Drug uptake and ribonucleotide profiles of blast-enriched and blast-depleted human bone marrow cell populations. A density cut method was used to prepare two subpopulations of bone marrow cells which were enriched (BE) and depleted (BD) respectively of blast cells. Marrow aspirates were obtained from 32 patients, 26 of whom had acute leukaemia. The uptake of a variety of chemotherapeutic agents by these two subpopulations and the acid-soluble ribonucleotide profiles of the populations were compared and significant differences were found in drug uptake by BE and BD subpopulations. For some drugs such as cytosine arabinoside, uptake was greatest by the BE cells, while for 5-azacytidine the BD subpopulation took up the greatest amount of the drug. The preparation of the BE subpopulation also permitted the recognition of several patients with acute leukaemia whose blast cells possess nondetectable levels of ATP, UTP, and GTP components in their acid-soluble fractions. The studies presented demonstrate the necessity of using purified cell populations when characterizing the drug uptake patterns and the soluble ribonucleotide profiles of the leukaemic cells. A simple method for enriching bone marrow aspirates for leukaemic cells is also presented.


Quantitation of the reticuloendothelial system clearance of soluble fibrin. Phagocytosis of particulate fibrin has been previously established as a function of the reticuloendothelial system (RES). More recently, reticuloendothelial cells have been shown to bind soluble fibrin/fibrinogen (f/F) complexes in vitro. To quantitate RES clearance vs microthrombus formation, varying doses (0.1-6 mg/kg) of 125I-soluble f/F was injected into rabbits. One hour later the animals were killed, at which time 48 +/- 8% of the 125I f/F had been cleared from the blood. Homogenized organ samples were separated into insoluble pellet, soluble protein bound, and free 125I. Treatment of other samples with plasmin prior to homogenization differentiated the insoluble 125I into RES cleared (intracellular-plasmin resistant) vs microthrombi (plasmin sensitive pellet 125I). 125I-f/F was chiefly found in liver and spleen. Injection of low f/F concentrations resulted in no plasmin sensitive pellet 125I. 3 mg/kg f/F caused small, variable amounts of plasmin sensitive pellet 125I, chiefly in the kidney. With 6 mg/kg, 21-50% of the insoluble 125I in all organs was plasmin sensitive, and occasional 1-2 mm thrombi were found. The data indicate complete and rapid RES clearance of small amounts of soluble f/F from the blood, without microthrombi being formed. The RES was acutely saturated at 1.5-3.0 mg f/F/kg, which is equivalent to immediate conversion to fibrin of 1-2% of the intravascular fibrinogen pool.


Comparison of heparin and a semi-synthetic heparin analogue, A73025. I. Kinetics of clearance from the circulation of man following intravenous injection. A study has been made of a low molecular weight semi-synthetic heparin analogue, A73025, that may be clinically useful as an antithrombotic agent because of its reported high specificity for antithrombin III. The clearance from the circulation of both heparin and the analogue has been studied in man following intravenous injection. Heparin obeyed almost first order kinetics when assayed using a specific anti-Xa assay and first order kinetics when measured with KCCT. At high concentrations the heparin analogue was cleared with first order kinetics when assayed both with the anti-Xa assay and with KCCT. At low concentrations the analogue produced between one half and two-thirds of the anti-Xa activity of an equal dose of heparin, producing only a small prolongation of KCCT. With increasing dose, the more specific anti-Xa potentiating effect of A73025 decreased because of a flattening of its anti-Xa dose-response curve. These results suggest that the analogue might be useful as an antithrombotic agent when it is used as a prophylactic agent.


Comparison of heparin and a semi-synthetic heparin analogue, A73025. II. Some effects on platelet function. A comparison has been made of some effects of a semi-synthetic heparin analogue, A73025, and heparin upon platelet function. In several of the in vitro tests performed, such as their potentiating effects on ADP and adrenaline induced aggregation and their effects on the aggregation of washed platelets by activated factor X, heparin proved to be more potent than A73025. Following intravenous injection of twice the quantity of A73025, an equivalent anti-factor Xa activity was obtained, in the agreement with our previous studies. However, it was found that PRP containing heparin and A73025 with comparable anti-Factor Xa acitvity responded differently to the addition of thrombin, as A73025 barely inhibited thrombin induced aggregation. Similarly, A73025 had little effect on the dilute thrombin clotting time of plasma, following intravenous injection. Heparin and A73025 were neutralized to approximately the same degree by a crude PF4 preparation.


Immunological studies in combined factor V and factor VIII deficiency. Plasma samples from patients with inherited combined factor V and factor VIII deficiency were examined by immunological methods for the presence of factor V and Factor VIII-related antigens. A factor V-related antigen was consistently demonstrated in all plasma samples by inhibitor neutralization assay using a non-precipitating rabbit antibody. Factor VIII-related antigens were detected by inhibitor neutralization using human antibody and by electroimmunoassay using a precipitating rabbit antibody. The amounts of factor V and factor VIII-related antigens present in the patient's samples were similar to those found in normal human plasma. The findings confirm the presence of normal levels of factor VIII-related antigen in the plasma of these patients and suggest that inactive antigenic determinants of procoagulant factor V and procoagulant factor VIII are also present. The results are consistent with the possibility that a common precursor of porcoagulant factor V and factor VIII is defective in these patients.


The exchangeable splenic platelet pool in response to selective adrenergic beta-i-receptor blockade. The aim of the present work was to investigate the effect of selective beta-I-blockade on the exchangeable splenic platelet pool (ESPP). Therefore, 50 mg of metoprolol (a selective beta-I-receptor blocking agent) was given by mouth to three groups of subjects: (1) 15 healthy volunteers, (2) five asplenic subjects, and (3) 10 patients with different myeloproliferative disorders (MPD) with and without splenomegaly. The platelet count was determined 90, 150, 210, 270 and 330 min after the ingestion of the drug. In the group of healthy controls a significant increase (P less than 0.005) in the platelet count occurred and amounted to about 10% over baseline. The average peak value was reached at 150 min and the elevation in platelet count was maintained more than 4 h. An increase in the platelet count was also induced in patients with MPD, but the mean for the peak value only reached borderline significance (0.10 greater than P greater than 0.05). In the group of asplenic subjects no change in the platelet count occurred. It is concluded that acute oral administration of metoprolol causes a significant release of platelets from the ESPP. This platelet release is, however, no enhanced if the ESPP is enlarged.


Assay of ristocetin co-factor using fixed platelets and a platelet counting technique. A new assay of ristocetin co-factor has been developed which is based on platelet counting using a Coulter Counter. A modified method of washing and fixing platelets has also been devised to provide a suitable platelet preparation which can be used in this assay. These fixed platelets have consistently proved to be satisfactory and have given high levels of maximum percentage aggregation. They have been stored for periods up to 6 months without significant deterioration. The method of platelet counting is simple in operation and sensitive to relatively low levels of platelet aggregation. It is precise and seems to offer distinct advantages over existing methods.


A sex difference in the platelet count.

A sex difference in the platelet count. A study of the platelet counts of 868 blood donors aged 18-65 showed a higher mean count in women than in men, the difference in the premenopausal age groups being highly significant (P less than 0.001) and of the order of 40-70 x 10(9)/1. The mean counts of women taking a contraceptive pill did not differ significantly from those who were not.


Radioimmunoassay of human eosinophil cationic protein. A radioimmunosorbent assay has been developed which allows the detection in serum of a cationic protein derived from eosinophil granulocytes. In 34 healthy individuals the mean level was 31 microgram/1. with a range of 5-55 microgram/l. The serum concentration of 'eosinophil' cationic protein was correlated (p less than 0.001) to the number of eosinophil granulocytes in peripheral blood. Quantitation of 'eosinophil' cationic protein in serum might be useful in the study of eosinophil granulocyte turnover and function in vivo.


Increased survival of haemopoietic pluripotent stem cells in vitro induced by a marrow fibroblast factor. When mouse bone marrow was incubated in medium conditioned by marrow fibroblasts, the survival of pluripotent stem cells (CFUs) was considerably greater than when marrow was incubated in fresh medium. This increase in CFUs survival depended on the age of the marrow fibroblast culture, the initial number of cells in the culture, and the concentration of the conditioned medium. Medium conditioned by fibroblasts from other adult tissues--spleen, bone, and subcutaneous tissue--did not increase CFUs survival, but medium conditioned by embryo bone did. The increase in CFUs survival by marrow-fibroblast-conditioned medium was not accompanied by any change in the total number of nucleated cells of the incubated marrow nor by any comparable increase in the survival of granulopoietic stem cells (CFUc) or erythropoietic stem cells (BFUE). These results indicate that marrow fibroblasts produce a factor that increases the survival of CFUs, which may be involved in the role of marrow stroma in the control of haemopoiesis.


Kinetics of erythroid and myeloid stem cells in post-hypoxia polycythaemia. The number of erythroid burst-(BFU-E) and colony-forming units (CFU-E), as well as of myeloid-macrophage colony-forming units (CFU-C), has been evaluated in tibial marrow and spleen of ex-hypoxic polycythaemic mice, at sequential time intervals after the end of hypoxia. In both marrow and spleen, the kinetics of the CFU-E pool is characterized by a sharp fall from above normal to lower than normal values. BFU-E and CFU-C however rise from below normal to higher than normal levels. These results have been correlated with both the erythropoietin (Ep) and the erythropoietic activity curves. It is apparent that Ep levels largely control both the differentiation and the amplification of the CFU-E pool and it is suggested that Ep may act as a 'survival  factor' at the CFU-E level and/or increase the flow of cells from BFU-E to CFU-E. The difference in response between CFU-E and BFU-E favours a clearcut distinction between these populations, whereas the similarity between the BFU-E and CFU-C response suggest a close relationship between these two cell populations. It is also of interest that the murine spleen functions as a large reservoir of erythroid microenvironment for hypoxia-induced stress erythropoiesis.


Membrane proteins of incubated erythrocytes: effect of sulphydryl inhibition. Incubation of erythrocytes with various sulphydryl inhibitors for 24 h leads to an accumulation in isolated membranes of globin as well as an unidentified polypeptide of apparent molecular weight 24 000 on polyacrylamide gel electrophoresis. Accumulation of both these components does not appear to be directly related to erythrocyte adenosine triphosphate and reduced glutathione levels. The 24 000 molecular weight polypeptide is probably derived from the erythrocyte cytosol, as determined by polyacrylamide gel electrophoresis of the non-haemoglobin proteins of the cytosol. Together with globin it forms an integral part of the 'spectrin-actin lattice' of sulphydryl-inhibited erythrocytes, as both these components can be detected, together with spectrin and actin, after extraction of such membranes by Triton X-100. We postulate that this leads to inherent damage and distortion to the membranes of such erythrocytes.


Haemolytic anaemia associated with glucosephosphate isomerase (GPI) deficiency in a Black South African child. Haemolytic anaemia in a Black South African child was found to be associated with reduced glucosephosphate isomerase activity in the red cells. Apart from the haemolytic anaemia, there was no other clinical evidence of dysfunction. Family studies pointed to an autosomal recessive mode of inheritance, with the symptomatic homozygous propositus having a marked enzyme deficiency and the asymptomatic heterozygotes showing intermediate levels of activity. Biochemical characterization showed that, apart from being thermolabile, the electrophoretic mobility and the kinetic properites of the variant enzyme were similar to those of the normal wild type.


The fragility of normal and abnormal erythrocytes in a controlled hydrodynamic shear field. Fresh human erythrocytes (suspended in a compatible isotonic viscous saline medium containing plasma) were disrupted by the uniform shear stresses generated in the laminar flow field of a conventional cone and plate viscometer. A range of normal fragilities was established and blood samples from patients having certain well-defined haematological abnormalities were found to be partially or completely outside these limits. The present technique is sensitive enough to distinguish between young and old cell fractions isolated from the same original population and also appears to be able to resolve discrete sub-populations having different mechanical fragilities within unfractionated samples from certain patients (e.g. macrocytosis). This technique provides additional information which could aid or facilitate diagnosis and might eventually form the basis of a routine screening test in clinical haematology.


The measurement of red cell lifespan using 59Fe. Red cell lifespan has been measured using 51Cr and 59Fe in 19 patients. 59Fe can be used to give results which agree closely with those obtained using 51Cr provided that the plasma 59Fe clearance curve is properly defined and the data analysed correctly. In some patients elution of 51Cr may be more than three times the normal level and the use of 59Fe may provide the only reliable estimate of red cell lifespan.


Absorption of inorganic and haemoglobin iron in coeliac disease. Absorption from a 5 mg dose of iron as Fe++ or haemoglobin iron was studied using a Total Body Counter in control subjects and patients with coeliac disease. In both groups the majority of subjects were iron deficient. Thirteen control subjects, 13 patients with untreated coeliac disease and 14 on treatment with gluten-free diet had both absorption tests. Absorption of Fe++ iron was reduced in untreated coeliac disease. This was particularly significant in iron deficient patients. Absorption was improved on treatment with gluten-free diet; In contrast, the absorption of haemoglobin iron was not affected in coeliac disease, indicating that absorption of iron in this form is not dependent on the integrity of the mucosa of the proximal small bowel.


The histone content of chromatin preparations from leukaemic cells. The histone compositions of chromatin preparations obtained from different adult laukaemias were compared and showed differences between myeloid, monoblastic and lymphoblastic types. The differences were observed whether or not the myeloid precursors were mature or blast forms. Mixing experiments revealed that a potent histone protease was present in the myelocyte chromatin fraction which, unlike most histone proteases, appeared not to be inhibited by serine esterase inhibitors. It is concluded that the differences observed in the histone patterns do not reflect the histon composition present in the cell but are created by proteolytic degradation during the isolation procedures. However, these may still provide some help in identifying myeloblasts in undifferentiated leukaemias.


Nuclear labelling of leukaemic blast cells with tritiated thymidine triphosphate in 35 patients with acut leukaemia. A new technique which detects the presence of DNA polymerase and primer-template DNA by measuring the in vitro incorporation of [3H]thymidine-5-triphosphate (3H-TTP) into nuclei of leukaemic blast cells (LBC) was used in 35 patients with acute leukaemia. The 3H-TTP labelling index (3H-TTP LI) exceeded the fraction in DNA synthesis by a factor 1.4-24.3. The values of 3H-TTP labelling in the bone marrow always exceeded those obtained in the blood. In addition 10 normal bone marrows were studied; here, the 3H-TTP LI either exceeded or equalled the fraction of the proliferative pool in DNA synthesis.


Erythroid colony forming cells in aplastic anaemia. The concentration and erythropoietin dependence of erythropoietic progenitor cells (CFU-E) were examined in 13 patients with aplastic anaemia at different stages of their disease. The CFU-E incidence was shown to be quantitatively diminished in aplastic anaemia but tended to recover to normal values if the disease recovered. In addition the CFU-E showed a qualitatively different response to stimulation by erythropoietin, being resistant to low concentrations but responsive to concentrations greater than 0.2 U/ml whereas there was a linear response in the controls up to 0.5 U/ml.


Cytochemical profile of human haematopoietic biopsy cells and derived cell lines. Twenty-three human haematopoietic cell lines, normal and mitogen stimulated peripheral blood lymphocytes and tumour material from fresh leukaemias, myelomas and lymphomas were investigated with a panel of cytochemical reactions. Normal and mitogen stimulated lymphocytes, non-neoplastic lymphoblastoid cell lines (LCL), lymphoma lines with B-lymphocyte characteristics, chronic lymphocytic leukaemia and fresh lymphocytic lymphomas reacted weakly or negatively with all stains. T-lymphocyte acute leukaemia lines were PAS and alpha-naphtyl acetate esterase positive. Myeloma lines and fresh myelomas were strongly beta-glucoronidase positive. A histiocytic lymphoma cell line was strongly esterase positive with naphtol AS-D acetate esterase inhibited by NaF. The three fresh histiocytic lymphomas, however, reacted as the lymphocytic lymphomas suggesting a lymphoid origin. A myeloid leukaemia line was strongly positive for acid phsophatase. No major disagreement was noted between the reactivity of established neoplastic lines and the corresponding fresh biopsy cells indicating an unaltered qualitative expression of enzyme production after prolonged in vitro culture.


Ferritin in human liver cells of homozygous beta-thalassaemia: ultrastructural observations. Homozygous beta-thalassaemia is a disease in which there is a progressive iron overload from infancy to death in early adulthood. Liver biopsies from 10 patients in various stages of this disease were examined by electron microscopy. A number of round or oval lysosomal structures, containing lamellae different from myelin figures, were seen in all patients, including those with minimal iron overload. Ferritin molecules were seen either in relationship with the lamellae forming arrays, or in paracrystalline arrangement, or with no organized form. There were practically no ferritin molecules in sub-cellular compartments other than cell sap and lysosomes. The density of cell sap ferritin was constant beyond infancy, but the number of iron-laden lysosomes increased with age. The stages in the process of iron seclusion, seen even in advanced phases of iron overload, are described. Ferritin is thought to accumulate in lysosomes by a transmembraneous movement, but other explanations are considered.


Inhibition of platelet function with 2,3-dihydroxybenzoic acid. 2,3-Dihydroxybenzoic acid (2,3-DHB) inhibits the second wave of platelet aggregation release of serotonin, and malonaldehyde production. The effect is concentration dependent and reversible in vitro and in vivo. 50% inhibition of platelet aggregation induced in vitro with 70 micron adrenaline was obtained with 1.5 mM 2,3-DHB. Malonaldehyde production was inhibited by 50% with 0.4 mM 2,3-DHB. Serotonin release was 50% inhibited by 50% with 0.08 mm 2,3-DHB. Neither desferrioxamine nor various benzoic acid derivatives with iron-chelating properties showed the effect. Only benzoic acid derivatives with the potential to terminate free radical reactions through the formation of an ortho- or paraquinone structure inhibit the second wave of platelet aggregation. These studies support the concept that the second wave of platelet aggregation is mediated through free radical reactions.


C-scan ultrasonography in orbital diagnosis. A C-scan imaging facility has recently been added to the ultrasonic system in use at Moorfields Eye Hospital, London. The technique is explained and typical C-scans are presented to demonstrate the normal orbital fat and optic nerve, together with selected pathological conditions in the orbit. The C-scan facility permits imaging of the orbital contents in the coronal plane. This coronal plane imaging, together with high resolution and sensitivity, makes this a useful technique for demonstrating orbital lesions and it is hoped helps in the accurate measurement of the diameters of the optic nerve along its length. The problems associated with C-scanning are discussed.


Complicated retinal detachment and its management with pars plana vitrectomy. Fifty patients with retinal detachment accompanied by vitreous haemorrhage, perforating eye injuries, intraocular foreign bodies, massive preretinal retraction,.giant tears greater than 180 degrees, and proliferative retinopathies underwent pars plana vitrectomy, cryocoagulation, scleral buckling, and intravitreal gas injection. Intraoperative complications included minimal to moderate bleeding and iatrogenic retinal tears, but no retinal dialysis was produced at the pars plana sclerotomy site. Postoperative complications included recurrent vitreous haemorrhage, rubeosis, haemolytic, erythroclastic, or neovascular glaucoma, transient increase of intraocular pressure, uveitis, and macular pucker. Phthisis bulbi occurred in 6 eyes; in 3 of these eyes enucleation was required. Successful reattachment was accomplished in 56% of these complicated retinal detachments, most of which had been considered inoperable by conventional techniques. Visual improvement was achieved in 46% of eyes. Follow-up ranged from 6 to 29 months.


Keratoconus and coexisting atopic disease. The association of keratoconus and atopic disease has been reported on several occasions but the only controlled clinical study that has so far been published found no evidence to support this view. Since it is now known that atopy is often associated with changes in various immunoglobulins, particularly IgE, it was considered desirable to determine the immunological profiles of a large series of keratoconus cases in order to seek evidence for coexistence of the two conditions in one individual. In this study of 182 cases of keratoconus a definite history of atopy was found in 35% compared with 12% in the matched control group. The serum IgE was significantly raised (P less than 0.001) in keratoconus and markedly so in those cases with associated atopic disease. Serum levels of IgG and IgM were also raised, but contrary to the findings of other observers IgA levels were normal. These findings suggest that atopic traits are more common in patients with keratoconus than in general ophthalmic patients.


On the relationship between strabismic amblyopia and eccentric fixation. Landolt C and grating acuity are compared with that normally expected of the eccentric fixation region for 10 strabismic amblyopes. The findings suggest that 2 populations of amblyopes exist. For some amblyopes visual function is that predicted of the eccentric region used for fixation, whereas for other amblyopes there is a further pathological reduction in visual function. These findings may have an important bearing on the type of orthoptic treatment used for amblyopia.


Gaze failure, drifting eye movements, and centripetal nystagmus in cerebellar disease. Three abnormalities of eye movement in man are described which are indicative of cerebellar system disorder, namely, centripetally beating nystagmus, failure to maintain lateral gaze either in darkness or with eye closure, and slow drifting movements of the eyes in the absence of fixation. Similar eye movement signs follow cerebellectomy in the primate and the cat. These abnormalities of eye movement, together with other signs of cerebellar disease, such as rebound alternating, and gaze paretic nystagmus, are explained by the hypothesis that the cerebellum helps to maintain lateral gaze and that brain stem mechanisms which monitor gaze position generate compensatory biases in the absence of normal cerebellar function.


Anterior segment surgery early after corneal wound repair. Penetrating wounds of the cornea require immediate repair, generally within 24 hours. Tight closure of the wound and a reformed anterior chamber are the primary goals of surgery. However, there is no guarantee that further surgery will not be required for maintaining the healthy function of the anterior segment. At the second operation the effect of the procedure on the previously repaired wound is of prime importance, since in many cases the operation needs to be done before corneal healing is completed. In our series the lens, which was either partially or completely cataractous at the initial operation, became intumescent at different times afterwards, and an immediate removal was necessary. No change in the preoperative wound sealing or transparency of the cornea could be detected after lens surgery performed between 24 hours and 21 days from the initial corneal repair.


An improved method for DNA alkaline gradient analysis and its application to the effect of carcinogens on mouse liver DNA. An alkaline sodium iodide density gradient technique is described, for use in sedimentation rate centrifugation studies of in vivo induction of single strand breaks in DNA. The combination of this type of gradient with a sensitive fluorometric DNA estimation makes it possible to analyze very small amounts of DNA without any need for labeling the nucleic acid with radioactive thymidine.


Quantitative variation of a 60S ribosomal protein during growth of the fungus Podospora anserina. During the growth phase, in the fungus Podospora anserina, a variation is observed in the composition of the ribosomal proteins. A protein of the 60S subunit which is absent in the ribosomes from 2 days old cultures becomes gradully more abundant as the culture time is prolonged.


Myelin consists of a continuum of particles of different density with varying lipid composition: major differences are found between normal mice and quaking mutants. Mouse brain myelin consists of a continuum of particles of different densities, as shown by sucrose density gradient centrifugation. In normal animals most of the material (65 per cent) is concentrated between 0.6 and 0.7 M sucrose (the maximum being found at 0.66 M sucrose, corresponding to 23 per cent). The density differences among various myelin fractions are related to their protein/lipid ratios, as lighter fractions contain less protein and more lipid. Lipid analysis shows a decrease in the amount of every lipid from the lightest to the heaviest fraction: the light fraction is richer in phosphatidyl-ethanolamine, phosphatidyl-serine and cerebrosides. The distribution is highly abnormal in purified myelin from Quaking mutant ; very low quantities of myelin with normal density are found, but unexpected large amount of high density particles are found, possibly related to a "pre-myelin" material (oligodendrogial) processes which are not maturing into normal myelin).


Bovine follitropin. Isolation and characterization of the native hormone and its alpha and beta subunits. 1) A reproducible procedure was developed for the purification of bovine follitropin. 2) The method involved ammonium sulfate precipitation, ion exchange and adsorption chromatography, concanacaline-A-Sepharose chromatography and gel filtration. 3) A specific radioligand receptor assay was used to monitor each chromatographical step. 4) The potency of highly purified bovine follitropin as measured by Steelman and Pohley bioassay was 62 times the NIH-FSH-B1 standard preparation. 5) Contaminations of bovine follitropin by other glycoprotein hormones such as thyrotropin and lutropin amounted to 3 and 0.45 per cent by weight respectively as measured by specific radioimmunoassays and radioligand receptor assays. 6) The subunits alpha and beta of bovine follitropin were obtained by incubation in acidic urea, the chains being then separated by anion exchange chromatography. The subunits were subjitted to complete characterization. The amino-terminal residue of the alpha subunit is phenylalanine while a half cystine residue was found at the aminoterminal end of the beta chain. 8) Cross-contamination of the alpha and beta subunit preparations was measured by specific radioimmunoassays and amounted to 0.02 and 0.1 per cent by weight respectively.


[Estrogens and cell multiplication in the adenohypophysis of the male rat: in vivo and in vitro studies]. A single dose (1 microgram) of oestradiol sub-cutaneously injected to an immature male rat promotes a transitory increase of the pituitary mitotic activity, the maximum of which is reached between 32 and 48 hours ; the observed fluctuations are similar to those previously described for the thymidine kinase activity. In these conditions, the concentration of blood prolactin remains unaltered, as were those of LH and FSH. It follows that hyperplasy of the pituitary can be quickly induced by doses of oestrogen that do not affect significantly the hormone release. Using Moxestrol, a synthetic oestrogen not bound by the oestradiol plasma binding protein, we show that in the very young rat, the in vivo responsiveness of the pituitary increases and reaches its maximum by day 17. This results can be tentatively related to the ontogeny of the oestradiol receptors in the pituitary described by others ; all our attempts to induce the thymidine kinase in cultured glands remained unsuccessful.


Changes of serum gonadotropin concentrations in premature babies submitted to phototherapy. In order to determine if phototherapy was influencing any change in plasma gonadotropin levels, we have compared a group of 8 premature infants (4 males and 4 females) who have been treated with phototherapy because of jaundice, to a control group of 6 premature infants who did not require phototherapy. During the third and fourth week of life, luteinizing hormone (LH) and folicule stimulating hormone (FSH), increased simultaneously in a significant range in phototherapy treated females. In the group of treated males, LH but not FSH increased significantly. Constant phototherapy and/or the sudden stopping of the treatment in the jaundiced premature newborn female is responsible for a marked and transient elevation of gonadotropins. A clear mechanism of the observed phenomenon with pathways including the retina, pineal gland and hypothalamus, is not apparent.


Postnatal development of cardiac output distribution measured by radioactive microspheres in rats. Distribution of cardiac output was measured in rats, 9, 18, 25, 42 and 64 days old, by means of 85Sr-labelled microspheres 15 micrometer in diameter. The fractions of the cardiac output supplying the heart, lungs, cerebrum, hindbrain, kidney, liver, spleen, stomach, small intestine, large intestine, bones and muscles of the hindlegs and skin were estimated. The values obtained were further related to the relative weights of the respective organs. The distribution of cardiac output changed with age, the changes being most pronounced in the brain, kidney and small intestine.


Maternal-fetal relationships in corticosteroid metabolism. Corticosterone in fetal mouse tissues after injection of mothers with 14C-corticosterone was determined by acetylation with 3H-acetic anhydride and cocrystallization to constant specific activity. The corticosterone content of whole fetal tissue varied between gestational days 13 and 17 from 641 to 300 ng/g. Specific activity of fetal hormone remained essentially constant; after a 15-min pulse this was as much as one-quarter that of maternal hormone. Placenta, head and liver showed distinctly different patterns which changed during this time, with a decrease in conversion of corticosterone to 11-dehydrocorticosterone. A sharp increase occurred in the activity of fetal liver 11beta-hydroxysteroid:NADP oxidoreductase activity. This mitochondrial enzyme, pH optimum 6, KM = 33 micrometer, reduced the metabolite, raising the relative amount of corticosterone in the fetus from 16 to 91%. 1 day after removal of maternal adrenals both maternal and fetal corticosterone were normal, indicating ability of fetal adrenals to function. Maternal corticosterone, however, crossed the placenta readily and it is considered likely that, normally, the maternal hormone predominates. Regardless of origin, corticosterone is maintained by enzymatic conversion in a distinct manner in different tissues.


Caffeine pharmacokinetics in young and adult dogs. The pharmacokinetics of caffeine were studied in young (age: 1 day, 7 days, 14 days, 30-45 days) and adult dogs following a single intravenous dose of 50 mg/kg. Mean (+/-SE) plasma elimination half life (T1/2) was 47.5 (+/-5.35) h in 1-day-old puppies, as opposed to 6.66(+/-0.85) h in adult dogs. A rapid decrease in plasma T1/2 values occurred during the first 2 weeks of life. At about 14 days of age caffeine plasma T1/2 was similar to that of adults. The volume of distribution was greatest (0.94+/- 0.03 liters/kg) and the total body clearance was smaller (2.81 +/- 0.73 liters/kg/min X 10(-4)) in the 1-day-old animals. The much smaller body clearance of caffeine in the newborn as compared to the adult dog could be due to a lower rate of metabolism and/or renal excretion of this drug in the young.


Noradrenaline appearance in guinea pig brown adipose tissue. Its significance in neonatal nonshivering thermogenesis. A rapid growth of the guinea pig brown adipose tissue occurred during the last third of fetal life. Endogenous noradrenaline was measurable was measurable from day 55 of gestation and rose until birth. The maximal noradrenaline concentration was achieved on the first day of extrauterine life and remained constant during the postnatal period. So, noradrenaline was present in brown adipose tissue at birth and could mediate the neonatal nonshivering thermogenesis activation as suggested in the discussion.


Superoxide dismutase activity and lipid peroxidation of the rat liver during development. The present work was an attempt to understand the effects of oxygen toxicity in the early neonatal period and was performed using rat liver homogenate and mitochondria as examples of superoxide dismutase (SOD) activity and lipid peroxidation. SOD activity of the liver was extremely low during the fetal period and approximately the 5th day after birth. However, a rapid increase in the level of activity was observed from about the 10th day after birth. By the 20th day, this had reached 88% of the level in the adult rat. Peroxidated lipids, in an inverse relation to SOD activity, occurred at high levels during the fetal and early neonatal period, but rapidly decreased after the 10th day. It can be considered, therefore, that protection against oxygen toxicity is inadequate in such rat livers during the fetal and early neonatal periods, but that it is well established by the 10th day after birth.


Rodent brain growth stages: an analytical review. Study of data in the literature on rat and mouse brain growth from birth to weaning reveals a stagewise growth in average brain weight. Rapid growth occurs in the intervals between days 0-6, 8-12, and 17-23 after birth. Slow growth periods then lie in the intervals 6-8, 12-17, and after 23 days. The first slow growth period is signalled by events occurring at its end: substantial acceleration of synthesis of RNA, DNA, protein, and myelin. The second slow growth period is characterized by at least a 3-day interval during which there is very little increase in average brain weight compared with what occurs just before and just after that period; the correlation among 12 studies is highly significant. Implications are discussed for cross-species' extrapolation of findings about brain development.


Skin barrier properties in the newborn. Transepidermal water loss and carbon dioxide emission rates. Relative permeabilities of newborn and adult skin to small molecules were determined by measuring emission of carbon dioxide and water vapor through skin. Transepidermal water loss (TEWL) measured on the forearm of 22 term infants was lower than that observed in 30 control adults (0.31 +/- 0.09 vs. 0.39 +/- 0.15 mg/cm2/h). There was no significant difference between newborn carbon dioxide emission rates (CDER) and adults CDER. When environmental temperature was raised from 74 to 80 derees F, large dramatic increases in adult TEWL were observed in contrast to small increases in newborns. This phenomenon suggests diminished eccrine activity in the newborn. No correlation of TEWL or CDER with respect to birth weight, sex, age or gestational age was observed. Similar permeability to carbon dioxide in neonates and adults and a decreased TEWL in neonates compared to adults suggest that even at birth the skin functions as an efficient barrier to these molecules, penetration rates, in adults, of other polar compounds should be similar to those in neonates.


Placental abnormalities in victims of the sudden infant death syndrome. Placentas from 79 victims of the sudden infant death syndrome (SIDS) were compared with placentas from 30,640 controls who survived in a search for evidences of infections or other disorders that might have damaged the SIDS victims before birth. Placentas from the SIDS victims had an increased frequency of acute funisitis, acute chorioamnionitis, lymphocytic infiltration of the decidua and macrophages in the fetal membranes. The acute funisitis and chorioamnionitis were associated with preterm deliveries and were probably related to amniotic fluid bacterial infections which are a common cause of premature delivery.


Oxypurine excretion in normal newborn infants. Hypoxanthine, xanthine, uric acid, 6-hydroxypurine, 2,6-hydroxypurine and 2,6,8-hydroxypurine, respectively, are the catabolic products of purine-containing compounds in the human body. Each of the compounds was determined, by enzymatic spectrophotometry, in the 24-hour urine samples of 23 newborn infants. The hypoxanthine excretions on the 1st, 2nd and 3rd days were 1.1 (0.7-1.6), 0.9 (0.1-1.4) and 0.7 (0.1-1.5) mumol/24 h/kg body weight. The xanthine excretion in the 1st, 2nd and 3rd days was: 0.5 (0.3-1.2), 0.6 (0.3-2.0) and 1.2 (0.4-1.9) mumol/24 h/kg body weight. The uric acid excretion in the 1st, 2nd and 3rd days was: 61 (33-150), 61 (20-142) and 76 (40-127) mumol/24 h/kg. All the values are given as median and 10% percentiles. The hypoxanthine excretion decreased significantly (p less than 0.05) and the xanthine increased correspondingly throughout the 3 days (p less than 0.05). The excretion of hypoxanthine plus xanthine showed no significant change throughout the 3 days, and comprised approximately 2.5% of the total oxypurine excretion.


Differential responses to prenatal malnutrition among neonatal rats. Female rats were fed (A) protein-restricted diet 1 month prior to mating and throughout pregnancy, or (B) protein-free diet during 10-20 days of pregnancy. At birth, four parameters of the offspring, body weight, cerebral weight, cerebral DNA, and cerebral protein were well correlated with each other, and were significantly lower than in the controls fed stock diet. The malnourished population had on the average 30-70% "outstanding low" individuals (parameter values more than 2 SD below the mean of the control); this is 13-20 times more than in the control. Even in malnourished populations a certain number of individuals escaped malnutrition (parameter values not lower than the mean of the control): they appear to be those which in normal populations would be well above the average. These individuals escaped malnutrition not by taking advantage of their littermates: the latter, though malnourished, were still better than the average in the malnourished group. The mechanisms by which some of the malnourished females differentially provide enough nutrients for one of their fetuses, and more than the average for its littermates, may involve differential mobilization of maternal nutrient among individual mothers, as well as differential blood supply to individual placentas or placental transfer to individual fetuses.


Fetal growth retardation following maternal morphine administration: nutritional or drug effect? The effects of maternal morphine administration on maternal nutrition and on fetal growth have been systematically examined in a rabbit model. Significant alterations in maternal food intake occurred morphine exposure. These nutrition changes did not result in fetal growth retardation. Fetal morphine exposure was associated with significant reductions in fetal weight, length, placental weight and in the weights of most organs including the brain. When organ weight was considered as a fraction of total fetal weight morphine exposure was associated with a significant increase in the relative weight of the brain and a significant decrease in the relative weight of liver and kidneys. These narcotic effects were dose dependent.


A multifunctional prosthesis control system based on time series identification of EMG signals using microprocessors. This paper describes a real-time system for separation among several limb functions, in order to provide multifunctional control of an upper-limb prosthesis for above-elbow amputees. The system employs microprocessor hardware and is based on identification of voluntary myoelectric signals resulting from isometric contractions of the musculature of the residual limb, and on subsequent discrimination of these signals for control of the several degrees of motion of the prosthesis. The system requires only one to two electrode sites. (Contrary to the usual placement of electrode pairs directly over specific muscle bellies, to eliminate crosstalk, we prefer to place our electrode pair between muscles so as to acquire the different weakly-correlated signals associated with each of several different voluntary functions). The system satisfies the various practical constraints of weight, volume, and speed, as arise in practical prostheses. Preliminary amputee tests on the system have resulted in an 85 percent success rate using 8-bit double-precision micro-computer hardware.


The final illness in cancer: the widow's perspective. Widows of cancer patients were compared with other widows in general and with widows of men with chronic cardiovascular disease in particular, special attention being given to the vicissitudes of the final illness. Despite the recent emphasis on the need for open communication about the impending death between the dying patient and his family, interviews with 73 women whose husbands had died of cancer revealed that 40% of those who had been told their husband was dying refused to accept the warning. Only 29% of the couples openly discussed the possibility of the husband dying of his disease. More than half of those who did not talk with their husband about the impending death reported that this made no difference to their initial adjustment to bereavement. The stress for a woman of her husband's final illness leads to an especially difficult bereavement period; for example, significantly more widows of cancer patients than of patients with other illnesses perceived themselves to be in poor health during the initial bereavement period. Some of the problems specific to cancer patients and their families are described, along with recommendations for their alleviation.


Evaluation of Duogastrome (carbenoxolone sodium) for the treatment of duodenal ulcer: a multicentre study. A double-blind study was carried out in 152 Canadian patients, 76 given Duogastrone (carbenoxolone sodium) capsules, 50 mg qid, and 76 given placebo capsules qid for 6 weeks. All patients had a duodenal ulcer diagnosed by roentgenography or endoscopy, or both. Evaluation of the efficacy of Duogastrone therapy was based on data from the 119 patients (59 treated with Duogastrone and 60 with placebo) who met all the strict requirements of the protocol. The ulcers healed completely in 75% (44/59) of the patients treated with Duogastrone and in 48% (29/60) of those treated with placebo; this difference is significant (P less than 0.01). The proportions were similar in the patients assessed only endoscopically: 76% (32/42) and 55% (26/47), respectively. In the group treated with Duogastrone the following side effects were noted: weight gain, edema, mild hypokalemia, increase in blood pressure and slight increases in serum concentrations of lactic dehydrogenase and alkaline phosphatase. None was serious. However, close clinical monitoring by weekly visits to their physician is recommended for every patient undergoing Duogastrone therapy, at least during the 1st month.


Brachial plexus injury.

Brachial plexus injury. A 28-year-old man shot himself in the left posterior triangle of the neck with a shotgun. At the initial operation secondary repair of the resultant brachial plexus injury was decided upon in view of the difficulty in assessing lesions in continuity at this point after injury. The patient had total brachial plexus palsy. Nine weeks after the injury sensory and motor function were returning and the only element of the brachial plexus not showing evidence of nerve fibre continuity was the musculocutaneous nerve. Sural nerve autografts were sutured between the trimmed proximal and distal stumps of this nerve. By 4 months after the injury there was further improvement in both sensory and motor function, and by 18 months there was sensation in the autonomous zones of both median and ulnar nerves and good return of muscle power.


Effects of phosphate supplementation on intact and fractured femora of rats: a biomechanical study. The production of a better and stronger healing bone has attracted the interest of many investigators in the past. Numerous substances have been used to increase both the strength and the rate of production of fracture callus. Recently phosphate, administered orally, has been suggested for this purpose. A biomechanical study was conducted with rat femora and variable doses of phosphate in this regard. Phosphate was found to benefit osteomalacic bones but to have no effect on normal bones and a toxic effect in high concentrations.


Long-term treatment of severe hypertension with minoxidil. Minoxidil, a new potent hypotensive agent, was used as the primary antihypertensive agent in 11 patients--10 men and 1 woman aged 35 to 54 years with severe hypertension that was refractory to treatment with maximal (or maximally tolerated) doses of conventional antihypertensive agents. Six patients had severely impaired renal function and three of them were undergoing long-term hemodialysis. The patients were given 2.5 to 40 mg/d of minoxidil for periods of 2 to 29 months. All except one who was almost anuric received propranolol and diuretics. Blood pressure was controlled satisfactorily in all patients. In two patients the hypertension became partially resistant after 1 year of treatment. The main side effects were sodium retention, tachycardia and hirsutism. Renal function remained stable or improved and hemodialysis was discontinued in two patients. Minoxidil is a remarkably potent hypotensive with relatively few side effects and seems particularly advantageous in patients with chronic renal failure.


Current medical management of duodenal ulcer disease. Each of three agents used in the treatment of duodenal ulcer--magnesium--aluminum antacids in high doses, cimetidine and carbenoxolone sodium--appears to enhance the rate at which ulcers heal, although their ability to control symptoms has been less clearly demonstrated. Since a large proportion of ulcers heal either without treatment or when the patient is given a placebo, a rational management plan should emphasize the removal of known irritants and the provision of symptomatic relief while spontaneous healing is allowed to occur. Lack of response to such a regimen warrants more specific investigation and therapy. On the basis of current evidence, cimetidine appears to be the preferred therapeutic agent.


Gas-liquid chromatographic analysis of the monosaccharide composition of acid glycosaminoglycans (mucopolysaccharides) derived from animal tissues. Quantitative, gas-liquid chromatography was investigated for analysis of the monosaccharide composition of acid mucopolysaccharides from animal tissues. The method entailed the analysis of the trimethylsillyl (Me3Si) derivatives of methyl glycosides on two liquid phases. Good resolution of monosaccharides was achieved by use of columns of SE-30 and Apiezon-M. The procedure was tested with chondroitin 4-sulfate, and the results were slightly different from those of Mathews et al. When the analysis is performed according to this method, important points are: (1) absolutely anhydrous, methanolic hydrogen chloride is necessary, to ensure detection of hexosamines and sialic acid; and (2) high moisture in the air obstructs high recovery of methyl glycosides and their Me3Si derivatives, except in the case of neutral sugars.


Haemodynamic changes during tilt after autonomic blockade in spontaneously hypertensive rats. The haemodynamic shifts during head up and head down tilt were investigated in adult spontaneously hypertensive rats (SHR) and matched normotensive control rats (NCR) under nembutal anaesthesia and autonomic blockage. During head up tilt a greater fall in blood pressure and stroke volume was observed in SHR than in NCR, while the reverse was true when tilted in the opposite direction. This altered cardiac response to venous filling, also observed in patients with essential hypertension, is suggested to be caused by an altered Frank-Starling relationship of the hypertrophied heart in hypertensive individuals.


Correlation of the mechanical responses of the heart with the norepinephrine overflow during cardiac sympathetic neural stimulation in the dog. The changes in heart rate and right ventricular contractile force were measured in anaesthetised dogs during stimulation of each ansa subclavia, and the responses were correlated with the overflow or norepinephrine (NE) into the coronary sinus blood. The increase in heart rate was considerably greater during stimulation of the right than of the left ansa subclavia. Conversely, left ansa stimulation had a slightly greater effect on right ventricular contractile force than did right-sided stimulation. The changes in norepinephrine overflow into the coronary sinus blood paralleled the alterations in contractile force; during stimulation at 2 and 4 Hz, the rates of norepinephrine overflow were 50 and 34% greater, respectively, with left-sided than with right-sided stimulation. On both the right and left sides, stimulation of the anterior limb of the ansa subclavia produced greater increments in heart rate and contractile force than did stimulation of the posterior limb. Similarly, the rates of norepinephrine overflow during anterior ansal stimulation were 100 and 75% greater than during posterior ansal stimulation for the right and left sides, respectively. Thus, both limbs of the two ansae subclaviae innervate the myocardial regions drained by the coronary sinus, but the greatest innervation arises from the anterior limb on the left side.


Effect of aminophylline on coronary reactive hyperaemia following brief and long occlusion periods. The effects of an intracoronary aminophylline infusion, adjusted to give a constant concentration of 25 microgram.cm-3 coronary blood, on the reactive hyperaemic responses following coronary occlusion for 4, 10, and 25 heart beats were investigated in anaesthetised, open-chest dogs. The vasodilator effect of intracoronarily-administered adenosine and the hyperaemic response after coronary occlusion for 10 and 25 heart beats were both significantly diminished under the influence of aminophylline. However, the decrease in the coronary dilator effect of adenosine amounted to 80%, whereas the hyperaemic response was diminished by only 20%. The hyperaemic response following a coronary occlusion for only 4 heart beats remained unchanged. The present results obtained with aminophylline suggest at least a partial involvement of adenosine in mediating reactive hyperaemia after sufficiently long periods of coronary artery occlusion.


Effects of oxygen on acute myocardial infarction: a thermographic study in the dog. An acute myocardial infarction was created in a series of dogs by ligation of a branch from the left anterior descending coronary artery. The effects on the infarction with 100% oxygen were studied by thermography in 23 animals. The changes in the infarction size were registered on polaroid photographs. In 10 dogs the infarction showed a uniform cool area, permitting accurate measurement by cutting out and weighing the black, infarcted area from the photographs. During oxygen administration 2 dogs showed a considerable increase in the cool area and 6 other dogs a moderate but significant increase. The remaining 2 dogs in this group showed non-significant change in the infarcted area. In the other 13 animals the cool area was not sufficiently uniform to allow accurate measurement. However, all the dogs in this group, except one, presented a visable increase of the cool area of varying degree. High oxygen supply does not seem to have a favourable effect on an experimentally induced acute myocardial infarction. It is known to promote a lowering of the coronary artery perfusion pressure. In addition to this, it may somehow decrease the arterial supply from the vascular bed round the ischaemic area.


Effects of hypercholesterolaemic serum on aortic explants from normal rats. Aortic explants obtained from normal adult rats and composed of all 3 tunics were cultured in a semi-synthetic gelosed medium supplemented by 10% serum. Explants cultured with normocholesterolaemic serum kept their in vivo characteristics for more than 12 days at electron microscope and histometabolic levels. However, explants showed considerable differences when cultured in a medium with hypercholesterolaemic serum. Cell proliferation in the tunica media and enhanced synthesis of macromolecular components of the extracellular matrix were observed. These laterations occurring inside the explants, which had kept all their tissular relationships, suggest that this culture system may be valuable for further studies on atherosclerotic processes.


Arterial glucocorticoid receptors: the binding of tritiated dexamethasone in rabbit aorta. Current concepts of the mechanism of the physiological action of both mineralocorticoids and glucocorticoids include an initial step in interaction between the steroid and specific receptors in the cytoplasm of target tissue cells. Using cells from rabbit aorta as a model system, we have studied the cytoplasmic binding of 3H-dexamethasone and 3H-aldosterone. Aorta cells appear to contain binding sites with a high affinity (Kd 4 degrees C approximately 1.3 X 10(-8) mol) for dexamethasone, and with specificity appropriate for glucocorticoid receptors. Under similar experimental conditions, mineralocorticoid receptors could not be demonstrated.


Postnatal ultrastructural changes in the cat myocardium: a morphometric study. In order to understand more clearly the basis for our previously observed postnatal age related changes in the mechanical performance of the cat myocardium we have carried out a quantitative ultrastructural analysis of right ventricular papillary muscles obtained from adult cats (1.8 to 2.3 kg), infant cats (16 days of age), and neonatal kittens (less than 72 hours old). Volume fractions were calculated for myofibrils, sarcoplasm, mitochondria, lipid, sarcoplasmic reticulum (SR), golgi, and nuclei. The myofibril content of neonatal fibres was significantly less than that of the infant or adult groups (P less than 0.05 and 0.005 respectively). In addition the infant fibres contained a smaller volume of myofibrils than the adult ones (P less than 0.001). The mitochondrial content of the neonatal fibres was also significantly less than that of either the infants' (P less than 0.005) or adults' (P less than 0.001). These data provide an anatomical basis for the progressive age related increase in mechanical performance of the cat myocardium, in postnatal life.


Failure of saralasin acetate, a competitive inhibitor of angiotensin II, to diminish alveolar hypoxic vasoconstriction in the dog. The role of angiotensin II in the pulmonary vasoconstriction induced by alveolar hypoxia was investigated with the competitive inhibitor of angiotensin, saralasin acetate. Unilateral alveolar hypoxia was induced in dogs by ventilation of one lung with 100% N2 through a double lumened endotracheal cannula while maintaining adequate systemic oxygenation by ventilating the other lung with 1oo% O2. Pulmonary perfusion was monitored with 133Xe and external detectors. In 8 dogs perfusion to the test lung on room air before N2 ventilation was 49.2% (SEM +/- 3.8) of total lung perfusion. After 7 min of nitrogen ventilation, perfusion to that lung was 35.6% (SEM +/- 2.9) of cardiac output (P less than 0.001), a reduction of 27.5% (SEM +/- 2.4). After infusion of 6--24 microgram.kg-1/min of saralasin acetate, beginning 2 min before the alveolar hypoxic challenge and continuing through it, unilateral alveolar hypoxia continued to reduce perfusion to that lung by 28.8% (P = 0.6 from control). In 2 dogs a higher infusion of 60 microgram.kg-1/min failed to reduce the alveolar hypoxic vasoconstriction and in 2 dogs a 15 min infusion of 6 microgram.kg-1 of saralasin acetate before alveolar hypoxia and continuing through it, still failed to inhibit alveolar hypoxic vasoconstriction. Thus, no role was demonstrated for angiotensin II in acute alveolar hypoxic vasoconstriction of the dog.


Physiological, biochemical, and morphological characteristics of myocardial anoxia: the use of a semi-perfusion canine preparation. Regional myocardial anoxia was produced in dogs by perfusion of the left circumflex artery (LCA) with deoxygenated blood. Isolated sarcoplasmic reticulum fragments (cardiac relaxing system) showed decreased Ca2+ binding and uptake. The ability of isolated mitochondria to utilise long-chain fatty acids was markedly reduced. This model has revealed inherent biochemical differences between ischaemia and anoxia.


New approach to local thermodilution: use of pig tail catheters to avoid basic difficulties. The use of pit tail catheters and the placing of the thermistor distal to the lumen for the cold injectate have allowed the development of a new catheter for local thermodilution with many advantages. Apart from its small size and possibility of percutaneous introduction, the spatial orientation of the thermistor to the rest of the catheter and to the port of injection ensures: (a) its absolute thermal insulation; (b) avoidance of contact with vessel walls: and (c) constant spatial relationship between the lumen for injection and the thermistor as regards the dynamics of flow and temperature change.


Thrombogenic properties of arterial catheters: a scanning electron microscopic examination of the surface structure. We performed 300 consecutive coronary arteriographies with 2 different kinds of catheters: polyurethane catheters and polyethylene catheters. The thromboembolic complication rate for investigations with each type of catheters is compared to the surface structure as seen with the scanning electron microscope (SEM). The complication rate was 21.4% for polyurethane catheters and 0.3% for polyethylene catheters. The inner surface of polyurethane catheters was irregular, while the inner surface of polyethylene catheters appeared smooth. The outer surface of polyurethane catheters was slight irregular, while the outer surface of polyethylene catheters was smooth. These results are compared to other investigations of the surface structure of coronary catheters and to reports on the thromboembolic complication rate at coronary arteriography. It is concluded that the 2 types of catheters have different thrombogenic properties and that the surface structure is of major importance for this difference.


Comparison between regional myocardial blood flow measurements and results of exercise tests. The relationship between regional myocardial blood flow and the results of exercise tests were evaluated in 54 patients, 40 of whom had angiographically demonstrated coronary artery disease (CAD) and 14 had normal angiograms. After 20 patients had 2-step tests, 20 had bicycle ergometry, and 14 had treadmill tests, regional myocardial specific blood flow (RMBF) at rest was determined by selective injections of xenon-133 into the left coronary artery and quadrantic washout measured with an Anger camera. RMBF (ml/min/100 gm, mean +/- SE) was significantly lower in patients with coronary artery disease (72 +/- 3) than in normals (91 +/- 7, p less than .05) but RMBF in 12 CAD patients with negative exercise tests (75 +/- 6) was similar to regional myocardial blood flow in 28 coronary artery disease patients with positive exercise tests (71 +/- 4). Degree of ST depression did not influence results. Although measurement of RMBF and exercise testing are both useful procedures in the evaluation of patients with CAD, the data in the present study indicate the RMBF measurements at rest cannot predict the result of the postexercise ECG and vice versa.


Specification of angulated projections in coronary arteriography. In coronary arteriography cranial and caudal angulations are combined with oblique angulations to obtain additional views. The angulations are obtained with a variety of equipment rotating about different axes. The planes and axes in and about which the patient and equipment rotate are defined and the equipment is grouped according to the axes about which it rotates. It is shown that a simple definition of the angulation of a projection may be obtained using concepts and terminology consistent with current radiological practice. One group of equipment then gives directly from the rotation of its component parts the angles specifying the projection. For other equipment, the angles specifying the projection are calculated and tabulated for angles of rotation of the equipment from 0 to 90 degrees. Thus, equivalent projections for the different equipment may be found and compared.


Closed foramen ovale: a potential entrance to left atrium. The anatomy of the limbus and its relationship to the fossa ovalis were studied in 90 normal human hearts in an attempt to explain the clinical success of blunt trans-septal catheterization. Previously reported rates of patent foramen ovale (25-35% of adult specimens) were confirmed, well below the reported rate of success for blunt trans-septal catheterization (67-87%). A possible reason for this success is the fragile attachment of the fossa ovalis to its limbus in nearly all hearts without persistent patency.


Aneurysmal dilatation of the right ventricular outflow tract in infancy: severe form of Uhl's anomaly? A previously unreported cardiovascular malformation is presented consisting of aneurysmal dilatation of the right ventricular outflow tract associated with a cardiomyopathy, a possible variant of Uhl's anomaly. The patient presented at 8 days of age with mild cyanosis and congestive failure. Cardiac catheterization revealed severe cardiomegaly associated with very poor pump function of both right and left ventricles. The present case is unique in showing 1) severe aneurysmal dilatation of the right ventricular outflow tract. 2) only partially absent right ventricular musculature documented before death by the pressure tracing and cineangiocardiograms, and 3) the first quantitation of both right and left ventricular size and function in this syndrome. A review of previous cases of Uhl's anomaly indicates that this case may represent a variant of that condition and that intrauterine myocarditis or myocardial infarct should be considered in regard to etiology.


Ventricular septal defect following blunt trauma: spontaneous closure of residual defect after surgical repair. As a result of blunt chest trauma a patient developed a large ventricular septal defect (VSD). After surgical closure of the defect a grade 2/6 systolic murmur persisted. One year later findings were the same and left ventriculogram revealed a small residual VSD. Two years after the operation the systolic murmur had disappeared. We postulate that gradual endothelialization and possibly small thrombi (formed around and over the Dacron patch graft) caused the defect to close. This case serves to illustrate some of the Dacron patch graft) caused the defect to close. This case serves to illustrate some of the complexities in the diagnosis and management of an acquired VSD. To our knowledge this is the first reported spontaneous closure of a VSD occurring after incomplete surgical repair.


Assessing the blalock-hanlon atrioseptectomy at cardiac catheterization. Blalock-Hanlon atrial septectomy (BH) is performed to increase systemic and pulmonary venous mixing at the atrial level. Failure of clinical improvement may be related to inadequate intraatrial communication. A simple catheterization technique employing a balloon catheter is used to assess the presence or absence of the limbus of the foramen ovale following BH, since persistence of the limbus of the fossa ovalis after BH is associated with significantly smaller percentage of communication (atrial communication area/total atrial area).


Comparison of the performance of pigtail catheters with different number of sideholes. The standard 12 sidehole pigtail catheter is compared with pigtail catheters with 6, 8, and 10 sideholes in 40 patient studies. The catheter with fewer sideholes performed as well as the standard catheter with respect to the quality of left ventricular opacification, lack of catheter recoil during angiography, and absence of complications. An in vitro study confirmed that better flushing of the terminal segment beyond the sideholes is achieved with the 6 sidehole catheter compared to the 12 sidehole catheter. It is anticipated that this feature will decrease the risk of thromboembolism associated with the use of the pigtail catheter.


Transbrachial selective arteriography of the neck vessels: our experience in 258 cases. We have developed a catheter that facilitates the study of the neck vessels via a brachial arteriotomy so that other vascular areas (heart, kidneys, etc) can be studied in the same procedure. The catheter has a preformed curvature with a tapered, closed-end distal tip. We have successfully utilized this catheter in 258 consecutive patients, 133 (52%) of whom had undergone concurrent studies of other vascular areas, usually cardiac catheterization with coronary arteriography. No major complications occurred with the use of this catheter. We have found that with this catheter we can study the neck vessels via the brachial approach safely and easily and perform studies of other vascular areas using the same arteriotomy.


Preformed catheters for simplified transbrachial coronary arteriography. The experience in 700 patients of transbrachial selective coronary arteriography using a preformed catheter is described. The excellent plastic memory of torque control of the polyurethane catheter combined with the characteristic gentle curve permit rapid and easy intubation of the coronary arteries. The so-called "difficult" cases encountered with the classic Sones technique have been catheterized with ease employing the technique described in this report. The exceptionally low complication rate (no deaths), abbreviated catheterization time, a success rate of 99.2%, and the high quality cine angiographic films make this technique a highly useful and effective method of transbrachial coronary arteriography.


A review of studies of the socio-familial backgrounds and educational facilities of the homes of moderately educationally subnormal children. A search of the literature indicates the paucity of information on the backgrounds of ESN(m) children, despite the important contribution made by the home to the cognitive development and educational achievement of the children. The information that is available tends to support the notion of a syndrome of familial moderate educational subnormality. Evidence from one investigation points to certain ethnic differences which may be important in any programme of intervention.


Observations on a therapeutic residential setting for autistic children. A therapeutic milieu for children labelled with a diagnosis of early infantile autism is described. This study, in a residential setting near Washington DC, USA, discusses the various procedures adopted for alleviating the problems encountered with these children, such as the formation of social relationships, language formation, and compulsive behaviour.


Manual asymmetries of motor sequencing in boys with reading disability. Boys with reading disability were asked to tap two mechanical keys in time to the beat of a metronome, with left and right hand alone, and with alternating hands. On the single hand trials these boys tapped as well as normal boys with both left and right hands, but when asked to alternate hands, their tapping stability, particularly of the left hand, deteriorated significantly and was worse than that of much younger normal boys. It is argued from evidence from patients with surgical commissurotomies that the motor deficiency in synchronizing left and right hands may be due to a disturbance in interhemishperic cooperation in the boys with reading disability, and it is suggested that the reading problems of these children may be the consequence of a developmental delay in interhemispheric cooperation.


Dichotically-stimulated ear differences in musicians and nonmusicians. A dichotic listening task involving violin melodies was given to 32 musicians and 32 nonmusicians. The former group demonstrated a right ear superiority, while the latter performed better with the left ear. Right ear scores distinguished between the groups, but left ear scores did not. Additionally, the left-handed subjects in both groups showed smaller amounts of ear asymmetry than their right-handed counterparts. The results were interpreted as demonstrating that musicians mainly use the left hemishpher to process musical stimuli, while nonmusicians use the right. It is thought that as a person becomes more musically adept, increasing use is made of a left hemisphere sequential analytic mechanism. The apparent functional symmetry of left-handers could also be due to the confounding effect of having two distinct sub-groups within this population, i.e., true left-handers, and those with the cortical organization of right-handers.


Music perception and cerebral asymmetries. Six experiments investigated the detection of pitch, rhythm and harmony changes in music perception. While RTs did not differentiate between ears for detecting a changed note in either a single line melody or a five note whole tone sequence, the right ear was more accurate. The left ear was faster, and the right more accurate in detecting rhythm changes in a five note sequence. The ears did not differ in detecting harmony changes. Finally, the right ear proved consistently more sensitive (d') in recognizing excerpts from unfamiliar melodies, and except only for female nonmusicians, the left ear was more sensitive for familiar melodies. If the adoption of differintial listening strategies determines the direction of laterality differences such as these, then familiarity also seems important in determining listening strategies.


Spatial memory and hemispheric locus of lesion. Corsi's cube test was given to 40 control and 80 brain-damaged patients to assess the relation of different aspects of spatial memory to the hemispheric locus of lesion. Spatial span was found affected by injury producing visual field defect (VFD), regardless of the side of the lesion. Delayed reproduction of a 3 cube sequence (which was within the span of every patient) was performed more poorly by patients with right hemisphere damage and VFD than by controls. This was true whether the delay was unfilled or filled with a counting activity, the two conditions being equally effective in bringing about the inferiority of the right brain-damaged group. Learning to criterion up to a maximum of 50 trails a supraspan sequence was failed by 65% of right brain-damaged patients with VFD, a percentage significantly higher than that found not only in the control group, but also in any other brain-damaged group. These findings point to the dominant role played by the posterior region of the right hemisphere in subserving spatial memory mechanisms, especially when the acquisition of stable traces is requested.


Hemispheric differences in dot detection. Two experiments are reported using normal subjects which show a superior detection for dots in the left visual field. This is shown to be more pronounced for stimuli of reduced contrast and for male subjects. The cerebral activation hypothesis of hemispheric asymmetries is tested and found to contribute towards a visual field advantage to some extent but a structural account is also suggested. It is considered that the right hemisphere is prepotent for dealing with simple perceptual stimuli even when there is no spatial component for the task.


Aphasics' defective perception of connotative meaning of verbal items which have no denotative meaning. This study deals with the question of whether in aphasic patients the grasping of connotative meaning is disturbed. The method used was the "maluma - takete" type (Koehler, 1947): matching of synthetic words to meaningless figures. It was proven that asphasics from different countries with different languages have a disturbed perception of connotative meaning. There was a correlation with the severity of language comprehension disturbance in aphasics.


The correlation of the phi function of the difference score with performance and its relevance to laterality experiments. It is shown that there is a generic correlation between the phi functions of differences in pairs of scores and the averages of pairs of scores. This correlation can be approximated extremely accurately given only the means, variances, and covariance of the two scores in the sample data. Thus, even when difference scores are transformed into their phi equivalents, these are still not independent of performance level.


'Diagnostic overkill?' An analysis of 88 negative renal angiograms. 11.3% of 776 renal angiograms evaluated retrospectively displayed normal findings. The main reasons which had led to the misuse of angiography in our cases were: technically poor urograms, incorrect interpretation of anatomical variations and the lack of other examinations associated with the urogram. A diagnostic plan including all less invasive and dangerous procedures is proposed placing sonography in central position.


Renal hamartoma: therapeutic aspects.

Renal hamartoma: therapeutic aspects. Hamartomas are benign renal tumors. In most cases they can be diagnosed by means of angiography. Treatment varies in accordance with clinical manifestation and progression. Symptom-free hamartomas need no treatment. In case of bleeding, embolization may be performed. Nephrectomy ought not to be performed save in emergency or if malignancy is suspected.


Difficulties in bladder rupture diagnostics. 4 cases of false-negative and 2 of false-positive bladder rupture diagnosis are presented. Diagnostic difficulties are encountered when: (1) intestinal loops have got into the bladder stopping its hole; (2) the rupture dissects the bladder wall and not extravasation is visible on cystograms, and (3) there exists and additional urethral rupture.


Renal function after warm ischaemia. II. Marked protective effect of intravenous inosine given prior to 60, 90 and 120 min of warm ischaemia. Rats were given 10 or 20 mg of inosine dissolved in 1 ml of 0.9% saline, or a control solution of 1 ml of 0.9% saline, intravenously 10 or 20 min before induction of left renal warm ischemia for 60 min. Further groups of rats were treated with 20 mg inosine or with saline alone 20 min before longer periods of warm ischeamia of 90 and 120 min duration. All animals had immediate contralateral nephrectomy. In all inosine-treated groups the mean plasma creatinine was lower than in their respective control groups and these differences were statistically highly significant.


Mass spectrometric trace element analysis of calcium oxalate uroliths. Mass spectrometric trace element analysis of whewellite and weddellite uroliths revealed 55 elements, from which 20 could be well assessed quantitatively. The total trace element content in weddellite increased by 77.5% with respect to whewellite, the main portion being made up from Na, P, Mg, and Cl. In physiological conditions weddellite is stabilized by trace elements. The importance of trace element analysis of Si, Al, Sr, Rb, S, F, Cl, and Br in uroliths is indicated.


Leiomyosarcoma of the prostate: a case report. A case of leiomyosarcoma of the prostate in a 26-year-old man is presented. The short duration of symptoms, the typical sensation at rectal palpation, and the sudden fast increase in growth are stressed. The bad prognosis justifies an agressive therapeutical approach.


Memory for a geometrical configuration in the cognitively impaired elderly. The objective of this study was to analyze the mnemonic reconstruction of a complex spatial configuration in a group of 10 men and women, 70-88 years, with a diagnosis of organic brain syndrome and 10 controls matched for age, sex and educational background. A Piagetian model of a geometrical configuration with contingent and non-contingent properties was used to establish a heirarchical order of memorial organization for spatial structures. Subjects were evaluated one hour and one week after learning in reconstruction tasks. Although individuals with dementia performed more poorly than the age-matched controls, the hierarchy of chosen characteristics reflected a schematic progression in the organization of spatial memory in both groups.


Performance on cognitive tasks in predicting the behavioral competences in the institutionalized elderly. The questions under consideration concern quantitative and qualitative aspects of the relationship between cognitive abilities and behavioral competences in the elderly institution residents. The former was assessed by an array of five cognitive measures, namely, two Piagetian tasks, Set Test, WAIS Vocabulary and Digit Span subtests and the WMS Associative Learning subtest and the latter by the Stockton Geriatric Rating Scale (SGRS). The overall variance in common between the two sets of variables was approximately 70 percent. Of the cognitive tasks, those most highly predictive of behavioral competences were the Piagetian tasks, Set Test and, to a lesser extent, WAIS Vocabulary subtest. Of the four SGRS factors, that predicted to the greatest extent was apathy, with physical disability to a lesser extent.


Statistical bias in cross-sequential studies of aging. In an earlier published study (Botwinick & Arenberg, 1976) it was argued that cross-sequential designs used in studies of aging and intelligence bias results in favor of a larger main effects F ratio for cohort than for time of measurement. As a consequence, purely ontogenetic influences are likely to be misinterpreted as generational. The present paper gives conclusive proof of the statistical bias inherent in these designs. In addition it shows that, for any given number of measurement occasions, the degree of bias increases with the number of different cohorts tested. An explanation of the statistical problem in intuitive terms is also provided.


Adult age differences in cognitive abilities and educational background. A large sample of men and women between the ages of 20 and 79 years were given specially devised, adult-relevant tests of vocabulary and information as well as portions of the ABLE test of educational achievement. The familiar pattern of decline with age was found in the ABLE subtests, but not in the adult-relevant tests, which lends support to the position that age trends in tests of cognitive abilities depend significantly upon test contents.


A comparison of general and age-specific factors associated with political behavior. Sociological research has focused on relationships between status, participation, efficacy, and political behavior with less attention to the influence of discontinuty in life circumstances on political activity. In contrast, gerontologists have explored the implications of age-specific and life change factors for political orientations but conflicting hypotheses have been derived. On suggests that discontinuity will decrease political activity while the other contends that discontinuity will politicize individuals. This study compares the relative contribution of life change and age-specific factors, demographic characteristics, and efficacy to voting and political interest. Data were collected by personal interviews with a random sample of 169 men and women 65 or over. Voting and political interest had somewhat different antecedents, but participation in multi-age groups and efficacy increased both while age-graded participation decreased political activity. Discontinuity, in general. had less effect on political behavior than demographic characteristics and efficacy.


Age, rate and instructional conditions: empirical support against the pacing variable. The present study was an attempt to determine if the pacing effect was an artifact of the confounding of presentation rate and total learning time. Two presentation rates were factorially varied with three instructional conditions for two different age groups in a paired-associate and free-recall task. The results of the study replicated the pacing effect when learning time was deliberately confounded. When total learning time was equated for the presentation rates the pacing effect was not replicated, demonstrating that pacing is an artifact. It was suggested that the total time principle, not pacing, was the viable explanatory concept. The results of the manipulation of instructional conditions suggest that it is inappropriate to assume that a set of instructions will result in equivalent performance for both young and old samples.


RNA-RNA hybridization between influenza viruses. A study is described of the RNAs of recombinant viruses made from A/PR/8/34, which is non-infectious for man, and wild human Influenza A strains. By RNA-RNA hybridization it was possible to determine the proportion of the genome donated by each of the parents. The technique can be applied as a biochemical marker to detect the recombinants among parental viruses and moreover, it is a method to select the attenuated viruses among the recombinants.


Problems in the use of live influenza virus vaccines in patients with chronic bronchopulmonary disease. A brief review is presented of the problems existing in the organisation and execution of clinical trials of live attenuated influenza vaccine in patients with chronic pulmonary disease. Such trials must be designed to determine the safety of the procedure as well as its immunological effectiveness.


Clinical acceptability of live influenza vaccine in high risk subjects and children. Experience with three consecutive recombinant strains. Reactogenicity and immunogenicity of three recombinant strains, Alice, RIT 4025 and RIT 4050, were re-examined by a retrospective analysis of the data from clinical trials and routine vaccination campaigns. Special emphasis was put on the acceptability of vaccinal strains for the elderly, patients with chronic pulmonary diseases, subjects with atopy and children, as well as on the safety of repeated administrations of the vaccine to the general population. The incidence and nature of postvaccinal symptoms in high risk populations were similar to those observed in healthy subjects. Tolerance of the vaccine by children (2-10 years old) was excellent for both Alice and RIT 4050 strains. At the present time, we have evidence that the vaccine was administered to approximately 2500 subjects without any significant adverse effects, during the course of two or three consecutive vaccination campaigns. This holds true also for 12 vaccinees who received the vaccine for more than three years. The maximal number of doses administered to one person was 14. The vaccinal strains studied have been shown safe and immunogenic both in the general population and in high risk subjects and children.


Live influenza vaccine in patients with chronic bronchopulmonary diseases. A multicenter study with two consecutive vaccinal strains. Live influenza vaccines RIT 4025 and RIT 4050, containing the recombinants of A/Scotland/840/74 and A/Victoria/3/75 with A/PR/8/34 virus respectively, were administered during the vaccination campaigns 1975-76 and 1976-77 to patients with established chronic bronchopulmonary diseases. The study was designed to assess the clinical acceptability of these vaccinal strains and to measure the effects of vaccination on pulmonary function in this population. Clinical and respiratory function findings were compared in a control group of healthy volunteers. Good immunogenicity and good clinical tolerance were found in both populations. Pulmonary function tests had been performed before administration of the vaccine and repeated several times during the post-vaccinal period; the longest post-vaccinal follow-up of respiratory function in patients was four weeks. Apart from transient fluctuations, no significant changes in pulmonary function were found; results obtained in the group of patients were not different from those o0served in healthy subjects. These results correlate very well with observations reported with previous vaccinal strains (Ann and Alice) in pulmonary "high risk" patients.


Dynamics and specificity of influenza virus antibodies as well as IgE values in serum and nasal fluid after repeated local application of live bivalent influenza vaccine. A long term study with bivalent live influenza vaccine was carried out in 18 subjects with no previous history of egg protein hypersensitivity. Experimental conditions included a nine-fold vaccination schedule with collection of serum and nasal fluid. The parameters studied were determination of serum and local antibody formation as well as the demonstration of specific IgE antibodies in serum and nasal fluid. HI antibody response was observed in 100% of the vaccinees against vaccine related strains but not to antigenically remote isolates. NI antibodies could be demonstrated in serums and to some extent in nasal fluids. Special attention was given to induction of specific IgE antibodies to egg protein, however no indication for a vaccine induced sensitization could be detected when total and specific IgE concentrations of serum and nasal fluid were determined.


Studies of respiratory function in volunteers given live influenza virus vaccine. Measurements of peak flow, vital capacity, FEV1 and flow volume studies were performed in healthy volunteers for 20 weeks following intranasal vaccination with live-attenuated A/Victoria/3/75 recombinants or placebo. Despite differing attenuation of the two candidate strains, no effect on pulmonary function was detected.


Procedures for characterisation of the genetic material of candidate vaccine strains. Two procedures for characterising the genomes of recombinant influenza viruses are described. The first of these involves ribonuclease T4 oligonucleotide fingerpart analysis of separated viral RNAs labelled either in vivo or in vitro and the second utilises polyacrylamide gel electrophoresis to identify the double-stranded molecules formed by hybridisation between the complementary and virion RNAs of two viruses. Although the latter method is more suitable for routine screening purposes, both procedures are suitable for distinguishing between equivalent RNA components of closely related viruses.


The assay of influenza virus structural antigens in vaccines by rocket immunoelectrophoresis. The internally situated influenza virus structural antigens (matrix and nucleoprotein) and the glycoprotein hemagglutinin were assayed using rocket immunoelectrophoresis or single radial diffusion following disruption of purified virus with 1% w/v sodium sarcosyl detergent. Electrophoresis was carried out for 1-4 h in 0.05 M barbitone buffer at pH 8.6. The potency estimations of HA and M activity were similar for the two methods for bivalent beta-propiolactone inactivated whole virus vaccines.


[Detection of ovalbumin in influenza vaccine by electrosyneresis]. Counterimmunoelectrophoresis was used for the detection of ovalbumin in influenza vaccine preparations throughout a purification process applied to allantoic fluids of embryonated eggs. With an antiserum able to detect ovalbumin to a concentration of 0.31 microgram/ml, the progressive elimination of this contaminant was followed until the final preparation of purified concentrated vaccine. This easy procedure appeared to be specific and highly sensitive.


Serological response to an adsorbed killed trivalent influenza vaccine (including A/New Jersey 8/76 antigen). The serological evaluation of a trivalent vaccine (A/Victoria 3/75, A/New Jersey 8/76, B/Hong Kong 8/73) has been done by HI and NI tests on 77 paired sera representing all age groups. The percentage of seroconversion induced by the antigens A/Victoria 3/75, A/New Jersey 8/75 and B/Hong Kong 8/73 were 85.95 and 89.6 respectively and the percentage of protective antibodies (greater than 1:40) were 84.4, 72.7 and 80.5 respectively.


Human responses to purified surface antigen invluenza vaccine (Fluvirin). The dose response to a bivalent purified surface antigen vaccine containing A/Victoria/3/75 and B/Hong Kong/8/73 has been studied in volunteers. Over the range studied the response was very flat for both components insofar as the HI antibody was concerned. The lower, but still satisfactory, conversion rate to the B component may reflect the absence of previous experience with this strain. In another study in schoolboys a trivalent surface antigen containing A/New Jersey, A/Victoria and B/Hong Kong at 200 I.U. each was compared with a whole virus vaccine containing 400 I.U. of each of the three strains. There was a significant reduction in reaction rate in boys receiving the subunit vaccine. Seroconversion rates were comparable for the two vaccines, except in the case of the New Jersey component when they were significantly better for whole virus than for subunits.


Potentiation of the immune response to influenza virus subunit vaccines. Influenza subunit vaccines are poorly immunogenic in unprimed lower animals and man and a method was sought to potentiate the humoral response. Intact heterologous influenza A virus vaccine (A/Victoria/3/75 [H3N2]) potentiated the antibody response of hamsters to A/NJ/76 [Hsw1 N1] subunit vaccines but large doses of intact virus were required. Studies in seronegative young human adults showed that much lower doses of homologous A/NJ/76 [Hsw1 N1] virus potentiated the antibody response to both the hemagglutinin and neuraminidase subunits of A/NJ/76 influenza vaccines. This suggests that future influenza subunit vaccines for use in seronegative people should contain a small amount of whole virus vaccine, sufficient to potentiate the immune response to the subunits but insufficient to be reactogenic.


Anti-ovalbumin sensitizing ability of influenza vaccines in guinea pigs. The anti-ovalbumin sensitizing ability of four highly purified commercial influenza vaccines was tested in guinea pigs by means of passive cutaneous anaphylaxis. Aluminimum-adsorbed and fluid vaccines as well as pretreatments by one or two subcutaneous inoculations were compared. The two adsorbed vaccines induced significant sensitization after just one inoculation while the two fluid vaccines revealed their sensitizing ability almost exclusively after repeated administration.


Antibody response in humans after administration of whole-virion and split vaccine prepared from two different influenza A/swine viruses. Previous findings with sera of several different animal species had indicated a close antigenic similarity between the X53 recombinant (possessing both surface antigens of A/Swine/New Jersey/76 virus) and the A/Swine/Ann Arbor/31 (AA) virus (1). Since the latter virus grows much better in chick embryos than the former, we examined the possibility of using the Ann Arbor virus instead of X53 for inactivated vaccine production. The present paper describes our findings in sera of subjects immunized with either whole-virus or split vaccine prepared from AA virus.


Antibody response to anti-A/New Jersey/76 vaccines. Experimental inactivated influenza vaccines prepared with strain X 53, derived from A/New Jersey/76 virus were injected to several groups of subjects. Different compositions of vaccine were used and the subjects were selected from different age groups. Antibody responses were measured 15 days after vaccination; it was then possible to evaluate the conversion rates, the percentages of subjects showing a protective level of antibodies and the average level of antibodies. The results show that a very small dose of antigen, probably acting as a booster, gives very good results in the older age group. On the other hand, young adults (below 23) react to a much lower degree to the vaccine. The results are discussed in relation to the age distribution of preexisting antibodies in the experimental groups and in the general population in France.


Biological, genetic and biochemical characterization of a cold-adapted recombinant A/Victoria/3/75 virus and its evaluation in volunteers. A recombinant virus AA-CR19 was produced that contains RNA segments coding for one polymerase protein, the nucleoprotein and the matrix protein of cold-adapted A/Ann Arbor/6/60, but HA, NA and two other genes coding for polymerase proteins from A/Victoria/3/75. The nonstructural protein gene is probably derived from A/Ann Arbor/6/60, but may contain a spontaneous mutation. Biological characterization of AA-CR19 showed that it possesses the gene(s) responsible for cold-adaptation and temperature-sensitivity of the A/Ann Arbor/6/60 parent. At a dose of 10(7.2) TCID/50. AA-CR19 was found to be immunogenic and attenuated for seronegative volunteers.


Persistence of influenza A/New Jersey/76 (Hsw1N1) antibody one year after vaccination. Serum HI and neuraminidase-inhibiting (NI) antibody measurements were made at 3, 32 and 50 weeks after inactivated influenza Hsw1N1 vaccination of 438 adults in 1976. Although the highest postvaccination geometric mean HI titers were observed in persons greater than or equal to 52 years of age, the rate of antibody decline was similar in adults of all ages. In 14 children who had a seroconversion following two doses of whole virus or split virus vaccine, the geometric mean HI antibody titer was lower after the second vaccine dose than the peak titer observed in adults, and the decrease in titer was also more rapid by 4 to 7 months. One year after influenza Hsw1N1 vaccination of adults, the prevalence of homologous HI antibody greater than or equal to 40 was 71% to 97%, whereas only two of the 14 children maintained similar titers at 5 to 7 months. Neuraminidase-inhibiting antibody titer formation occurred more frequently in those without prevaccination NI antibody, but the rate of decline was also greatest in this initially seronegative group. The rate of antibody decline at one year in the population with preexisting antibody was similar to that observed for HI antibody decline in a primed population. Heterologous influenza A/Victoria/3/75 (H3N2) HI antibody formation occurred in 22% of adults aged 25 to 51 after Hsw1N1 vaccination and in 12% of those over the age of 51, but the rate of heterologous antibody decline was more rapid than that observed for homologous antibody.


Serological responses to whole and split A/New Jersey vaccines in humans and mice following priming infection with influenza A viruses. Experiments were performed in mice to investigate the role of previous infection on responses to A/NJ/76 vaccines. Results from human studies have demonstrated that the serological responses to A/NJ/76 vaccines varied according to the age of the vaccinee and appeared to be related to their previous exposure to the different strains of influenza A virus. Mice were infected with influenza A viruses representative of the major strains (Hsw1N1, HON1, H2N2, H3N2) and later inoculated with varying doses of whole or subunit A/NJ/ML virus vaccines. Results from these experiments demonstrated a low antigenicity in non-primed mice of the subunit vaccine compared to whole-virus vaccine, but that the antigenicity of both vaccines was enhanced in mice primed by previous infection with earlier H0 and H1 viruses. The responses of heterotypically primed mice were qualitatively similar to those of primed humans following A/New Jersey vaccination.