/ml) improved V(max) of the earliest propagated premature action potentials by shifting the takeoff potential to more negative levels in both Purkinje and ventricular fibres.6 Membrane conductance in fibres mounted in a single sucrose gap chamber was increased by the drug (2 mug/ml) in both fibre types in normal and in Na(+)-deficient solutions. This increase was attributed to an increase in membrane K(+) permeability produced by the drug.7 All these effects are similar to those of lignocaine, diphenylhydantoin or aprindine, and can explain the antiarrhythmic action of mexiletine.


Relaxation of isolated taenia coli of guinea-pig by enantiomers of 2-azido analogues of adenosine and adenine nucleotides.

1 2-Azido photoaffinity analogues of adenosine 5'triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), and adenosine have been synthesized and tested on guinea-pig taenia coli. 2 2-Azido-ATP and 2-azido-ADP were approximately 20 times more potent than ATP as relaxants of taenia coli, and required prolonged washout times before recovery of the muscle. 3 2-Azido-AMP and 2-azidoadenosine were 2 to 12 times more potent than ATP, but took much longer (up to 100 s) to reach maximal relaxation. This behaviour is different from that of AMP and adenosine which were much less potent than ATP. 4 L-Enantiomers of adenosine and adenine nucleotides were also tested. L-ATP and L-ADP were 3 to 6 times less potent than ATP and ADP, and L-AMP and L-adenosine were inactive. 2-Azido-L-ATP and 2-azido-L-ADP were approximately 120 times less potent than 2-Azido-ATP and 6 times less potent than ATP as relaxants of taenia coli. 2-Azido-L-AMP and 2-azidio-L-adenosine were almost inactive. 5 2-Azido derivatives are photolysed by u.v. irradiation to reactive intermediates. 2-Azido-ATP and 2-azidoadenosine might be suitable photoaffinity ligands for labelling putative P2 and P1 purine receptors respectively. 2-Azido-L-ATP and 2-azido-L-adenosine could be useful controls for nonspecific labelling.


Influence of fasting and cimetidine on the relationship between ulcerogenic and anti-inflammatory properties of indomethacin.

1 Further studies have been carried out on the relationship between ulcerogenic and anti-inflammatory properties of indomethacin in the rat. 2 Fasting, which increases gastric and reduces intestinal lesions, enhances the anti-oedema properties of indomethacin. 3 The presence of intestinal lesions, greatly increases the anti-oedema properties of indomethacin through a mechanism(s) unrelated to the specific pharmacological properties of this drug. 4 Studies with cimetidine, have shown that the enhancement of anti-oedema effects produced by fasting are due to specific pharmacological properties of indomethacin rather than to non specific effects related to the presence of gastric ulcers. 5 The greater anti-inflammatory effects of indomethacin in fasted as compared to fed animals must be attributed to the greater amount of indomethacin available for tissue distribution rather than other mechanisms associated with free fatty acid mobilization. 6 In view of ineffectiveness in preventing intestinal lesions, the use of cimetidine for prevention or reduction of indomethacin-induced gastrointestinal disturbances in humans is contraindicated.


Analysis of anomalous pKb values for metiamide and atropine in the isolated stomach of the mouse.

1 In the isolated, lumen-perfused, stomach preparation of the mouse, metiamide was found by kinetic analysis to behave like a simple competitive antagonist of histamine-stimulated acid secretion. However, the pK(B) estimate of 5.08 was significantly lower than that found in guinea-pig atrium (6.0) or rat uterus (6.1) suggesting that H(2)-receptors might not be homogeneous.2 A similar analysis showed that atropine also behaved like a simple competitive antagonist of bethanechol-stimulated acid secretion and the estimated pK(B) (7.65) was significantly lower than the standard estimate of this parameter in guinea-pig ileum (9.0). Either the muscarinic cholinoceptors in mouse stomach were also anomalous or the preparation was introducing a systematic error. Lumen perfusion might distort this type of kinetic analysis by allowing steady-state conditions but not true equilibrium to develop at the receptor compartment due to loss of antagonist into the gastric secretion. Drug interactions at receptors in the muscle layers of the stomach would be expected to be much less sensitive to this error.3 When the atropine-bethanechol interaction was measured on the contraction of the isolated, lumen-perfused, stomach of the mouse the necessary conditions for simple competition were not met even though the sensitivity to atropine was obviously increased. The criteria for the expected simple competition were being obscured by events at low antagonist concentrations. Alterations in agonist or antagonist concentrations could be more or less eliminated so that physiological antagonism, perhaps by release of 5-hydroxytryptamine, was considered. This was supported, to some extent, by finding that, when stomachs from animals pretreated with reserpine were used, the kinetic analysis was normalized and gave a pK(B) of 8.99. Apparently, the muscarinic receptors in mouse stomach are homogeneous with those in other tissues.4 Therefore, we conclude that our results no more point to heterogeneity among histamine receptors than they point to differences in muscarinic cholinoceptors because this type of kinetic analysis can be readily distorted by special features of the measuring system.


Some properties of 5-hydroxytryptamine receptors in the hindquarters of the rat.

1 The rat hindquarter preparation, as described, responds with reproducible vasoconstriction to noradrenaline and tryptamines. 2 The receptors involved in these responses are distinct. 3 Evidence of heterogeneity of tryptamine receptors was not obtained. 4 The 5-hydroxytryptamine (5-HT) antagonists, methysergide and cyproheptadine, although very potent, displayed antagonism of a non-competitive type whereas a series of phenothiazines and phentolamine displayed competitive antagonism against 5-HT. 5 For the phenothiazines the order of increasing potency was promazine less than chlorpromazine less than triflupromazine.


Development of tolerance to the prolongation of hexobarbitone sleeping time caused by cannabidiol.

1 The effects of acute and subacute cannabidiol (CBD) administration on hexobarbitone sleeping time and on some constituents of the hepatic microsomal drug-metabolizing system were assessed in the mouse.2 Acutely administered CBD prolonged sleeping time; but with subacute treatment, tolerance to the effect rapidly developed.3 Brain hexobarbitone concentration upon awakening was unchanged by either acute or subacute CBD treatment, which suggests that neither the prolongation of sleeping time nor the tolerance is the result of a change in sensitivity of the central nervous system to the barbiturate.4 Acute CBD treatment increased the half-time of hexobarbitone in the brain, which returned toward normal with the development of tolerance.5 Acutely, CBD caused a 30% decrease in hepatic cytochrome P-450 level; with tolerance, the cytochrome concentration returned to normal.6 The evidence suggests that the CBD-induced prolongation of barbiturate sleeping time and the tolerance to this effect are the result of changes in the rate of drug metabolism, which are related to changes in the amount of cytochrome P-450.7 The effects of CBD on the hepatic microsomal drug-metabolizing enzyme system are different from those attributed to SKF 525-A and piperonyl butoxide because the cannabinoid does not decrease cytochrome P-450 quantitatively by complex formation, it does not produce a recovery overshoot in the cytochrome concentration and, finally, it does not cause an induction of the hexobarbitone-metabolizing enzymes.


Interactions of (+)-amphetamine and chlorpromazine on neurones in the lower brain stem of the rat.

1 The ability of chlorpromazine to antagonize the effects of iontophoretic application of (+)-amphetamine to single neurones in the medulla and lower pons of anaesthetized rats has been studied. 2 Chlorpromazine, administered systemically or iontophoretically, consistently and specifically antagonized the excitatory actions of (+)-amphetamine, but not those of noradrenaline on the same neurone. 3 It is concluded that chlorpromazine reduces the effect of (+)-amphetamine by a presynaptic mechanism. 4 (+)-Amphetamine did not mimic the prolonged inhibitory response of some neurones to noradrenaline but often excited these neurones and chlorpromazine blocked these excitatory responses to (+)-amphetamine.


Coronary anaphylaxis in vitro.

1 The reactivity of isolated coronary arteries and cardiac veins of the calf to selected chemical mediators of anaphylaxis and to sensitizing antigen (horse plasma) was studied. 2 Both the coronary arteries and cardiac veins contracted to bradykinin, 5-hydroxytryptamine (5-HT), prostaglandin E2 (PGE2), PGF2 alpha, histamine and carbachol. 3 Isoprenaline and PGE1 relaxed vessels which had been partially contracted by PGF2 alpha, PGE2, histamine, 5-HT, bradykinin, carbachol or antigen. 4 Horse plasma (antigen) contracted coronary vessels obtained from sensitized calves, but not from control calves. Subsequent antigen 'challenge' produced 'densensitization' (tachphylaxis). After 1 or 2 h of rest, the anaphylactic response partially recovered although there was no change in tissue reactivity to the exogenous agonists. 5 Specific doses of atropine, mepyramine (H1-blocker) and methysergide (5-HT antagonist) did not modify the anaphylactic reaction in coronary arteries, suggesting a negligible role for these biogenic amines. 6 Compound PRD-92-EA (a new anti-allergic agent) exhibited non-specific receptor blocking activity towards histamine, 5-HT and carbachol and inhibited the coronary anaphylactic reaction.


The cardiovascular pharmacology of 7-propyl-theo-phylline-dopamine (D4975); comparison with dopamine and dobutamine.

1 The effects of a newly developed dopamine-xanthine derivative, 7-propyl-theophylline-dopamine (D4975), have been examined in cats anaesthetized with sodium pentobarbitone. When administered intravenously (in doses as low as 0.5 to 1.0 micrograms/kg) it increased systemic arterial pressure, left ventricular (LV) dP/dtmax, dP/dt at fixed ventricular isovolumic pressures and cardiac output. Heart rate effects were minimal. 2 D4975 was about 5 times more active than dopamine or dobutamine in elevating LV dP/dtmax or dP/dt at common peak isovolumic pressures (CPIP) and about 10 times more active than dopamine at increasing systemic arterial blood pressure. The effects of D4975 were also more prolonged than those of the other two agents. 3 The effects of D4975 on LV dP/dtmax were greatly reduced by the prior administration of propranolol. D4975 has no effect on peripheral beta 2-adrenoceptors. 4 It is suggested that the effects of D4975 on the myocardium involve both beta 1-adrenoceptor stimulation and inhibition of phosphodiesterase and that the marked and prolonged pressor response is due to resistance to enzymatic breakdown by monoamine oxidase. 5 The results suggest that D4975 might prove valuable in the treatment of the hypotension and reduced myocardial contractility of shock, especially as it is possible to select a dose that increases LV dP/dtmax without increasing either heart rate of systemic arterial pressure.


Presynaptic inhibitory action of 5-hydroxytryptamine in dog isolated saphenous vein.

1 The effect of 5-hydroxytryptamine on contractile responses to sympathetic nerve stimulation has been studied in the dog isolated saphenous vein.2 Electrical stimulation (0.1 to 10 Hz) of dog saphenous vein strips produced frequency-dependent contractions. Contractions produced by stimulation at 2 Hz were almost completely blocked by tetrodotoxin (3.1 x 10(-8) mol/l) or phentolamine (5.0 x 10(-6) mol/l) but mecamylamine (5.0 x 10(-6) mol/l) had little effect. This suggests that the contractions were mediated predominantly through noradrenaline release from postganglionic noradrenergic nerves.3 Contractions produced by intermittent electrical stimulation at 2 Hz were inhibited by 5-hydroxy-tryptamine (1.0 x 10(-9) to 1.0 x 10(-7) mol/l) in a concentration-dependent manner whilst contractions induced by exogenous noradrenaline were not affected.4 The inhibitory action of 5-hydroxytryptamine was most marked at low frequencies of stimulation and with low pulse numbers.5 High external calcium concentrations (3.9 and 5.2 x 10(-3) mol/l) reduced the inhibitory action of 5-hydroxytryptamine.6 Cyproheptadine (1.0 x 10(-8) mol/l to 1.0 x 10(-6) mol/l) or morphine (1.0 x 10(-7) mol/l to 1.0 x 10(-5) mol/l) did not antagonize the inhibitory action of 5-hydroxytryptamine. Methysergide (1.0 x 10(-7) mol/l) slightly reduced the contractions produced by electrical stimulation and only weakly antagonized the action of 5-hydroxytryptamine.7 It is suggested that a 5-hydroxytryptamine receptor exists presynaptically in the dog isolated saphenous vein strip and that stimulation of this receptor by low concentrations of 5-hydroxytryptamine inhibits the release of noradrenaline from noradrenergic nerves. This receptor type is resistant to blockade by ;classical' 5-hydroxytryptamine antagonists.