Semipermeable membrane techniques in quantitative enzyme histochemistry. Non-structurally bound, partially structurally bound or weakly structurally bound enzymes diffuse out of sections during the histochemical incubation period. Fixation of sections does not help to prevent diffusion since the enzymes may be inactivated by their chemical reaction with the fixative. Moreover watery fixatives cause partial leakage of enzymes into the fixative solution. The inclusion of macromolecular substances in the incubation media only partially prevents the leakage of enzymes. In the technique discussed here a semipermeable membrane is interposed between the incubating solution and the tissue section. Because only molecules with a molecular weight of 20 000 can penetrate the membranes, diffusion of enzymes is prevented, whereas substrate molecules and other components necessary for the staining reaction diffuse through the membrane. This technique is suitable for the histochemical demonstration of activity of oxidoreductases, transferases, hydrolases and isomerases. Particular attention is paid to how far semipermeable membrane methods are suitable for quantitative histochemical studies of enzymes.


Criteria for the validation of quantitative histochemical enzyme techniques. Some practical criteria are suggested for establishing the precision, reproducibility, validity and specificity of quantitative histochemical techniques used for assaying the activities of enzymes in single cells and tissue sections. To be valid, a technique should ideally pass 12 tests. Principally these involve proving that the mean absorbance or fluorescence of the specific final reaction product (FRP) is related to section thickness, incubation time, substrate concentration and the concentration of enzyme in situ. However, the formation of appreciable amounts of non-specific FRP may interfere in the determination of the true enzyme activity. This and other difficulties are illustrated with data obtained from an investigation of Meijer's semipermeable membrane technique for assaying acid phosphatase in unfixed sections of muscle.


Microphotometric determination of enzyme activities in cryostat sections by the gel film technique. Use of the gel film technique in microphotometric determinations of enzyme activity is described. The microscope photometer is computer-controlled. It is programmed to deal with repetitive measurements at up to 12 selected positions within a tissue section and to evaluate recorded reaction rates statistically. Films of polyacrylamide gel with entrapped glucose-6-phosphate dehydrogenase are used as a model to demonstrate the correlation between local enzyme activity and the microphotometrically determined reaction rate. Enzyme activities at different positions in the same tissue section are determined and compared. Activity profiles of five enzymes (glutamate dehydrogenase, lactate dehydrogenase, malate dehydrogenase, succinate dehydrogenase, NAD-dependent tetrazolium reductase) in the liver are presented and show non-uniform intra-acinar distribution patterns. These results are interpreted in the light of the metabolic zonation of the hepatic acinus. Further applications of the method are discussed.


The effect of kallikrein on central effects of acetylcholine in rats receiving indomethacin and prostaglandin E1. Kallikrein given in combination with acetylcholine (ACh) increased the central inhibitory action of ACh as measured in the Lat's test, duration of thiopental sleep and inhibition of electrogenic convulsions. Indomethacin aboished the potentiating effect of kallikrein on these actions of ACh, PGE1 did not play a significant role in the influence of kallikrein on the central action of ACh. However, inhibition of prostaglandin synthesis with indomethacin plays an important role in the interaction of kallilkrein and ACh.


Quantitative cytochemical analysis of (single) cultured cells. Human fibroblasts or amniotic fluid cells can be cultivated in special dishes with a bottom of thin transparent plastic foil. After quick freezing and freeze-drying small groups of cultured cells or single cells can be isolated by dissecting small pieces of plastic foil under the stereomicroscope. These can be incubated in (sub)microlitre volumes of substrate and the absorbance, fluorescence or radioactivity can be measured and expressed per cell. When absorbance is measured with a microscope spectrophotometer in 1-10 microliter, microcuvettes, the minimum amount of coloured product that can be determined is of the order of 10(-11) moles. Incubation under paraffin oil in 0.05 microliter of substrate, followed by fluorescence measurements in 1-5 microliter with a microscope fluorometer, allows down to 10(-14) mol of methylumbelliferone, which is the end-product in many analyses of lysosomal enzymes, to be detected. (Re)cycling procedures have an even greater sensitivity (10(-15)-10(-19)mol) but they are more complicated and limited to NAD(P)(H)-dependent reactions. Several radiometric procedures have also been adapted for the analysis of small numbers of cultured cells but most of them still require 10(4)-10(5) human fibroblasts. These microtechniques allow rapid prenatal diagnosis of at least 20 different genetic metabolic diseases to be made within 7-14 days after amniocentesis at the 14th-16th week of pregnancy. Enzyme assays on single cultured cells have also enabled complementation studies to be done on heterokaryons after hybridization of different types of mutant fibroblasts, as well as investigations of the intercellular exchange of lysosomal enzymes between normal and mutant cells.


Microdensitometry.

Microdensitometry. Microdensitometry, or microspectrophotometry, is the measurement of the concentration or mass of a chromophore in microscopically defined regions, and is governed by well-established laws of physics. Initially it proved of value in Feulgen cytophotometry of the relative amounts of DNA in individual nuclei of isolated cells. It has now achieved wide applicability to the measurement of cellular biochemical activity by means of stoichiometric chromogenic reactions. The validity of some of these measurements has been confirmed by comparative biochemical and microdensitometric assays. Thus microdensitometry, even of heterogeneously distributed chromophores, can be precise, provided that the technique is operated with due regard to its limitations within the laws of physics. The potential errors include: variation in thickness of tissue sections (path-length); scatter; glare; diffraction; occlusion of light by optically dense particles; and the inhomogeneity error. However, under correct conditions for the cytochemical reactions and for operating the microdensitometer, these potential errors become small or negligible. Thus the highly sensitive cytochemical bioassay of thyrotropin exemplifies the precision that can be achieved by controlled use of microdensitometry.


The constant proportion enzyme group concept in the selection of reference enzymes in metabolism. Comparative analyses of enzyme activity patterns reveal groups of enzymes with constant proportions and enzymes with variable proportions of their maximum activities. Constant proportion groups comprise enzymes of unbranched metabolic sequences or functionally related pathways. Ratios of constant proportion groups reflect metabolic correlations, which may be used as discriminative magnitudes of  metabolic specialization. Comparison of closely related muscles reveals that differences in the absolute levels of the constant proportion group enzymes of glycolysis parallel differences in maximum glycolytic flux rates. This holds for near-equilibrium as well as for non-equilibrium enzymes. In any case, maximum enzyme activities are significantly higher than maximum metabolic flux rates. Maximum enzyme activities therefore do not permit conclusions on maximum metabolic capacities to be drawn. They may, however, be compared in closely related tissues or different metabolic conditions of a given tissue as relative magnitudes of maximum flux rates. Reference enzymes of constant proportion groups as well as of other enzymes which are representative of distinct metabolic pathways may be used in this sense for the evaluation of enzyme activity patterns. Selection of appropriate enzymes depends on the aim of the intended study, on a thorough knowledge of their individual properties, and on the possibility of measuring their maximum activity under reproducible conditions.


Use of enzyme activities as indices of maximum rates of fuel utilization. It can be shown theoretically and experimentally that the maximum activities in vitro of enzymes that catalyse near-equilibrium reactions in vivo must be considerably higher than the maximum flux through that pathway. Consequently, the activities of such enzymes cannot provide quantitative information on the maximum possible flux through a pathway. On the other hand, the maximum activity of an enzyme that catalyses a non-equilibrium reaction in vivo may provide quantitative information. Such possibilities must be tested experimentally. Thus the maximum flux through a given metabolic pathway is measured (or calculated) and compared with the maximum in vitro activities of enzymes that catalyse non-equilibrium reactions in that pathway. Catalytic activities similar to the flux suggest that such enzymes may be useful as flux indicators. For example, phosphorylase or phosphofructokinase activities provide a quantitative indication of maximum flux through glycolysis-from-glycogen (i.e. anaerobic glycolysis); hexokinase activities provide a quantitative indication of maximum flux through glycolysis-from-glucose; 2-oxoglutarate dehydrogenase activities provide a quantitative indication of maximum flux through the citric acid cycle. The advamtages of the use of enzyme activities in this manner include simplicity, general applicability to pathways, tissues and animals, and minimum intervention (particularly in larger animals including the human species). One disadvantage is that the properties of the enzyme must be known in detail before an assay that gives maximum activities can be developed, and the properties of enzymes that catalyse non-equilibrium reactions may be complex. These considerations emphasize the dangers of quantitative interpretation of the maximum flux through pathways from 'near-equilibrium' enzymes or from 'non-equilibrium' enzymes whose properties have been inadequately studied.


The place of histochemical techniques in toxicology, pharmacology and pathology. The uses of histochemistry in pathology (experimental and clinical), pharmacology and toxicology are considered and their restrictions are discussed. In time-course studies of drug effects in animals the research worker must choose an appropriate histochemical technique for evaluating the changes seen in the tissues, if any, during the study. Acid phosphatase is shown to be a marker enzyme which may be active in both cell multiplication and tissue necrosis; results obtained with it must therefore be interpreted with caution. The need for histochemical techniques to match experimental conditions is emphasized. The restrictions of fixation and tissue preparation are also emphasized. Histochemical and biochemical techniques should be used together where appropriate, and the results should be analysed carefully. Indiscriminate use of histochemistry and quantitation is deplored.


Tissue stabilizer methods in histochemistry. Quantitative studies in the 1960s established that the tissue disruption and enzyme loss which occurs when unfixed cryostat sections are incubated could be prevented with high concentrations of polyvinyl alcohol without inhibition of enzyme activity. This use of polymeric stabilizers has been largely confined to studies of 'soluble' dehydrogenases in tissue sections. However, optimum conditions for 'soluble' enzymes in cut sections may not be ideal for membrane-bound enzymes or for whole cells, where an over-stabilization of membranes can lead to restricted entry of reagents and thereby low activities. Lower concentrations, or other stabilizers such as Ficoll (a synthetic polysucrose) and collagen polypeptides, have been used in such cases. Suggested criteria for a tissue stabilizer are: (i) The stabilizer should be chemically inert, of defined and constant composition, and generally available; (ii) The tissue must remain structurally intact during the incubation, and the final preparation should look 'clean' and have the proper morphology; (iii) The component being assayed must remain inside the section, and not diffuse into the incubation medium. Ideally, it and any reaction product should remain at their original loci, although it may not always be possible to verify this; (iv) Recorded activities should be comparable to those found in biochemical systems under similar conditions.


Clinical significance of monitoring plasma levels of psychotropic drugs. The possible clinical significance of plasma level monitoring of psychotropic drugs in psychotic patients is described. In particular, data obtained with children and 'resistant' psychotic patients are presented. The results in children indicate the existence of a good relationship between side-effects and haloperidol plasma levels as well as between adverse effects and chlorimipramine plasma levels. Furthermore, an age effect on haloperidol clearance could be shown. Relationship between haloperidol and chlorimipramine concentration and effects could be observed for tics and enuresis respectively but not for psychotic reactions. Data in adult patients illustrate on the one hand possible causes of variability in plasma levels of haloperidol and, on the other hand, the fact that poor bioavailability is not the cause of lack of response in 'resistant' schizophrenic patients.


Principles of pharmacokinetics.

Principles of pharmacokinetics. A compartmental representation of the body is often used to explain the principles of pharmacokinetics, where the compartments are purely hypothetical and bear no relationship to real tissues or organs. In recent years a more physiological approach has been emphasized. Differences in derived kinetic parameters, such as elimination half-life, volume of distribution and clearance, as a function of drug, patient and route of drug administration, are more easily understood when related directly to primary physiological variables, such as blood flow, enzyme activity and drug binding. In turn this allows a convenient conceptual framework for describing and predicting both unbound and total drug concentrations in many clinical situations.


Adrenergic and serotonergic mechanisms in depression and their response to amitriptyline. Our investigations into the chemical pathology of the affective disorders have indicated that depressed patients not only have significantly reduced rates of accumulation of 5-hydroxytryptamine (5-HT) into their blood platelets but their peripheral alpha-adrenoreceptors are supersensitive. Investigations into the mode of action of amitriptyline have centred on these abnormal adrenergic and serotonergic mechanisms in depressed patients. We have not detected any significant relationship between blood platelet 5-HT re-uptake inhibition and therapeutic response to amitriptyline in depressed patients, although there is a significant correlation with plasma levels of the drug. It is interesting to note that nortriptyline, the major metabolite of amitriptyline, blocks the alpha-adrenoreceptor but the degree of blocking of this supersensitive receptor is significantly correlated to poor outcome. Amitriptyline does not appear to correct these abnormal mechanisms in depressed patients. These results are discussed with reference to other pharmacological actions of amitriptyline and other antidepressant drugs.


The role of plasma level monitoring of tricyclic antidepressant drugs as an aid to treatment. Use of the tricyclic antidepressant drugs is the most common pharmacotherapeutic approach to the treatment of depression. It is a common clinical experience to find that a fair proportion of patients fail to show a satisfactory response and that others complain of side-effects. Important factors which influence this situation are the diagnostic criteria used to select patients for drug treatment, the dosage prescribed and individual compliance. Measurement of plasma drug concentrations has been proposed as a more rational way of increasing the efficacy of antidepressant medication and avoiding toxicity. A number of studies have shown a correlation between plasma concentrations of these drugs and clinical effects, but the relationship is far from simple. With amitriptyline and nortriptyline there is good evidence for a 'therapeutic window' within which maximum antidepressant action is obtained. Many patients being treated with these drugs have plasma levels outside recommended therapeutic ranges. Experience in our department has shown that there are a number of clinical situations where routine plasma level monitoring of selected antidepressants is of value: (1) inadequate clinical response; (2) side-effects/toxicity; (3) complicating medical conditions; (4) suspected poor compliance; and (5) long-term therapy. Such measurements are a relatively simple and inexpensive way of maximizing the benefits of drug therapy and a means of tailoring drug dosages to suit individual requirements.


Clinical application of the monitoring of anticonvulsant drug levels. The drug treatment of epilepsy poses considerable problems, including the high prevalence and early age of onset of seizures, the relatively poor prognosis in many patients, prolonged polypharmacy, chronic toxicity, and uncertainty of the relative efficacy of individual drugs. The application of recent knowledge of the clinical pharmacology of the major anticonvulsants offers a partial solution to several of these problems. Although there is no therapeutic range for any drug applicable to all patients, a more simple rational and effective approach to treatment is possible with the guidance of serum level monitoring. In new referrals, there is considerable potential for monotherapy, and the avoidance of polypharmacy and chronic toxicity. Reduction in polypharmacy in chronic patients is more difficult, but in many can be achieved with reduction in toxicity, and sometimes improved seizure control. Further studies will provide a clearer picture of the limits to modern anticonvulsant therapy, the relative efficacy of individual drugs, and the potential for improved long-term prognosis.


The logistics of drug monitoring.

The logistics of drug monitoring. Although opinions differ to some extent there is increasing belief in the value of monitoring plasma levels for effective therapy with neuropsychiatric drugs, especially with anticonvulsants. Monitoring should not be on a comprehensive and routine basis, but should be selective and discriminating. In these circumstances the expenditure incurred on the laboratory operations involved might work out for Britain at about pounds 5 million per year. This figure should be compared to a total annual expenditure from the prescribing of neuropsychiatric medication amounting to an estimated pounds 40 million per year. The benefits thus achieved in patient care, together with the possible economies in prescribing, could well merit this monitoring exercise. In terms of personnel and administration, the laboratory facilities could be organized on a regional, or on a district general hospital, basis.


Drug concentrations in neuropsychiatry: alternative approaches. The practical value of measuring plasma concentrations is to optimize treatment in order to attain the best balance in each particular patient between wanted clinical therapeutic effects and unwanted adverse and side-effects. This increase in treatment efficacy can be concurrent--that is, the treatment is monitored and the dosage changed as necessary--or predictive, where the results of a test dose can be used to calculate the appropriate dosage. Wanted effects include: (1) the attainment of adequate drug concentrations for the minimum period of time necessary, as in the use of antibiotics; (2) the suppression of symptoms, as in the use of the benzodiazepines in anxiety states; (3) the use of drugs to improve function, e.g. levodopa in Parkinsonism; (4) drugs are used to prevent episodes of illness; and (5) complex suppression of symptoms, as with the antidepressives and antipsychotics. The biological alternatives to plasma level monitoring depend on establishing an empirical relationship between the putative monitor and the clinical response. Such measures avoid the problem of estimation of drug concentration at the receptor. Examples include monoamine oxidase activity in platelets, the uptake of amines into platelets, neuroendocrine measures such as prolactin concentrations, the electroencephalogram, and peripheral measures such as pulse rate, pupil size and tremor.


Drug concentrations in neuropsychiatry. Methodological pitfalls: the influence of experimental design on results. The valid study of relationships between pharmacokinetic measurements and clinical effects of psychotropic drugs depends on: (i) analytical methods for the drugs; (ii) the fluid assessed and pharmacokinetic derivations; (iii) clinical assessments and the nature of psychiatric illness; and (iv) statistical work. Standard problems with analytical methods include lack of specificity, unjustified claims for sensitivity, and failure to recognize metabolites as potential analytical contaminants and compounds for separate study. Problems with pharmacokinetic derivations include inappropriate calculations and incorrect assignment of terms such as 'half-life'. Clinical difficulties mostly relate to variations between patient groups, selection procedures and rating methods, and to timing of samples. Statistical controversies concern the calculation of metabolite ratios, pooling of data from drugs and their metabolites, and abuse of statistical techniques. These methodological problems are illustrated by reference to work with phenothiazines, tricyclic antidepressants, lithium, benzodiazepines and anticonvulsants.


Interpretation of drug levels: relevance of plasma protein binding. Many centrally acting drugs bind extensively to plasma proteins, particularly albumin. It is generally the free concentration rather than the total concentration which determines the intensity of pharmacological action and the distribution and rate of elimination of a drug. Measurement of the total plasma concentration may therefore give a false idea of the amount of active drug available. Furthermore, variation in the degree of binding from one subject to another, and displacement of drug molecules by a second drug, may complicate the interpretation of serum levels when both bound and free drug are measured together. The strict use of therapeutic ranges of serum levels may therefore be harmful when a larger than normal proportion of the drug is free. In theory, monitoring the free concentration would have advantages, but on a routine basis this is not practical at present for technical reasons. Cerebrospinal fluid is an ultrafiltrate of plasma but lumbar puncture for routine monitoring purposes cannot be justified. Monitoring salivary concentrations is a practical alternative but for some drugs variation in the degree of ionization of the compound may make salivary levels unreliable.


Quality control of drug assays.

Quality control of drug assays. Most routine drug assay work is done by clinical chemists who, in general, are well aware of the importance of regular quality control checks. Few, however, have had extensive experience in analytical techniques for drugs, such as gas chromatography, and often underrate the difficulty in obtaining reliable results. Although antiepileptic drugs are among the easiest to measure, a North American study organized by Dr Charles Pippenger and a European study performed by the author demonstrated clearly the poor quality of results coming from many laboratories. From these studies have grown two external quality control schemes which together involve over 800 laboratories on a world-wide basis. Reports have indicated that the reliability of theophylline, tricyclic antidepressant and phenothiazine assays is also poor, and it might be expected that the problems will increase as attempts are made to measure drugs present in lower concentrations. Careful attention to quality control will be essential if physicians are to be provided with reliable results.


Lithium concentration and clinical responses. The clinical use of measurements of drug concentrations in blood is empirical and largely confined to compliance and toxicity monitoring. As currently used in once or thrice a day dosage, lithium treatment is pulsatile, the blood concentration varying threefold over 24 hours; routine measurements reveal nothing of this and therefore do not aid therapeutic use. In a pilot study it is shown that the plasma lithium concentration can be raised from 0 to 2 mmol/l in a few hours, inducing changes in both kidney function and neuropsychological tests after only short delay. This suggests that mania might be quickly controlled with rapid dosage and opens up a new way of analysing the mechanisms of lithium action, or of using it to reveal changes in cerebral functioning.


Blood levels of flupenthixol in patients with acute and chronic schizophrenia. Plasma levels of flupenthixol were estimated by three methods in 30 patients with acute schizophrenia and 29 patients with chronic schizophrenia. These levels were related to clinical response, anterior pituitary hormone secretion, platelet monoamine oxidase activity, the effects of the concurrent administration of anticholinergic drugs, and body weight. No clearcut relationships between plasma flupenthixol levels and any of these variables were demonstrated. The practical clinical value of the estimation of plasma flupenthixol is limited at the present time.


Studies on aminoacyl tRNA synthetases and transfer RNA in living Xenopus laevis oocytes. The microinjection of transfer RNA into amphibian oocytes permits one to study under in vivo conditions the reactions that affect this important macromolecule. A comparative study has been carried out between the in vivo and in vitro specificity of the aminoacylation reacton. The results obtained show that modifications of the tRNA structure affect aminoacyl-tRNA synthetase recognition in the same fashion in both conditions. The in vivo aminoacylation was not affected by the presence of puromycin (0.5mM) or cycloheximide (0.1 mM) which completely inhibited oocyte protein synthesis. An interesting difference was obtained between the in vivo and in vitro aminoacylation of tRNA with regards to temperature requirements. While the in vivo reaction was optimal at 25 degrees and was totally inhibited at 37 degrees, the in vitro was optimal, at the latter temperature. The inhibition of the in vivo reaction at 37 degrees was not due to inactivation of the enzyme. The transfer of the amino acid moiety to nascent proteins was studied by measuring the transfer of radioactivity from injected (14C) phenylalanyl-tRNA into hot trichloroacetic acid precipitable material. It was found that 30% or more of the amino acid became incorporated into oocyte proteins and that this incorporation was due to direct transfer from the aminoacyl-tRNA and was inhibited by puromycin and cycloheximide.


[Preliminary observations on activation of the alternative complement system by hemodialysis membranes (an in vitro study)]. In vitro studies showed activation by the alternate pathway of serum complement from normal subjects incubated with haemodialysis membranes. The mechanisms of such activation and its significance are discussed in the present paper.


[Action of complement in normal pregnancy and gestosis]. Behaviour of the complement system was studied in normal pregnancy, puerperium and in pre-eclampsia. CH50 showed no variations during normal pregnancy, excepting for first trimester, whereas it increased in puerperium. CVFAH50 increased steadily during all trimesters. C1q, C1s and C1-INH progressively decreased, while C3, C5, C9 and C3PA augmented. All values were clearly raised in puerperium. The decreased values of the early classical pathway components could be attributed to "blocking factors" (antibodies or immune-complexes) which could interfere with cellular immunity at fetoplacental level. The other components probably increase because there is a hormone-stimulated raised synthesis and a high turnover. The data obtained from pre-eclampsia did not reveal significant variations as compared to normal third trimester pregnancy, excepting for CVFAH50 which was reduced. This, however, does not exclude the possibility that there is an immunological pathogenesis of the pre-eclampsia, since activation of the C system is not always detectable in circulation.


Pathology of the placenta and cord in ascending and in haematogenous infection. The two main patterns of inflammatory response in the placenta and its adnexae are: (1) amniotic infection, usually bacterial ascending, with acute chorioamnionitis and funisitis; (2) haematogenous villitis, usually viral, with early necrotizing lesions and vasculitis and, later, chronic infiltrates and obliterative vasculitis. In amniotic infection most cells in the exudate are maternal. These leucocytes participate in antibacterial defence of the amniotic cavity in conjunction with substances such as zinc polypeptide and lysozyme and may contribute directly to fetal defence. Immunoglobulins may be produced in the cord of placenta only in protracted lesions such as 'healed' funisitis. Individual variations in the resistance of the membranes to bacterial penetration are possible. In viral infections a massive multifocal production by plasmacytes of immunoglobulins M, G and A is seen in affected villi. The secretion of non-specific antiviral substances in the infected placenta is possible. In all affected villi there is an activation of fixed macrophages (Hofbauer cells) that remain partly 'immature', i.e. are lysozyme-negative. Multifocal lymphoplasmacytic villitis is uncommon and has helped to focus the diagnosis on prenatal infection. In contrast, non-specific lymphocytic villitis is common; since there is no morphological difference between cases known to be associated with an infection, e.g. varicella, and the others, many cases may well be due to silent infection, although a graft-versus-host reactions remains a distinct possibility.


Prevalence of maternal and neonatal infections in a developing country: possible low-cost preventive measures. The frequency and duration of infectious illnesses in 408 pregnant rural women and 417 poor urban infants in Guatemala have been investigated, together with morbidity and mortality among the offspring of the rural women. Rural women suffered high rates of infection during the gestation period. Symptomatic illnesses, mainly acute respiratory infection and diarrhoeal disease, usually showed a higher incidence during the last months of pregnancy. Significant bacteriuria was identified in 21% of the women, though symptoms of urinary tract infection were found in about 25%. Vaginal infection was found in 38% of women at the beginning of pregnancy and in 79% at its end. Twelve per cent of women showed evidence of reactivated infections with cytomegalovirus, herpes simplex virus and Toxoplasma gondii. The neonatal mortality rate in the rural population was 37.7 per 1000 liveborn infants. Most deaths were among preterm babies. Significant bacteriuria was related to low birth weight. Morbidity in rural neonates was also high, but the illnesses were not severe and had a short duration. Neonatal morbidity in poor urban infants was also high. Breast-feeding had a protective effect: breast-fed rural and poor urban infants had a lower incidence of illness than urban babies who were not breast-fed. The influence of infection during pregnancy on the conceptus and some low-cost measures for reducing it are discussed. Measures for decreasing neonatal morbidity in rural and poor urban ureas are proposed.


Perinatal infections: the obstetrician's viewpoint. The obstetrician's role is to recognize and treat maternal systemic infections which may spread transplacentally to the fetus, and to ensure that the lower genital tract is kept free from pathogenic organisms, particularly during the last trimester of pregnancy. In some cases the obstetrician can reduce the likelihood of premature rupture of the membranes by inserting a cervical suture. Where this has not been possible conservative management should be used to keep the fetus in utero before the 34th week and more active after this time. In trapartum infections can be reduced to a minimum by keeping the membranes intact during early labour, by the aggressive use of uterine stimulants to avoid prolonged labour, by exerting extreme care to avoid sepsis during pelvic examinations and internal monitoring, and by earlier use of Caesarean section.


Factors in the mother/infant dyad that influence the development of infections before and after birth. A number of maternal factors strongly influence the development and outcome of fetal infections. Severely undernourished mothers produce neonates with evidence of an immunoincompetence that persists into later childhood. Mothers who fast during pregnancy develop metabolic acidosis much more rapidly than non-pregnant women. The metabolic acidosis leads to high fetal and neonatal death rates from a variety of pre-existing disorders, including infections. Such metabolic acidosis also appears responsible for the excessive fetal and neonatal deaths associated with maternal urinary tract infections. Finally, coitus during pregnancy markedly increases both the frequency of bacterial infections of amniotic fluid and the mortality due to them. The effects are greatest at mid-pregnancy and gradually decrease to term.


The genesis of amniotic fluid infections. Amniotic fluid infections manifested by an inflammatory response in the extraplacental membranes and subchorionic plate of the placenta are a common phenomenon thought to be due in most cases to ascending bacterial infections via intact membranes. Fatal spread to the fetus is much less common and more likely to occur in underprivileged communities. The probable reasons are nutritional deprivation in the mother or both, leading to production of a liquor with diminished ability to suppress bacterial growth. Zinc is one component of the antibacterial system but liquor levels of zinc vary widely and inconsistently with antibacterial activity. Dietary supplementation with zinc did not improve antibacterial activity of liquors in a population with diminished liquor antibacterial activity and large number of fatal infections. Other factors in the genesis of amniotic fluid infections may be interference with normal defence mechanisms as a result of coitus in late pregnancy and vaginal infections with Trichomonas vaginalis. Socioeconomic factors may play a role apart from their association with maternal nutrition, through diminished hygiene associated with insufficient use of water and insufficient availability and use of medical facilities.


Consequences of amniotic fluid infections: early neonatal septicaemia. This study describes the results of examination of blood cultures from infants born in a community with a high prevalence of fatal amniotic fluid infection. The incidence of first-week neonatal septicaemia was 5.5 per 1000 births. Septicaemia was detected in 38% within 12 hours and 75.6% within 72 hours of birth. The aetiological pattern of the septicaemia was similar to that of fatal amniotic fluid infections. The increase in mortality from septicaemia occurred in infants born after 34 weeks of gestation. Nearly 80% of the infections apparently occurred through intact membranes. Respiratory distress with or without radiological evidence of pneumonia was the only manifestation of septicaemia in most infants under four days of age. Low Apgar scores and multiple apnoeic episodes were more common in infants with septicaemia than in those without septicaemia. Neonatal jaundice with serum bilirubin in excess of 11 mg/dl was more common in septicaemic infants and indicated poor prognosis. Meningitis associated with septicaemia occurred in 3.8% and in all these infants the diagnosis of septicaemia was delayed beyond 72 hours. The results suggest that early recognition and treatment of antenatal bacterial infections may prevent mortality and morbidity from complications of septicaemia such as neonatal apnoea, meningitis and bilirubin encephalopathy.


Bacteroides meningitis successfully treated with metronidazole. Bacteriodes meningitis without associated cerebral abscess occurred in an elderly man who had a long history of chronic otitis media. Anaerobic cultures of the cerebrospinal fluid revealed bacteroides organisms. Sensitivity testing showed them to be resistant to penicillin and chloramphenicol but sensitive to metronidazole. Appropriate therapy with this agent eradicated the causative organisms and produced rapid clinical improvement.


The condition of surgery: an analysis of the American College of Surgeons' and the American Surgical Association's report on the status of surgery. The supply of surgical services--a function of both the number of surgeons and the amount of surgery each performs--was extensively studied as a basis for new public policies in medical practice. The Report concludes that there is a surplus of physicians performing surgery and recommends restricting their number through more rigorous board certification and reducing the number of new entrants to specialized training. But the technological criteria advanced to assure "quality" are not based on adequate empirical  evidence; and control by surgeons over their own numbers is likely to have uneven--and unfavorable--consequences for the public. The causes of surplus surgical capacity must be explained, and impediments to self-correction through competition in the "medical market" addressed in future policy.


Central nervous effects of a new tricyclic antidepressant (amitriptylinoxide). The central action of amitriptylinoxide was investigated in mice and rats using established models. The substance was found to possess antidepressant, drive-promoting properties which correspond to amitriptyline in their intensity or are superior even. In addition the pharmacodynamic spectrum of amitriptylinoxide displays a sedative component that is considered a desirable accompanying effect but is somewhat weaker than with amitriptyline. According to revealed differences in this work between the pharmacological activities of amitripytlinoxide and those of other tricyclic antidepressants, it became reasonable to undertake further studies to investigate its main and side effects.


A consideration of risk factors and development of chronic bronchitis in a five-year follow-up study of an industrial population. A five-year follow-up study in an industrial population showed that the prevalence and development of chest symptoms in men was related mainly to their smoking habits and, to a lesser degree, to age. Mean FEV1 values were related to age, and decrease in FEV1 was related to age and smoking habits. The levels of airborne dust and fluorides at the working places were related to the prevalence of chronic bronchitis (CB) symptoms, to the persistence of those symptoms during the five-year period, and to decrease of FEV1 values during that time. The decrease in FEV1 was especially noticeable among current smokers. The five-year incidence study showed that particular occupational factors do indeed have a real effect, but their meaning in the development of the CB syndrome is less marked than was expected from the prevalence rates.


Studies of factors regulating the ageing of human erythrocytes. II. Metabolic depletion of erythrocytes is not accompanied by a decrease of their sialic acid content during blood bank storage. Erythrocytes from human blood stored at 5 degrees C in anticoagulant-preservative solutions are considered, after a period from 21 to 24 days, unsuitable for transfusion. The nonviability of the cells appears due to metabolic impairment accompanied by a change of the biophysical properties of the cell but surprisingly not to a decrease of sialic acid of the membrane. The absence of proteolysis can be attributed to calcium chelation and to the stable levels of plasma protease inhibitors throughout the storage period. In fact, when erythrocytes are incubated for several days at 5 degrees C in protein-free media, release of sialopeptides from the membrane increases slowly and steadily, particularly if the medium is without glucose and adenine but contains divalent cations. Moreover, this phenomenon is strikingly amplified when incubation in protein-free media is carried out at 37 degrees C and once the ATP level has fallen below 5% of its initial value.


[Preliminary scanning electron microscope (SEM) observations of the rat renal parenchyma after microdissection]. Rat kidneys weighting between 250 and 300 g. were treated in HCl. A single nephron observed through SEM shows that the above treatment doesn't interfere with the ultrastructural morphology of nephron.


[Rapid method for identifying Candida of medical importance]. A rapid identification method of Candida yeasts of medical interest is proposed. It calls for morphological examinations (germ-tube and chlamydospore-test included), and reduced fermentation as well as assimilation tests, performed at defined temperature and inoculum concentration values.


[Evaluation of the degree of maturation of the cervico-vaginal epithelium in normal, inflammatory and dysendocrine states]. The AA. have determined the maximum percentage of the para-basal cells compatible with a phlogistic state resulting from the exam of 2400 cervical and vaginal smears from women of various ages that were not following therapies able to falsify the evaluations of the endocrine situations. At the objective exam the patients had no sure signs of erosions, thyroid illnesses, vitamin deficiency or cervical metaplasia. The aim of the research was to find a criteria of evaluation of the endocrine situations of the patients, that were not easily influenced by the variations of the karyopyknotic index and acidophilix that are met in the course of numerous illnesses.


[Role of the prostaglandin system in the monoaminergic control of prolactin release in the rat]. In ovariectomized rats treated with estradiol benzoate, the pre-treatment with bromocriptine or metergoline on increase of PRL secretion induced by some prostaglandins has been investigated. The PGs used were able to hinder the drop in PRL levels induced by metergoline, a blocker of 5-HT receptors, but not that produced by bromocriptine, a dopamine receptor agonist. Therefore it is possible to suppose that the PGs are involved in the monoaminergic hypothalamic regulation of the PRL secretion.


[Standardization criteria for the study of fetal lung maturity by means of gas-liquid chromatography of the fatty acid content of the amniotic fluid]. Gas-chromatographic analysis of the fatty acids (P/S ratio) in 10 samples of amniotic fluid and 10 samples of the pellets obtained after centrifugation of amniotic fluid at 3500 X g for 60 minutes were carried out to evaluate the effects of contaminants that might be present in amniotic fluid. The P/S ratio is used as an index of the degree of maturity of the fetal or neonatal lung. We propose a standard procedure of centrifugation for 60 minutes at 3500 X g followed by extraction and gas-chromatography as a rapid, valid way to measure the P/S ratio.


[Parenteral penicillin in rats: an experimental model of periodic EEG activity]. Parenteral G Penicillin has been administered to 10 rats and EEG pattern has been recorded. High voltage spikes appeared on one hemisphere, 12 to 25 minutes after injections. Gradually spike frequency and voltage increased till periodical EEG was observed  on both hemispheres. Such activity was synchronous, symmetrical, stereotyped and often accompanied by myoclonias. This pattern lasted from 45 to 100 minutes. The authors underline the analogies with the Ouabain model of epilepsy and with periodical EEG patterns in man.


[Effect of mescaline on cerebral cholinesterases and on exploratory behavior in rats]. In this study the Authors had the purpose to evaluate the action of a psychotomimetic substance (mescaline) on behavior (exploring behaviour and spontaneous motility) and on cerebral biochemistry (cholinesterase activity) of rat. The mescaline has shown to be active both on behaviour (increasing the spontaneous motility) and on biochemistry (decreasing the total cholinesterase activity). From the examination of the results of this work it could be cautiously assumed the hypothesis that the behavioural effects of mescaline are related (at least partially) to modifications of the cholinergic system at the cerebral level.


[Effect of LSD-25 on cholinesterases of the rat brain]. The indications for investigation on the LSD-25 "in vivo" activity on brain cholinesterases of the rat, have been considered. Indications of materials and method used have been supplied too. From the results obtained it emerged no clear evidence of a statistically significant inhibition of cholinesterases due to LSD-25. The results have been discussed and it has been evidenced that the lack of action of the psychotomimetic substance on cholinesterases could be only apparent or that the discrepancy between the LSD-25 anticholinesterase "in vivo" and "in vitro" action should be ascribed to the too scarce tissue levels which can be reached with the does utilized. Apart from the hypothesis, tending to explain the results obtained, it has been considered that the LSD-25 behavioural action, is not probably carried out thanks to a cholinesterase activity.


[Effect of scopolamine on the memory of exploratory behavior in the mouse]. In the present work it has been evaluated the action of scopolamine on the extent of exploration in mice, whose exploring behaviour had been already earlier examined. Such behaviour has been evaluated using a hole-board. The goal has been to detect the influence of the substance on the short-term memory of mice. The method used has shown to be effective. By the exam of the results of this work it can be concluded that the scopolamine at a dose of 1 mg/kg has an evidence effect of short-time memory in mice by causing a hypomnesia.


[Kinetics of 14C-cholic acid in the baboon under normal conditions and in cholestasis. Description and validity of a multicompartmental model]. A multicompartmental model was applied to the study of the plasmatic and biliary kinetics of the 14C-Cholic acid intravenously injected into a baboon in normal and cholestatic condition. For the evaluation of transfer rates FORTAN IV procedures were used, utilizing Powell method. The degree of fitting was: in normal condition in serum 7% for free and 35% for conjugated Cholic acid, while in bile 5% and 4% respectively; in serum in cholestatic condition 7% for free and 12% for conjugates. The high degree of fitting and reliable estimation of transfer rates suggest that the multicompartmental model applied represents most likely the physio-pathological conditions studied.


[Epidemiologic study of the focus of cutaneous leishmaniasis in Mokolo (North Cameroon)]. Fifty-eight patients with cutaneous leishmaniasis are studied in the North of Cameroon. All of them are living in an area located not further than 30 miles away from Mokolo. Both sexes are equally concerned. Young adults are representing the age group the most frequently infected. The greatest number of cases is observed in August and September during the rainy season. Uncovered parts of the body, the face and the limbs, are mostly concerned. They are only one, or more often many different lesions, which are separated one from the next, and which are evoluting naturally towards cicatrization, leaving usually a cicatricial mark. Diagnosis is achieved by discovering the Leishman-bodies in the smears or in the skin sections.


[Ecology of the focus of cutaneous leishmaniasis in the region of Thies (Senegal, West Africa). 3. Evaluation of the endemicity in the human population]. During the epidemiological survey of the cutaneous leishmaniasis focus of Keur-Moussa, the authors try to evaluate the disease frequency by using various epidemiological indices. The incidence showed variations from year to year (from 3.31 p. 1,000 in 1976 to 0.26 p. 1,000 in 1978). A 12.4% prevalence rate was established from a systemic investigation in January 1978. During the same survey, 57.8% of the population had a positive leishmanin skin test. The value and significance of these different rates are then discussed.


[Initial therapeutic trials of an antibilharzial agent, 35 972 R.P. in man]. 35,972 R. P. is a new schistosomicidal drug deriving from a thione dithiole pyrazinyl basic structure. It has been assessed with 125 patients suffering from an urinary tract schistosomiasis (69 cases) or from an intestinal schistosomiasis (56 cases). Five regimens have been followed. The last one was 1.50 g/day over 3 days and it included 75 patients. The clinical tolerance was satisfactory although vomiting was reported in 16 % cases and headaches were noted in 21 % cases. The efficiency was remarkable as 97 % patients were cured. New studies are been performed on a one day treatment basis.


[Contribution of Hoffmann's reflex, evoked on the soleus muscle, to the study of nerve conduction velocity from birth to age 5]. We tried to appreciate the maturation of the peripheric nervous system, in children from two days to five years old, by electrophysiological technics. Hoffmann's monosynaptic reflex is recorded on the soleus muscle and conduction velocity is calculated on the motor tibial nerve. So, we can follow the conduction velocities on the proximal and distal part of this nerve, from birth to five years of life. The conduction velocities develop in a parallel and approximately exponential way. The proximal conduction velocity remains always faster than the distal one but their difference decreases during the first 18 months of life and then remains constant. The evolution of the proximal conduction velocity explains that the conduction time slightly but significantly decreases during the first year of life in contrast to the increase of the nerve length. So, during the first year of life, nervous system maturation gets on very quickly and anticipates the skeletal growth.


[The recruitment of motor units during elbow flexions in man]. The density of spikes of spike output (SO) recorded by means of three bifilar semimicroelectrodes simultaneously implanted in the biceps brachii has been studied during elbow flexions performed against inertia and with a variable velocity (anisometric, anisotonic contractions). The total number of motor unit (MU) potentials as well as the force were sequentially measured during intervals of 30 msec. SO obtained during movements of very similar mechanical characteristics was different from one movement to another. However, when a small number of identical movements was summed an averaged SO was obtained that was representative of the instantaneous global activity of the biceps. Taking into account the respective values of the bin duration and of the interval between two successive discharges of a single MU, the averaged SO represents the number of active MU during the acceleration phase of the movement. Since in this type of movement the frequency discharge of each MU decreases during the acceleration phase, it appears that the increase of averaged SO represents the recruitment of MU during the movement. From the relation established between the instantaneous values of So and force it can be concluded that the shape of force increase in anisometric, anisotonic conditions is entirely related to that of MU recruitment, although the absolute value of force depends on both the firing frequency and the number of active MUs.


[Significance of electromyography of the diaphragm in respiratory physiopathology]. Adequate electromyographic method are available in order to record the electrical activity of the vertebral (oesophageal surface electrodes) and the right or left costal (concentric needle electrodes) parts of the diaphragm and in order to stabilize the EMG's base line (rejection of the electrical movement's artefacts by means of RC filters). The electromyographic patterns of the agonistic and antagonistic activity of the diaphragm in normal subjects have been clearly defined in different circumstances such as quiet ventilation and hyperventilation. Disturbances of the ventilatory diaphragmatic activity have been demonstrated by electromyography in different diseases: broncho-pneumopathies; supraspinal disorders, myopathies. In normal subjects, global motor responses of the diaphragm to the electrical stimulation of each phrenic nerve can be easily recorded with surface electrodes located in the oesophageal hiatus or placed over the lower intercostal spaces. The phrenic nerve conduction times was measured in 30 normal adults. The average value of this parameter was 7,5 +/- 0,53 msec for excitation on the right side and 8,2 +/- 0,71 on the left. The measurement of the phrenic nerve conduction time seems to provide a sensitive index of involvement of the nerve in diaphragmatic dyskinesias. Prolongation of conduction time was demonstrated in phrenic lesions of various aetiologies such as: peripheral polyneuropathies, traumatic sequelae, mediastinal tumors, phrenic neuritis or idiopathic diaphragmatic paresis. Electrical phrenic stimulation and prostigmin have permitted to establish the diagnosis of myasthenic bloc of the phrenodiaphragmatic transmission.


[The causes of death after acute myocardial infarction (author's transl)]. Following a brief outline on problems concerning methodology, the cause of death is analysed in 110 patients dying from acute myocardial infarction during hospitalization. Autopsy studied were carried out in 78 cases. Of the various causes, the most frequent were forms of contractile insufficiency (EPA, shock, shock + EPA, biventricular congestive heart failure) which were responsible for 50.90% of cases; followed by cardiac rupture (considered in a single group with electromechanic dissociations of the patients not submitted to autopsy studies since in the experience of the Authors cardiac rupture almost always presents with this pattern) with a frequency of 29%. The frequency of arrhythmias, on the other hand, is very low, particularly in the coronary care unit where it is practically a negligible causa mortis 2.72%): even if sudden death, in patients who were not monitored, is included amongst the arrhythmias, the percentage is still only about 10%. Embolism (usually pulmonary, but systemic in one case) was the cause of death in 5 patients (4.54%). Three patients over 80 years of age died from ischemic cerebral episodes. Age, sex, and site of infarction, do not appear, in the present series, to have a determinant effect in the cause of death; a higher frequency of rupture in the female sex was not, for example, confirmed. On the basis of the observations in the present series, any relationship between cardiac rupture and anticoagulating therapy, steroid treatment, application of endocavitary stimulators, or early ambulation is excluded. It is also excluded that reanimation, as hypothesized by some Authors, may be responsible for rupture.


[The evolution of cardiac impairment in Duchenne's muscular dystrophy. Electrovector-cardiographic, polycardiographic and echocardiographic aspects (author's transl)]. The Authors have submitted to an electrocardiographic, vectorcardiographic, mechanocardiographic and echocardiographic investigation 4 cases with Duchenne's disease, which had already been studied by the Authors several years before. The longitudinal study has demonstrated, above all, the striking capacity of the electrocardiographic aspects of the disease to evolve from a normal to a "pseudo-necrotic" pattern. Such evolution, among other things, provides an important argument against the interpretation that attributes the electrocardiographic and vectorcardiographic changes in the initial stages of the disease to a persistence of a QRS loop of infantile type on a genetic basis. But for rare exceptions, the systolic time intervals and kinetocardiogram, which showed early indicative changes on the first examination, have successively shown easily predictable behavior considering the poor cardiovascular conditions of the patients on the second examination. The echocardiogram has proved useful in demonstrating the morphological and functional changes of the ventricular walls and of the interventricular septum, besides the eventual associated mitral valve prolapse. The echocardiographic evaluation of the left ventricular performance in quantitative terms, however, seems somewhat unreliable owing to the difficulty of obtaining technically good images, due to the thoracic deformity. The dystrophic changes recently observed in the myocardium even at ultrastructural level can probably explain not only the electrocardiographic and vectorcardiographic abnormalities but also the kinetocardiographic and echocardiographic changes. Among the above mentioned theoretical and practical considerations the possibility should be underlined that some cases of cardiomyopathy labelled as "primary" are in fact unrecognized dystrophic cardiomyopathies.


[Comparative echocardiographic and vectorcardiographic study of 17 patients with Duchenne muscular dystrophy (author's transl)]. Cardiac impairment in Duchenne muscular dystrophy (DMD) is well known since many years. Degeneration of myocardial fibers and progressive scarring of the left ventricle, especially in the postero-basal and lateral portions, represent the habitual cardiac pathologic features of post-mortem investigations. Nevertheless many questions about etiopathogenesis and pathophysiology of "DMD cardiomyopathy" are still debated. Clinical, vectorcardiographic (VCG) and echocardiographic (ECO) data of 17 patients suffering from DMD are here reported. Patients were subdivided in two groups according to age: A) subjects from 4 to 10 yrs. (mean 0.22 +/- 1.82 yrs.), 10 cases; B) subjects from 11 to 20 yrs. (mean 15.2 +/- 2.8 yrs.), 7 cases. Both patients groups were compared with age-matched normal controls (group A1 and B1). Our results show: 1) cardiac clinical symptoms and signs, even if is present in infancy, become more evident in adult age; 2) echocardiogram allows an early diagnosis and accurate follow-up of such cardiac pathology. Group A patients, in comparison with his own control group, exhibited a significant impairment of the left ventricular function indexes (PWE, IVSE, SV, Vcf, EF%, delta S%). Moreover the older group of patients (group B), besides the alteration of the above mentioned indexes, exhibited a significant decrease of the PWT and an impairment of DEVM. This, in agreement with other Authors, gives evidence to the progressive deteriorating of cardiac function in DMD. 3) A significant correlation between ECO and VCG data is lacking. Nevertheless VCG also displays a clear tendency to get worse with age. Vectorcardiographic features well agree with the post-mortem findings of a progressive but scattered myocardial fibrosis with elective localization in postero-basal and lateral (free wall) portions of left ventricle. 4) For the most part, in our patients, cardiological instrumental findings (ECO and VCG) are well in agreement with clinical data and natural history of "DMD cardiomyopathy". The afore said methods of investigation appear very useful in the diagnostic and therapeutic management of such patients.


[Metoprolol effect on ECG exercise test in patients with stable angina pectoris. Computer analysis (author's transl)]. The effect of metoprolol in ECG experiments induced by a treadmill exercise test, was studied in 30 patients with stable angina pectoris. The study was a simple blind cross-over between metoprolol (150 mg/die) and placebo. The evaluation of ECG recordings (V5 lead) was carried out by a computer program. In order to assess the ST-segment depression, the ST 0.8 (Depression at 80 msec after R-peak) and AST (ST area) values were used. We observed an increased exercise tolerance after administration of metoprolol (P less than 0.001) and a significant reduction of ST segment depression for ST 0.8 (P less than 0.01) and AST (P less than 0.005) at the maximal commun work load attained by every patient in the metoprolol and placebo tests. When the evaluation of ECG measurements were performed at the maximal commun double product no significant modifications were observed.


[Diagnostic value of the continuous electrocardiographic monitoring (Holter) and of the electrophysiologic testings in patients with sino-atrial node dysfunction (author's transl)]. A twenty-four hours electrocardiographic recording and an electrophysiological study were performed in 48 patients with sinus bradycardia, 21 of them with symptoms suggesting a sino-atrial dysfunction. Both methods, and independently one each other, were not diagnostic in all symptomatic patients; on the contrary, they showed sinus dysfunction in patients without symptoms related to sino-atrial node dysfunction. These results induce to conclude that the two methods are complementary and that their results must be ever critically accepted, especially when a permanent cardiac pacing is indicated. Because of their not high sensitivity, some patients with sinus dysfunction are not recognised; there-after, the diagnosis is only possible, in these cases, on the base of clinical-signs.


[On the possibility of determining preoperatively the real diameter of aortic annulus (author's transl)]. The possibility of determining the real size of the aortic annulus on the basis of adequate angiocardiographic measurements has been retrospectively verified in a group of 10 patients who underwent aortic valve replacement. A good correlation (r = 0.99) was found between the predicted diameter of the aortic annulus and the size of the valve inserted at operation. The useful implications associated with prediction of the diameter of the aortic annulus are discussed.


[Stenosis of the common trunk of the left coronary artery. Personal experience with 17 patients]. The Authors have presented the clinical, hemodynamic, coronary arteriographic and left ventriculographic findings, and the results of medical and surgical treatment in 17 patients with main left coronary artery disease (MLCA). Clinically MLCA disease can only be suspected, in the AA's experience, if a patient presents with markedly positive exercise stress test and/or unstable angina. Coronary arteriography and left ventriculography confirmed the high incidence of associated 2-3 vessel coronary artery disease and of severe left ventricular segmental wall motion abnormalities. Surgical results and clinical follow up have indicated a better prognosis and quality of life in operated, compared with medically treated patients. Our experience confirms that MLCA disease is a dangerous clinical entity, which, when suspected, must be managed with proper indication to coronary arteriography and aorto-coronary bypass surgery, both associated, in our experience, with acceptable morbidity and mortality and good long term results.


[Cardiac rupture: a not infrequent complication of acute myocardial infarction. Report of five cases (author's transl)]. Five cases of cardiac rupture (CR) in acute myocardial infarction (AMI) (four men and one woman aged between 49 and 86 years, mean 64) are described. The incidence of CR was 4,7% of 106 cases of AMI and 20,8% of causes of death. In all cases, pathologic observations well agreed with electrocardiographic site of infarction. All patients had ECG pattern of transmural AMI: postero-inferior (2 cases), anterior (1 case); none of them had myocardial infarction in the past. Two patients had systolic hypertension on admission, during and immediately before death, and 3 patients were normotensive during the whole course of illness. All patients had severe, prolonged and resistant to opiate therapy chest pain, which reexacerbated immediately before death in two cases. 4 patients died within 24 hours after the onset of symptoms. Terminal ECG pattern was similar in these four cases: sudden sinus bradycardia and/or idio-ventricular rhythm, with a progressive slowing of heart rate and changes of QRS patterns of "agonic" type, preceded electrical activity cessation. In one patient, who died at the seventh day of illness, ventricular fibrillation was observed. The AA. stress the importance of the early recognition of clinical findings suggesting an impeding CR in order to relieve cardiac tamponade with pericardiocentesis and to perform, as soon as possible, surgical treatment.


[Carcinoid heart disease. Report of a case with triple valvular lesion (author's transl)]. A case of carcinoid syndrome, stemming from a tumor of the large intestine with hepatic metastases, is reported. Clinical features included cardiac disease with triple valvular lesion: tricuspid insufficiency with stenosis, pulmonary artery stenosis and mitral insufficiency. More recent views about the pathogenesis of the cardiac involvement in the carcinoid syndrome are reported, and the cardiac therapy is discussed.


[Postinfarction left ventricular aneurysm. A method for volume determination and its correlation with hemodynamic and angiographic parameters (author's transl)]. On the hypothesis that encroachment on left ventricular performance by postinfarction aneurysm (An) is related to its size, a method was investigated for the measurement of aneurysmal dimensions. On radioopaque plastic casts grossly ellipsoidal in shape with addition of masses in different position to simulate aneurysms, satisfactory data for volume calculation were obtained by the association of the ellipsoid formula applied to the contractile portion with the formula of the hemispheroid applied to the aneurysmal section, the difference between real and calculated volumes being not more than +/-5%. In 100 Pts. with previous myocardial infarction, showing at ventriculography akinetic-diskinetic segments of the left ventricular wall, the absolute volume of An and its percentage value of the total left ventricular volume (V An%) were measured. A statistical correlation was studied with other hemodynamic and angiographic parameters of left ventricular function. Cardiac index and angiographic stroke volume decreased with increasing V An%, but with a low correlation, of no statistical significance; only for An with a volume of 60% or more C.I. and SV were constantly reduced. The LVEDP, higher than normal in 80% of the cases, rose with increasing V An%, but with a correlation of low statistical significance. The EDV increased progressively and significatively with increasing V An%, resulting therefore in relation with the extension of noncontracting segment.


[Use of esophageal leads in the diagnosis of myocardial infarct with a postero-inferior site]. The electrocardiographic diagnosis results from the verification of a anomalous waves in one or more derivations. There are, however, some cases of infarct in which the electrocardiogram appears regular and there are other different situations in which a more less profound "a" wave can appear in the D3 and aVF derivations. The Authors have considered four groups of patients, in which only the oesophageal ecgraphic has allowed to obtain the right diagnosis, succeeding in filling the gaps of the diagnostic possibilities of the standard ecgraphic.


[Status of Hansen's disease in the State of São Paulo in 1978]. The authors describe the situation of endemic Hansen's disease in the State of São Paulo in 1978, presenting the prevalence and incidence rates of the disease in the several Regional Health Divisions of the State. An attempt to evaluate the Hansen's disease control programme carried out since 1976, is also presented, through the participation of the Health Units of the State in the activities of epidemiologic surveillance of the programme.


[Disability in Hansen's disease: a study of the reality in our milieu]. Considering the importance of rehabilitation in the policy for the control and prevention of hanseniasis, results of an investigation of incapacities in a population of affected individuals in São Paulo are presented. Discussion of these data and the identification of the potential resources for solving the problem lead to basic considerations about programmes for rehabilitation of such patients.


[Hansen's disease: its image, education, integration and physician-patient relationship]. Although still used in fund raising campaigns, the serious aspects of hanseniasis are less common now, thanks to early diagnosis and treatment. This new image of hanseniasis should be propagated by health education, especially directed to patients and contacts. Integration should refer not only to hanseniasis but also to leprologists, who became also "segregated", due to the pejorative "leprosy". The good relationship with the patient depends on the psychological capacity of the physician, revealed as soon as the diagnosis of the disease is made.


Leprostigma in hanseniasis.

Leprostigma in hanseniasis. Ignorance, fear and superstition surround the problems of hanseniasis. In almost all cultures the predominant attitude is emotion, disgust and rejection towards persons suffering from this disease. All efforts aimed at the control of hanseniasis are doomed to failure unless the significance of stigma and associated social and economic factors are given adequate consideration. A programme of destigmatization is outlined.


Diabetic status in leprosy.

Diabetic status in leprosy. The diabetic status of the local Jhansi patients (120 cases) was established before and after antileprosy treatment. Control studies were performed in normal healthy subjects (50 persons) without family history of diabetes mellitus. Random normals showed an incidence of diabetes only 2%, while leprosy patients (94 males and 26 females) had incidence of diabetic status of 14.2%. The highest incidence (19.3%) of diabetes was in lepromatous leprosy and lowest incidence (6.4%) in tuberculoid leprosy patients. Repeated studies in leprosy after treatment showed not only clinical improvement for leprosy but also disappearance of the chemical and latent diabetes mellitus and lowering of blood sugar levels in manifest diabetes mellitus. Incidentally it was noted that 'diabetic status' was worse among males (82.3%) and with advancing age. Association and improvement of diabetic status with specific treatment would tentatively suggest that Mycobacterium leprae lesions are not confined to skin alone but somehow also related to carbohydrate metabolism. A careful management of the chemical and latent diabetes may help in clinical management of leprosy too.


[Dimorphous Hansen's disease with outbreaks of Hansen reactions and visceral lesions]. The paper presents the case of a patient with borderline hanseniasis. After a long period of illness, he presented an outbreak with new lesions, that showed reactional tuberculoid aspects; he later presented lesions with clinical and histological aspects of Virchowian hanseniasis. This evolutional type is compatible with the pseudo-exacerbations outbreaks reported by Souza Lima. This patient also presented an Erythema Nodosum outbreak with cutaneous and visceral lesions, the latter occurring with great intensity in the liver parenchyma with clinical manifestations of icterus and hepatomegaly. The pathogenesis of the pseudo-exacerbations outbreaks is discussed, also the special situation of Borderline patients, subject to neurologic injuries during the pseudo-exacerbations outbreaks, and cutaneous, neurological and visceral lesions during the Erythema Nodosum Hansenicum outbreaks.


[Incidence of Hansen's disease in the State of São Paulo in 1978]. The authors describe and evaluate the distribution of 2.081 new cases of Hanseniasis, recorded in the State of São Paulo (Brazil) in 1978, according to the following personal characteristics of the patient: sex, age, place of birth, education level and housing. The distribution of the cases according to some characteristics related to the disease and to health care, are also described and discussed: clinical types of the disease, duration of the disease, occasion and manner in which the patient sought for health care (spontaneously or not). The geographic distribution of cases and the secular trend of new cases recorded in the last 10 years, are also presented and discussed.


Changes in somatomedin-like activity and concentrations of growth hormone and prolactin in the plasma of castrated growing lambs. Somatomedin-like activity was measured in the plasma of growing lambs using the porcine costal cartilage disk assay. Plasma concentrations were found to be high initially at 2 days of age (mean potency 1.02 plus or minus 0.13 (SEM) units/ml, n = 4) declined significantly by 8 days of age (mean potency 0.65 plus or minus 0.04 units/ml, n = 5, P less than 0.01, analysis of variance). Thereafter somatomedin-like activity declined slowly to reach its lowest concentration at 146 days of age (mean potency 0.61 plus or minus 0.04 units/ml, n = 5) then it rose slowly until 288 days of age (mean potency 0.61 +/- 0.04 units/ml, n = 5. These changes in somatomedin-like activity were accompanied by high initial plasma concentrations of growth hormone (24.8 plus or minus 4.8 ng/ml, n = 5) which declined under 188 days of age (2.8 plus or minus 0.04 ng/ml, n- 5) and then rose slightly until 288 days of age (13.8 plus or minus 9 ng/ml, n=5). Plasma prolactin concentrations showed a different pattern being low initially (47.8 plus or minus 8.7 ng/ml, n = 5) rising until 146 days of age (203 plus or minus 16 ng/ml, n = 5) and then declining to low value for the rest of the experiment. The relationships between these factors is not clear but somatomedin-like activity shows a pattern in the lamb which is highest when growth is faster (i.e. in the young lamb).


The influence of early nutrition on growth and the circulating levels of immunoreactive somatomedin A. The effect of nutrition during early development on growth and serum immunoreactive somatomedin A was examined in rats by rearing in small or large liters. At weaning, body weight, brain weight, liver weight and DNA content was significantly reduced in rats whose nutrition was restricted by rearing in large litters. Brain DNA content was significantly altered. Serum somatomedin A was significantly reduced in the growth-retarded rats as compared to those whose growth was enhanced by rearing in small litters. Similarly, maternal serum somatomedin A was significantly reduced in rats nursing large litters.


Placental diffusing capacity and its relation to fetal growth. The placental diffusing capacity for carbon monoxide was measured in unanaesthetized monkeys (M. Mulatta). Maternal and fetal blood was sampled from chronically placed catheters while the mother breathed 50 or 100 parts per million of CO. Diffusing was calculated from the amount of CO taken up by the fetus divided by the partial pressure difference across the placenta, it averaged 0.646 plus or minus 0.062 (SEM) ml x min(-1) x torr(-1) x kg(-1) of fetal weight. The significance of this index of respiratory gas exchange in the monkey placenta is discussed with respect to previous measurements in other species and with respect to fetal growth.


Progestagen metabolites in fetal sheep plasma: the effect of fetal nephrectomy. Fetal sheep (100-115 days gestation) were surgically implanted with femoral arterial and venous cannulae and then either sham-operated (control) or bilaterally nephrectomized. Following a 5-day recovery period, fetal blood samples (10 ml/48 h) were taken and the steroid sulphate fraction analysed as trimethylsilyl esters by gas-liquid chromatography (g. l.c.). Three progestagen metabolites were repeatedly detected in plasma samples from control and nephrectomized fetuses and identified by g.l.c.-mass-spectrometric techniques as 5 beta-pregnane-3 beta,20 beta-diol, 5 beta-pregnane-3 beta,20 alpha-diol and 5 beta-pregnane-3 alpha,20 alpha-diol. In three control fetuses the plasma concentration of both 5 beta-pregnane-3 beta,20 beta-diol and -20 alpha-diol showed a steady increase from about 0.5 micrograms/ml at 105 days to about 1.5 and 2-2.5 micrograms/ml, respectively, at 143 days gestation. A study in one fetus indicated that the values then fell precipitously by term (147 days) as plasma cortisol concentrations rose. In contrast, whilst no consistent patterns were seen in their concentration in five nephrectomized fetuses the levels were 2-10 times higher than the control values (0.5-10 micrograms/ml) at all stages. The plasma concentration of 5 beta-pregnane-3 alpha,20 alpha-diol was less perturbed by nephrectomy and only showed a slight increase over control values (0.2-0.5 micrograms/ml). Three sham-operated fetuses which aborted following infection also showed increased plasma concentrations of 5 beta-pregnane-3 beta,20 beta-diol and -20 alpha-diol, similar to the nephrectomized fetuses. It is postulated that high levels of circulating progesterone metabolites may reflect induced increases in adrenal endocrine activity culminating in premature activation of those changes in adrenal function which trigger parturition.


Chemical injury of the spinal cord of the rabbit after intracisternal injection of gentamicin. A single intracisternal injection of 0.4 ml of 1.25 and 2.5 percent gentamicin sulfate with preservative to healthy adult rabbits caused acute respiratory paralysis and severe seizure activity initially and paralysis of the limbs subsequently. In the white matter of the upper cervical spinal cord, multiple, minute, disseminated, spongy lesions were observed. They consisted of lysis of axis cylinders, edematous dilatation of myelin sheaths, and loss of astroglia and interfascicular oligodendroglia. Axonal end-bulbs formed at the periphery of the lesions. Clinically and morphologically, 0.025 and 0.25 percent gentamicin sulfate solution did not produce myelopathy. The spinal lesions were distributed differently from those of other chemical myelopathies in that they developed in the deeper white matter with sparing of marginal myelinated fibers. Circumscribed high concentrations and gentamicin, and vulnerability of myelinated axis cylinders and interfascicular oligondendroglia to gentamicin may be the main factors causing these lesions. When gentamicin sulfate without preservative was injected, neutrophil leukocyte infiltration occurred actively in the spongy lesions. In the cervical spinal ganglia some nerve cells underwent cytoplasmic vacuolation. In control animals a single intracisternal injection of saline or preservative did not result in the production of these lesions.


Cytologic observations on axotomized feline Betz cells. 1. Qualitative electron microscopic findings. Adult cats survived left lateral funiculotomy 1 to 153 days. The pericruciate cortex was studied electron microscopically in these as well as sham-operated and unoperated animals. Ten days after surgery Betz cells of the right pericruciate cortex displayed disaggregation of cytoplasmic ribosomes; random dispersal and degranulation of the normally compact arrays of cisterns of rough ER; in some cells perinuclear and peripheral disposition of remaining Nissl bodies; retispersion of the Golgi apparatus; and, uncommonly, neurofilamentous hyperplasia. Fourteen days postoperatively cytoplasmic ribosomes were largely regrouped in rosette arrangements and Golgi membranes were evenly distributed in the cytoplasm. Further reversion of the ER toward a normal appearance occurred 28 days postoperatively but substantial perikaryal atrophy had supervened in many neurons by 49-153 days after surgery. Evidence of nerve cell death was not found. Concentric membranous arrays derived from ER and associated with autophagic bodies and mitochondria were identified in dendrites of normals and cats that had been operated upon, perhaps more frequently contralateral to the spinal operation. Electron-dense and electron-lucent degenerative changes in dendrites also occurred, especially early after operation. Degenerating myelin sheaths were detected in the pericruciate cortex of animals that had been operated upon and sometimes were captured in the process of phagocytosis by oligodendrocytes as well as astrocytes and microglia. The long-term persistence of axotomized Betz cells, albeit in an atrophic state, and the reversibility of some of the cytologic responses to axon injury suggest that these neurons may retain a capacity for axon regeneration that could be mobilized, as by pharmacologic means.


A pigmented choroid plexus carcinoma: histochemical and ultrastructural studies. A large tumor of the left lateral ventricle in a 3 1/2 year old male was diagnostic of malignant choroid plexus papilloma (choroid plexus carcinoma) as observed histologically. Focal neoplastic epithelial cells contained yellow-brown pigment which was not entirely compatible with melanin by histochemical techniques. Ultrastructurally, the tumor had definite evidence of choroid plexus origin. The neoplastic cells contained electron-dense and lamellar bodies, as well as structures of intermediate type. Premelanosomes were not observed. Thus there was no evidence for neural crest melanin. It is suggested that the pigment is probably lipofuscin and melanin derived from lipofuscin by "melanization" through pseudoperoxidation.


Program-level evaluation using management information. This paper has summarized the development of a drug abuse treatment program MIS, and has shown that one can initially start with a manual system, use it to advantage, and then move into computer programming. In larger programs, it will most likely be necessary to use the computerized system. However, the author has found that implementation costs have not been great, and the system has certainly been worthwhile in light of the dimensions that have been added to the program. The computer MIS that has been developed is completely modularized from the perspective that either one or all modules may be used. Small programs that need only demographic data can use selected aspects of the system without having to pay for or use the rest. Those who only need counseling information can use just that, and those who only wish to have economic activity can also be selective. The strength of this MIS is based upon the fact that it is completely flexible; it is cost effective, and can be used by programs of any size. Finally, use of a sophisticated MIS in drug treatment programs adds a professional facet to service delivery which has long been missing in the drug abuse field.


The effect of mitochondrial dysfunction on glucose metabolism during shock. Hepatic glycogen content, blood glucose and lactate concentrations, and hepatic mitochondrial energy-linked functions were measured in rats in late hemorrhagic shock. As judged by correlation coefficients, the following significant relationships were noted: (formula: see text). Glycogen depletion, hypoglycemia, and lactic acidemia occurred frequently. However, alone or in combination, these variables did not relate significantly to need for or amount of shed blood uptake prior to sacrifice. Neither hepatic glycogen depletion nor uncoupled hepatic mitochondrial oxidative phosphorylation alone accounted for hypoglycemia. The genesis of hypoglycemia was determined by the occurrence of both these events in either sequence. When hepatic mitochondrial oxidative phosphorylation became uncoupled, the blood glucose concentration and hepatic glycogen content were linearly related (r = 0.94). This effect probably results from impaired gluconeogenesis due to mitochondrial dysfunction.


Regional gastric blood flow in cynomolgus monkeys with hemorrhagic shock and resuscitation. Five anesthetized cynomolgus monkeys were subjected to hemorrhagic shock (42 +/- 3 mm Hg) for four hours and then resuscitated with shed blood and intravenous fluids to restore mean arterial pressure and arterial pH to control levels. Regional gastric blood flow was measured by radioactive microspheres. Responses were similar in all regions, except mucosal blood flow increased significantly (from 20.1 +/- 5.1 to 42.1 +/- 7.6 ml/min 100 gm of tissue) in response to resuscitation in the antrum but not in the fundus or corpus. This difference in response may explain the occurrence of stress ulcers in the proximal stomach with sparing of the antrum.


Zymosan-induced resistance to endotoxin and hemorrhagic shock. Improved surgical techniques and judicial use of available antibiotics have reduced the number of postoperative complications over the past decade. However, septic and hemorrhagic shock occur all too frequently, and each carries with it an appreciable morbidity and mortality. Endotoxins and hemorrhage are both known to suppress the phagocytic activity of the reticuloendothelial system (RES). On the other hand, zymosan, a yeast (Saccharomyces cerevisiae) cell wall preparation administered intravenously, results in temporary RES hyperplasia and increased phagocytic activity. Dogs were pretreated with zymosan to determine the degree of RES stimulation and protection against endotoxin and hemorrhagic shock attainable. Twenty-five dogs received intravenous zymosan (10 mg/kg) on days 1, 2, and 3. Another 24 dogs served as controls. On day four, one-half the animals in each group received E coli endotoxin (1.5 mg/kg) intravenously. The other animals underwent two hours of hemorrhagic shock at a mean blood pressure of 40 mm Hg. Seventy-two hour survival was as follows: Endotoxin treated, 66.7% (8/12); endotoxin control, 27% (3/11); hemorrhagic treated, 53.3% (8/15); and hemorrhagic control, 28.6% (4/14). Hemodynamic, metabolic, and lysosomal enzyme parameters were evaluated. No zymosan toxicity was observed. These findings suggest that an RES stimulant such as zymosan could be incorporated as preoperative adjunctive therapy to induce resistance to these shock syndromes in the elective surgical patient.


The effect of indomethacin on cardiovascular and lysosomal mechanisms during experimental myocardial ischemia. The present study evaluated the effects of indomethacin (INDO) on cardiovascular and lysosomal mechanisms during experimental myocardial ischemia (MI). INDO (5 mg/kg) was infused IV prior to MI, and the results were compared to vehicle-treated and sham-operated dogs. INDO induced a slight hypertension after MI. Additionally, INDO attenuated the decline in coronary blood flow in the non-ischemic myocardium after MI. Myocardial lysosomes (biopsied three hours post-MI) were more labile in ischemic than in nonischemic tissue, and INDO had a stabilizing effect on lysosomes from ischemic tissue. Plasma activity of cathepsin was increased following MI, and INDO attenuated this increase. In the myocardium (biopsies three hours post-MI) prostaglandin A + E levels were suppressed 60% in both ischemic and nonischemic tissue with INDO treatment; prostaglandin F2 alpha levels were lower with INDO treatment but not significantly so. These results suggest that INDO has a stabilizing effect on lysosomes in vivo, possibly involving an endogenous prostaglandin mechanism, and this protective effect may attenuate lysosomal damage to the cardiovascular system during MI.


Glucagon treatment of hemorrhagic shock: improved survival and metabolic parameters in a murine shock model. One hundred-twenty Sprague-Dawley rats were shocked at 60 torr for 60 minutes and at the end of this period shed blood was reinfused. The animals were divided into three groups at random. These groups were either treated by N saline or glucose in N saline or glucagon in N saline. Glucagon treatment resulted in increased liver and muscle glucose-glycogen stores in the late period following shock. This was associated with a decrease in liver pyruvate and lactate and improved survival. It appears that glucagon more favorably affects the response to shock in this model than does treatment with glucose or saline.


Alterations in venous compliance in hemorrhagic shock. Nine dogs and one primate were placed on total cardiopulmonary bypass and subjected to a simulated hemorrhagic shock procedure. Venous compliance was determined by occluding the venous outflow catheters; venous flow and pressure drop were used to calculate resistance. Individual measurements were made for the superior (SVC) and inferior vena caval (IVC) beds. During hypotension, compliance increased equally in the SVC and IVC; following reinfusion, IVC compliance was consistently lower than SVC compliance. Resistance of the sVC system increased slightly more rapidly during early hypotension than did that of the IVC, but SVC resistance then decreased and remained significantly below that of the IVC system throughout the posthypotension period. These results are interpreted as indicating a different response of the two vascular beds, particularly an increase in IVC arteriolar resistance with a decrease in venous tone. To the extent that the splanchnic bed contributes to the IVC system changes, they are contrary to the concept of a maintained venous tone and decreased arteriolar tone after hemorrhagic shock.


The effect of arachidonic acid on the response of the isolated liver to hypoxia. Arachidonic acid, the precursor molecule of the bisenoic series of prostaglandins, was investigated for its ability to modify the response of isolated perfused livers to hypoxia. Rabbit livers were perfused at a constant rate of flow with Krebs-Henseleit bicarbonate buffer for two hours following the initiation of severely hypoxic conditions. This procedure resulted in significant increases in the wet weight of the liver, and also resulted in the release of intracellular enzymes into the perfusion medium. These changes were significantly attenuated in hypoxic livers receiving arachidonic acid during the two-hour perfusion period. Results of this study suggest that arachidonic acid may be of value in its ability to maintain cellular integrity during periods of cellular hypoxia.


Studies of the ischemic pancreas in shock. Exocrine pancreatic tissue from 65 male Sprague-Dawley rats was studied by light and electron microscopy to determine if acute lethal and sublethal alterations seen in the human exocrine pancreas following shock could be duplicated in an animal model. Two models were used: one in which 50% of the blood was withdrawn via cardiac puncture with no reinfusion and another in which the animal was subjected to a hypovolemic episode (40 mm Hg) for 60 minutes, with reinfusion of the blood. Animals were killed at various intervals, and pancreatic tissue was sampled for morphological study. No differences were seen between experimental and control animals by light microscopy. The main subcellular alteration seen using these models was the formation of numerous autophagic vacuoles. From these studies it appears that the alterations seen in the human pancreas in shock can be duplicated in the rat and that a shock model that involves removal of more than 50% of the animal's blood volume is necessary to cause irreversible cell damage to the exocrine pancreas.


Hypoxia, hyperammonemia, and cerebrospinal fluid metabolites. During hemorrhagic shock, increased uptake of NH3 from the gut with inadequate compensation by the liver results in hyperammonemia. The effect on brain metabolism of acute hyperammonemia alone, as compared with normocapnic hypoxia, was investigated in 11 pentobarbital anesthetized (30 mg/kg) dogs. These animals were paralyzed (pancuronium bromide) and artificially ventilated to maintain the end-tidal fraction of FETCO2) CO2 constant. Arterial blood and cerebrospinal fluid (CSF) samples were obtained following control, 30-minute hypoxia, 60-minute NH3 infusion, and 30-minute hypoxia combined with NH3 infusion. These were analyzed for PaO2, PCO2, pH, and NH3. CSF samples were further analyzed for glutamine, urea, lactate, pyruvate, and citrate. There were no significant changes in urea or citrate. Glutamine, lactate, and the lactate/pyruvate ratio were significantly elevated by hypoxia and by NH3 infusion. (formula: see text). Thus, an acute NH3 load is capable of disrupting aerobic glycolytic metabolism. Hence, hyperammonemia may affect brain function during shock.


Effect of moderate hemorrhagic hypotension on cerebral metabolism during ventriculocisternal perfusion in the conscious dog. Early changes in cerebral metabolism during hemorrhagic hypotension in conscious dogs have been studied with a chronic ventriculocisternal perfusion system. The mean arterial blood pressure was held above the lower limit of the cerebral autoregulatory curve. There was a rise of free fatty acids (FFA) in cerebrospinal fluid at 30 minutes after the onset of hemorrhage. The cerebral arteriovenous difference of oxygen (AVDO2), AVD-glucose, and AVD-pH increased significantly after 60 minutes of hemorrhage, while AVD-TCO2 (tissue culture oxygen) rose only slightly. These changes may reflect some of the metabolic alterations that occur in moderate hypotension.


Evidence for pathophysiologic arteriovenous shunting in the pathogenesis of acute gastric mucosal ulceration. The triad of gastric mucosal ischemia and lumenal acid and bile is known to be ulcerogenic. However, the explanation for progressive mucosal injury after resuscitation from hemorrhagic shock is not known, because ischemia does not persist. To test the hypothesis that persistent pathophysiologic arteriovenous shunting is the cause of progressive mucosal injury after shock, we studied in vivo canine gastric mucosal oxygenation and transmembrane potential difference during and after one hour of hemorrhagic shock with and without topical acid (160 mM HCl) and taurocholate (1 mM) in the mucosal bathing solution. Although systemic blood pressure and total gastric blood flow returned to normal after shock in all groups, only the group with topical acid and taurocholate developed mucosal erosions and had persistent hypoxia and inhibition of potential difference in surface epithelial cells. We conclude that pathophysiologic arteriovenous shunting persists in the superficial part of the gastric mucosa after shock. It is tempting to speculate that shunting may replace ischemia in the ulcerogenic triad during the postresuscitation phase of injury.


Influence of hyperglycemia on survival after hemorrhagic shock. Terms such as "insulin resistance" and "glucose intolerance" applied to shock-induced hyperglycemia suggest that this state may prejudice survival. However, our data indicate that posthemorrhage hyperglycemia improves short-term survival. Rabbits, either fed until the experiment or fasted for 24 hours, were shocked by rapid removal of 25% of their blood volume (BV) measured by 131IHSA. During the next 60 minutes, blood pressure (BP) was recorded, and the following variables were measured every 10 minutes: plasma volume (PV); arterial and venous plasma osmolality (PO), glucose, lactate, Na, K and hematocrit. Other fasted animals studied similarly received short intravenous pulses of hypertonic xylose after bleeding. The PO of fed animals, who all survived for 60 minutes rose to an extent accounted for by rises in glucose and lactate. A significant PV fluid gain was maintained for 60 minutes. The fasted animals, 42% of whom died before 60 minutes, had a flat glucose curve with a correspondingly small rise in PO. The PV fluid balance, after an initial small gain, became negative. Although a lower blood pressure in fasted rabbits was probably due to lack of PV refill, death resulted from hyperkalemia. Poor tolerance of fasted animals to shock is not attributable only to less glucose for energy metabolism, because when they received xylose, homeostatic features of fed animals were restored. The data suggest that, immediately after hemorrhage, glucose acts as a nonpermeant solute drawing fluid into the circulation. This study also shows that control of the nutritional status of animals used for shock models is important.


Ultrastructural study on kidney cell injury following various types of shock in 26 immediate autopsy patients. In acute renal failure in man following shock and trauma, an amazing discrepancy was found between the complete breakdown of renal function and the very modest histological and ultrastructural changes in "immediate autopsy" patients, even in those who sustained septic shock. Although, from this limited number of studies no satisfactory interpretation of the pathogenesis of acute renal failure can be deduced from the structural changes found, the findings do indicate that hypoxia plays a key role in aggravating the structural changes that induce permanent cell damage in man following shock of various etiologies including septic shock.


Effects of hydration and physical therapy on tracheal transport velocity. A new tracer method for quantitative measurement of tracheal transport velocity (mm per min) in dogs has been described. Using the same technique, the effects of dehydration, rehydration, postural drainage, and chest percussion on tracheal transport velocity were studied. Mean tracheal transport velocity decreased significantly (14.1 +/- 1.4) after dehydration (P less than 0.05) and reverted to normal (19.0 +/- 1.3) with rehydration in 10 dogs. After postural drainage in 7 dogs, mean tracheal transport velocity increased 39.7 +/- 1.78 (SE) per cent (P less than 0.01). After chest percussion in 6 dogs, mean tracheal transport velocity increased 50.9 +/- 1.22 (SE) per cent. With combined postural drainage and chest percussion, mean tracheal transport velocity increased 50.0 +/- 0.32 (SE) per cent. Although maximal improvement occurred after the combined therapy, the changes were not significantly different from those observed with each therapy alone. These therapeutic measures have been used empirically in the past. The present study gives some objective evidence for their beneficial effects in anesthetized dogs.