Heritable factors in the severity of affective illness. A review of clinical experience with 163 patients with primary affective disorder indicates that patients with a history characterized by recurrent depression interspersed with periods of hypomania (bipolar II) may have clinical courses that are distinguishable from bipolar I (depression with histories of mania) or unipolar patients. A prior history of suicide attempt and suicide after discharge from the research unit were most frequent among bipolar II patients. The family histories of bipolar I and bipolar II patients revealed similarly increased morbid risks for bipolar illness, whereas no bipolar illness was found in the first-degree relatives of unipolar patients. The suggestion that patients classified as bipolar II be separately considered in future studies of affective disorder is discussed.


Assortative mating in primary affective disorder. Psychiatric illness in spouses of patients with primary affective disorder was determined and compared to psychiatric illness in spouses of a nonpsychiatrically ill control group. An increase in affective illness in wives of bipolar male patients with affective disorder was found. There was no increase in affective illness among husbands of female patients. Marital status of these patients was evaluated and the percentages of patients who had never married or who had married but had ever been divorced or separated were similar to control data. Several of the marriages were quite stable over long time periods in spite of the severe recurrent affective illness experienced by these patients.


Uptake of 3,4-dimethoxyphenylethylamine-1-14C (14C-DMPEA) by rat tissues in vitro. Rat heart and spleen slices were incubated with 3,4-dimethoxyphenylethylamine-1-14C(14C-DMPEA) in Krebs medium at 37 C. At the end of 5-20 min of incubation, the heart did not take up the radioactivity while the spleen did. The Km and Vmax values of uptake in the spleen were 1 x 10(-4) M and 20 nmole/g per min, respectively, and the uptake was reduced to 16.0-35.1% in the cold (4 C) and to 40.3-64.0% in Na+-free medium. Thus, the uptake was an energy-dependent active process but was only partially Na+-dependent. Spleen slices incubated with 14C-DMPEA-free medium for 15 min following incubation with 14C-DMPEA retained 41.0-74.8% of radioactivity. The uptake was insensitive to norepinephrine (0.313 and 0.939 muM), dopamine (9.98 muM), 5-hydroxytryptamine (5 muM), cocaine (14.8 muM), 1-amphetamine (0.3 and 300 muM), d-amphetamine (300 muM), and normetanephrine (45.7 muM). 6-Hydroxydopamine treatment of rats, which produced 93% reduction in the splenic norepinephrine content, did not significantly reduce uptake. Thus, the uptake of DMPEA into the spleen is not by adrenergic neurones.


Concentration of 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan in the cerebrospinal fluid of depressed patients before and after ECT. Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5HIAA), tryptophan (TRYP), and homovanillic acid (HVA), were determined prior to electroconvulsive therapy (ECT) and after an average course of 6.7 ECT in six endogenous depressed patients. Depression rating scale (DRS) scores were also obtained by a "blind" research psychiatrist before and after ECT at the time of each lumbar puncture. ECT markedly reduced DRS scores but did not significantly alter CSF levels of 5HIAA, TRYP, or HVA. We found no correlation between ECT-induced DRS score reductions and changes in any of the CSF constituents studied, or between the absolute DRS score and the corresponding CSF concentration of any of the compounds. These data are consistent with those previously reported for ECT and do not suggest that ECT alters cerebral amine metabolism in depressed patients. Neither do they provide any evidence for direct amine mediation of the depression-relieving effects of ECT in man, nor for any relation between severity of depressive illness and CSF concentrations of 5HIAA, TRYP, or HVA.


Comparison of the effects of maprotiline (ludiomil) and clomipramine (anafranil) on serotonin uptake and tryptophan-binding in plasma. The influence of maprotiline or clomipramine on plasma tryptophan-binding and brain tryptophan was studied in rats. Neither compound altered tryptophan-binding nor brain tryptophan levels after acute of chronic treatment. In a comparative study maprotiline and clomipramine were administered to healthy volunteers for 4 days and the concentrations of total and free tryptophan in plasma were determined. Serotonin uptake was also measured in the platelets from these subjects. Maprotiline treatment did not inhibit serotonin uptake nor did it have any influence on plasma tryptophan binding. Clomipramine also had no influence on plasma tryptophan-binding but strongly inhibited serotonin uptake into platelets. These results confirm the earlier observation that maprotiline has no influence on serotonin uptake and can be clearly distinguished from clomipramine.


Prediction of the secondary and tertiary structure of plastocyanin. The amino acid sequences of nine plastocyanins were examined using four published methods for the prediction of secondary structure in proteins. The results of the four methods were combined in such a way as to maximize agreement, and the position of alpha helices, beta sheets, and beta turns in plastocyanin was predicted. From this result and other information, such as the position of conserved residues and the requirements for coordination of copper, a preliminary model for the mainchain folding of the molecule was presented.


Osmometric studies on self-association of pyrimidines in aqueous solutions: evidence for involvement of hydrophobic interactions. Vapour pressure osmometric studies were performed on stacking self-association of 25 uracil derivatives variously C- and N-substituted with polar and alkyl groups in aqueous solution at various temperatures. The respective equilibrium association constants Kst were computed on the assumption of the isodesmic model of self-association (K2=K3=...=Kn=Kst). Enthalpies of association for most of the compounds studied were obtained from the temperature-dependence of Kst, according to the van 't Hoff equation. Analysis of the equilibrium and thermodynamic parameters in terms of the association mechanism demonstrated the involvement of classical hydrophobic interactiors in the stabilization of complexes of di-and higher alkylated uracils. Data for the derivatives substituted with polar groups proved consistent with the predominant involvement of dipole-induced dipole forces in the association.


Kinetic cooperativity in the concerted model for allosteric enzymes. The cooperativity of enzyme-substrate interactions is investigated in the concerted allosteric model of Monod, Wyman and Changeux. The general case of K-V systems is considered, in which the two protomer conformational states R and T postulated in the theory differ in catalytic and binding properties. An expression for the Hill coefficient nH defined with respect to the asymptotic velocity V infinity to is analyzed in conditions which exclude substrate inhibition. Kinetic cooperativity is always positive (nH greater than 1) in the case of a dimer enzyme, and in the case of an inactive T state. Slight kinetic negative cooperativity (nH less than 1) occurs under restrictive conditions for larger numbers of protomers when the substrate binds significantly to the less active state of the enzyme, but the phenomenon remains negligible for trimers and tetramers. These conclusions differ from those obtained [A. Goldbeter, J. Mol.Biol.90 (1974) 185] with the Hill coefficient based on the absolute maximum velocity, which may exceed the experimental value V infinity to in K-V systems. The results extend those of Paulus and DeRiel [J. Mol. Biol. 97 (1975) 667] and support the view that in most cases, negative cooperativity is not compatible with a mechanism based on a concerted and conservative allosteric transition. The Hill coefficients for binding and catalysis are compared in K-V systems.


Equilibrium gel permeation: a single-photon counting spectrophotometer for studies of protein interaction. When a small column or flow cell packed with gel particles is completely saturated with a solution containing molecular species of interest, the average cross-sectional area occupied by the solute (partition cross section) is conveniently and precisely determined by direct optical scanning. For a mixture of interacting solutes this equilibrium gel permeation measurement yields the weight average of the species partition cross sections and the variation of this quantity with solute concentration permits determination of the solute interaction parameters (stoichiometry, equilibrium constants). We have developed a computer-controlled single-photon counting spectrophotometer for these measurements. The instrument exhibits high precision over a wide range of optical density. With counting times in the range of 10-1000 s the standard deviations on optical densities of protein solutions measured at 220 nm are typically 0.0006 at 1 OD, 0.002 at 2 OD, 0.005 at 4 OD. Beer's law tests show that deviations from linearity are less than these precision limits. Partition cross-section measurements for proteins can be made with an accuracy of better than 0.001 and information can be obtained with protein solutions at least as low as 1 mug/ml.


High-sensitivity linear dichroism as a tool for equilibrium analysis in biochemistry. Stability constant of DNA--ethidiumbromide complex. A stoichiometrical application of a sensitive method for linear dichroism (LD) detection is suggested for biochemical purposes. The complex formation between a binding site on a polynucleotide and a ligand may be studied with high precision if the following conditions are fulfilled: (1) The polymer can be given a fixed degree of orientation. (2) The site has a specific orientation with respect to the orientation axis of the polymer (e.g., intercalation). (3) The ligand has an anisotropic optical absorption property. The method was applied to studying the complex between DNA and ethidiumbromide, which was detected by LD with precision of +/- 0.5 X 10(-7) M in a 4 X 10(-4) M DNA solution, i.e., 0.1% occupation of the total site concentration can be detected. The complexation could be explained by a single type of site (n = 0.14 +/- 0.01 sites per nucleotide residue) and a stability constant K1 = (2.5 +/- 1) X 10(5) M-1 at 0.2 M ionic strength. From the specific LD an average angle 60 degrees was concluded between the helix axis and the long axis of the ethidiumbromide molecule. This value formally contradicts the Watson-Crick model or the intercalation model but may be explained by extension and deformation effects on the xhain by the flow.


A study of rhodopsin-detergent micelles by transient electric birefringence. The hydrodynamic method of transient electric birefringence has been used to study bovine rhodopsin solubilized in two detergents, 0.02% Ammonyx LO and 0.045% digitonin. All measurements are interpreted as the sum of two exponentials by which the relaxation times yield the rotary diffusion coefficients for ellipsoids of revolution. The semi-major and minor axes for prolate ellipsoid models have been calculated and their axial ratio, 6.8, in both detergents, is in line with recent reports on the structure of rhodopsin. Studies on bleached rhodopsin showed a large increase in axial ratio in 0.02% Ammonyx LO.


A comparative study on bovine alpha-lactalbumin and lysozyme by nanosecond fluorometry. Analysis of the time decay of fluorescence anisotropy of 1-dimethylaminoaphthalene-5-sulfonyl (DNS) and fluorescamine derivatives of bovine alpha-lactalbumin and lysozyme reveals that no significant differences in mean rotational relaxation times are present. While fluorescamine molecules appear to orient randomly on these proteins, DNS is bound with a preferential orientation. Other fluorescence characteristics of the labels are also cited.


A new technique for the detection of metabolites labelled by the isotope 13C using mass fragmentography. The detection of a small amount of 13C labelled methyl benzoate and its metabolites in human urine dosed 13C labelled aspirin was carried out by a new mass fragmentographic technique.


Biological implications of the reaction possibilities of the proximate carcinogenic compound, N-hydroxy-2-fluorenylacetamide. The biological implications, the reaction possibilities and the structure of different derivatives of N-hydroxy-2-fluorenylacetamide have been described.


Derivatization of aminoalkylphosphonic acids for characterization by gas chromatography mass spectrometry. A general derivatization method has been developed for both primary and secondary aminoalkyl-phosphonic acids. Derivatization is effected by reaction with trifluoroacetic acid and trifluoroacetic acid anhydride followed by esterification using ethereal diazo-n-butane. This method can be used for microgram quantities and permits ready characterization by both gas chromatography and gas chromatography mass spectrometry. The structure of this derivative has been verified by mass spectrometry and proton magnetic resonance. Fragmentation patterns were confirmed by high resolution mass spectrometry, isotope labeling and the formation of derivative analogs.


The mass spectrometric identification of dipeptide mixtures obtained from dipeptidylaminopeptidase. I--Hydrolysates. The amino acid sequence of a polypeptide can be deduced by an identification of all the dipeptides obtained from a Dipeptidylaminopeptidase I hydrolysate of the original polypeptide and its des N-terminal amino acid derivative. The components of such dipeptide mixtures can be readily identified from the chemical ionization (helium) mass spectra of their N-ethoxycarbonylpropenyl methyl ester derivatives without prior separation. The pyrolytic conversion of N-protected peptide dimethyltrideuteromethyl anilinium salts to their methyl esters in the direct insertion probe of a mass spectrometer was found to be most suitable for the derivatization of such dipeptide mixtures.


Mass spectral studies on prostaglandins. II--Prostaglandins E1 and E2. The mass spectroscopic behaviour of the methyl ester of prostaglandins E1 and E2 has been studied with the aid of low eV spectra, measurements on metastable ion decompositions and high resolution mass measurements. Mechanisms are proposed for the formation of the majority of the abundant fragment ions of these biologically important compounds. The mass spectra of free acids are also discussed.


The measurement of diphenoxylic acid in plasma following administration of diphenoxylate. The measurement of diphenoxylic acid, the major metabolite of diphenoxylate, has been performed in man using a deuterium labelled internal standard and multiple ion monitoring using a gas chromatograph mass spectrometer. The determination of plasma concentrations following administration of diphenoxylate to man is described.


A device for monitoring selected peaks in repetitively scanned mass spectra. A selective ion monitor for the Perkin-Elmer Model 270 gas chromatograph mass spectrometer is described.


Granulocyte function in experimental human endotoxemia. The effects of endotoxin administration on in vitro granulocyte function were studied in normal man. Four healthy volunteers received an intravenous injection of Pseudomonas endotoxin, 0.1 mug/kg. Endotoxemia resulted in transient neutropenia followed by a rebound neutrophilia. The nadir of the granulocyte count occurred at about 1 hr and maximal neutrophilia 2-4 hr after endotoxin administration. Throughout this time period, neutrophil phagocytosis and killing of Candida albicans were normal, as were resting and postphagocytic glucose metabolism and leukocyte random migration. However, postendotoxin neutrophils demonstrated a markedly decreased chemotactic response in Boyden chambers. The defect was maximal 1 hr after endotoxin administration and persisted 3-4 hr. These observations suggest that, in addition to neutropenia, endotoxin can transiently cause a chemotactic defect or select for a population of circulating neutrophils with an impairment of chemotactic activity.


Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes. The addition of 0.1 mug/ml of phorbol myristate acetate (PMA) to a suspension of resting human neutrophils causes a marked stimulation of all aspects of cellular oxidative metabolism normally associated  with phagocytosis. PMA induces a greatly increased rate of glucose oxidation via the hexose monophosphate shunt, increased production of superoxide anion and of hydrogen peroxide, increased cellular chemiluminescence, and increased iodination of protein material. The time course of hexose monophosphate shunt activation and of chemiluminescence are similar to those observed following phagocytosis of opsonized zymosan; the levels of activation achieved in all cases approximate those seen following phagocytosis. These phenomena are not simply reflections of altered cellular permeability, since PMA actually inhibits the uptake of radioactive 2-deoxyglucose and of uniformly labeled amino acids. The addition of PMA similarly inhibits the uptake of 14C-labeled bacteria, suggesting a competition  between the effect of the chemical and the process of phagocytosis. These results suggest that PMA activates the cell in the same manner as does phagocytosis. This compound should provide a useful tool for elucidating the metabolic events underlying the phenomena of phagocytosis and bacterial killing by polymorphonuclear leukocytes.


The anemia of chronic renal failure and chronic diseases: in vitro studies of erythropoiesis. The presence of a serum factor in chronic renal failure (CRF) which inhibits erythropoietin-stimulated erythropoiesis was studied, using a technique in which dog marrow cells were stimulated to produce heme in the presence of human serum. In the total series comparing 27 normal sera with 52 CRF sera, less heme was synthesized when the system contained CRF sera (total series, p = 0.0001). There was no evidence of inhibition of heme synthesis by serum from 12 patients with the anemia of chronic diseases (CD). Mixing experiments with normal and CRF sera suggested that this defect in CRF serum was not due to lack of a factor necessary for heme synthesis. Addition of urea, creatinine, and guanidinosuccinic acid to normal serum did not impair its ability to support erythropoiesis in this system. These data demonstrated that serum from patients with CRF contains a material inhibiting erythropoiesis in vitro, We propose that the material is responsible, in part, for the clinically severe anemia seen in these patients.


Sterospecific tissue uptake and nuclear accumulation of testosterone in the development of the mouse erythropoietic spleen. A double isotope ratio technique was used to estimate the specific binding of testosterone (T), as opposed to its biologically nonactive stereoisomer, epitestosterone (Epi T). The mouse erythropoietic spleen formed in response to a phenylhydrazine-induced hemolytic anemia was used as the target organ. Spleen minces from preanemic mice, as well as those in the early and late phases of erythropoietic spleen development, were incubated with 10(-9) M of 14C-T and 3H-EpiT, and the selective uptake of T was calculated from the 14C/3H ratio measured in the media before and after incubation, as well as in the subcellular fractions of the minces. Preferential uptake of T was seen in the early phase of development, but not in spleens obtained from preanemic animals or those in the late phase. There was no evidence of metabolic conversion of T or EpiT. The selective uptake of T by early phase spleens was reflected in a preferential nuclear accumulation of T. These data represent the first demonstration of a specific binding of T in vitro to a developing erythroid tissue.


Effect of erythropoietin on chromosomal protein synthesis. The spleen of the exhypoxic polycythemic mouse was employed to study the effect of erythropoietin on the synthesis of chromosomal proteins. At 1, 3, 18, 36, 45, and 72 hr after injection of erythropoietin, spleens were removed, minced, and incubated with 3H-arginine for 1 hr. Chromatin was isolated from the labeled splenic tissue and separated into histone and nonhistone protein (NHP) fractions. An increase in the incorporation of 3H-arginine into NHP occurred within 3 hr and into histones by 18 hr. Incorporation of 3H-arginine into both histones and NHP was maximal by 45 hr and had declined by 72 hr. Total histone specific activity increased fivefold while NHP specific activity increased twofold. Histones and NHP were fractionated on polyacrylamide gels and a double isotope labeling proceudre was used to study the synthesis of the individual histone proteins and NHP. Following administration of erythropoietin, there was a coordinate increase in the specific activity of all five major histone proteins and most of the NHP. The earliest change in specific activity of both histones and NHP occurred prior to the appearance of morphologically identifiable erythroblasts in the spleen.


Regeneration of blood-forming organs after autologous leukocyte transfusion in lethally irradiated dogs. II. Distribution and cellularity of the marrow in irradiated and transfused animals. Dogs were given transfusions of cryopreserved autologous mononuclear blood leukocytes after 1200 roentgens (R) (midline dose) whole-body x-irradiation. Bone marrow repopulation was studied by means of histomorphological methods at days 9 and 10 after transfusion of an average of 3 X 10(9), 7 X 10(9), 13 X 10(9), and 31 X 10(9) cells. The return of marrow cellularity to normal values was related to the number of cells transfused. With low cell doses (3 X 10(9) and 7 X 10(9)), the marrow regeneration at 10 days was focal. There were groups of cells (colonies) showing either erythropoiesis, myelopoiesis, or megakaryocytopoiesis in the osteal niches of the trabecular bones. Frequently such niches were seen showing complete cellular recovery next to niches with complete aplasia. With higher cell doses, all niches showed hemopoietic regeneration, and the cellularity approached normal values. No hemopoietic regeneration was observed in those skeletal parts that do not show hemopoiesis, even under normal circumstances.


Acquired XO/XY clones in bone marrow of a patient with paroxysmal nocturnal hemoglobinuria (PNH). Cytogenetic studies showed both 45XO and 46XY clones in the bone marrow of a 76-yr-old male with a 17-yr history of paroxysmal nocturnal hemoglobinuria (PNH). 55Fe incorporation studies demonstrated that both clones involved the hematopoietic stem cells. The loss of the Y chromosome may reflect an aging phenomenon, rather than be related to the PNH.


Mechanism of dilutional anemia in massive splenomegaly. Twenty patients with anemia and massive splenomegaly were studied in order to elucidate the mechanism by which splenomegaly results in plasma volume expansion. In 18 patients, increased plasma volume accounted for most of the anemia. Fourteen patients had an exaggerated renin response to standing, mean 1967 +/- 613 (SE) ng angiotensin ll/100 ml plasma (p less than 0.05). The mean resting forearm blood flow was increased 3.47 +/- 0.32 (SE) ml/100 ml forearm tissue (p less than 0.001). The venous capacitance was normal, as contrasted to a marked decrease in venous capacitance in patients with anemia of comparable degree without splenomegaly. Cardiac indices were increased in 10 of 11 patients (range 4.1-8.1 liters/min/sq m). In nine of ten patients oxygen consumption was increased (range 147-231 ml/min/sq m). Splenectomy was performed on 14 patients. Splenic blood flow was elevated in four of four patients (range 750-2000 ml/min). Splenic A-V oxygen difference was exaggerated in seven of seven patients and in three of three patients splenic indocyanine-green dye dilution curve failed to show an early peak suggestive of A-V shunting in the spleen. Free portal pressure was elevated in 12 of 12 patients and decreased immediately after splenectomy. The intravascular albumin mass decreased in ten patients, was unchanged in three at 2-4 mo after splenectomy, and was accompanied by a rise in the plasma albumin concentration in nine. These data suggest that a flow-induced portal hypertension with expansion of the portal vascular space is an important early hemodynamic change. This finding, together with a decreased peripheral resistance, probably results in a decrease in effective intravascular volume, resulting in stimulation of the renin-angiotensin-aldosterone system and other renal hemodynamic changes necessary for salt and water retention. Splenectomy usually accomplishes a complete reversal of these abnormalities and correction of the anemia.


Immunologic evidence that the properties of human antihemophilic factor (factor VIII) are attributes of a single molecular species. Preparations of human plasma rich in antihemophilic factor (AHF, factor VIII) correct the coagulative defect of classic hemophilic plasma, form precipitates with specific heterologous antiserum, and support aggregation of platelets by ristacetin and retention of platelets by columns of glass beads. Whether these various properties can all be attributed to a single molecular species is disputed. Antiserums were prepared in rabbits to partially purified AHF and to high molecular weight (MW) and low MW fragments separated by gel filtration through columns of agarose in the presence of 0.25 M calcium chloride. Antiserums to AHF and to its high or low MW fragments all inactivated procoagulant AHF in plasma or in preparations of AHF. In contrast, antiserums to AHF and its low MW fragment inactivated procoagulant AHF in the low MW fragment, while that against the high MW fragment lacked this property. Thus, the low MW fragment appeared to have some antigenic sites not present or accessible to the antiserum against the high MW fragment. In agreement with this, the low MW fragment did not block antiserum against the high MW fragment as tested by the capacity of this antiserum to inactivate functional AHF in plasma. These immunologic studies support the view that the various properties of preparations of human AHF are attributes of a single molecular species.


Activation of the coagulation system in polycythemia vera. Thrombosis is one of the major complications of polycythemia vera. Seventeen patients with polycythemia vera in good hematologic control were evaluated for abnormalities of the coagulation system. Activation of the intrinsic coagulation cascade was suggested by low levels of factor XII, prekallikrein,  and kallikrein inhibitors in 12 of 17 patients. The group also demonstrated a significant increase in soluble fibrin complexes using plasma gel filtration on 4% agarose. Fibrin degradation products were normal and antithrombin III levels were slightly elevated. It appears that patients with polycythemia vera have chronic activation of the coagulation system, probably initiated by activation of factor XII. No correlation between the degree of coagulation abnormalities and thromboembolic complications was evident in this group of patients.


Preferential involvement of chromosomes no. 8 and no. 21 in acute leukemia and preleukemia. Chromosome analyses were performed by a direct method on bone marrow cells of 147 patients with acute leukemia and preleukemia; in 53 chromosomally abnormal cell lines were found. Chromosome abnormalities due to structural alterations were observed in 48% of the aneuploid patients. Using the ASG banding technique, the exact identification of the abnormal chromosomes was successfully made in 22 aneuploid patients. Even though variability between patients existed in the chromosome changes; the nonrandom occurrence of some chromosome abnormalities was revealed, involving most frequently chromosomes No. 8 and No. 21. Abnormalities of chromosome No. 22 were not encountered, contrasting sharply with the frequent involvement of this chromosome in chronic myelogenous leukemia. The significance of the preferential involvement of No. 8 and No. 21 chromosomes is discussed in relation to leukemogenesis.


Polyamine concentrations in bone marrow aspirates of children with leukemia and other malignancies. High-pressure liquid chromatography analysis of polyamines in bone narrow from leukemic and nonleukemic subjects demonstrated increased concentrations of putrescine, spermidine, and spermine associated with increased cellularity. The most striking abnormality was the marked elevation of putrescine. Bone marrow polyamine analysis may be an adjunct for evaluation of leukemia patients.


Chromosomal banding patterns in acute nonlymphocytic leukemia. Bone marrow chromosomes obtained from 50 of 55 consecutive adult patients with acute nonlymphocytic leukemia were analyzed with quinacrine fluorescence. Twenty-five patients showed a normal karyotype and 25 an abnormal karyotype on the initial samples available for analysis. Among the 25 patients with abnormalities, the marrow cells contained 48 chromosomes in one case, 47 in two, 46 in ten, 45 in nine, 43 in two, and 42 chromosomes in one case. Seven of the ten patients with 46 chromosomes had abnormalities, primarily balanced translocations, that were not detected with the standard Giemsa stains. The analysis of all of the data available revealed the presence of nonrandom chromosome changes such as the addition of No. 8, the loss of No. 7, and a gain or loss of one No. 21. the most frequent structural rearrangement was the translocation between the long arm of No. 8 and No. 21, which may also be associated with the loss of a sex chromosome. Chromosomal abnormalities decreased or disappeared during remission; the same abnormality recurred in relapse. Chemotherapy did not appear to produce a stable clone of aberrant cells. Evolution of the karyotype occurred in eight patients, in five of whom an additional No. 8 was observed. This pattern of chromosomal evolution in patients with acute leukemia was very similar to that observed in patients with chronic myelogenous leukemia in the blast phase.


Unregulated growth of murine leukemic cells and suppression of normal granulocyte growth in diffusion chamber cultures. The patterns of proliferation of C1498 mouse acute leukemic cells have been studied using the diffusion chamber technique of cell culture. These malignant cells grow to the same maximal cell concentration irrespective of initial cell input. Leukemic cells proliferate equally well with or without the stimulus of prior host irradiation. When cells cultured for several days are diluted to the original input concentration and recultured, they rapidly proliferate back to maximal cell number. All of these findings are in sharp contrast to the behavior of granulocytes from normal mouse marrow grown in the same culture system. Co-culutre of equal numbers of normal marrow cells and leukemic cells results in virtually complete inhibition of normal marrow cells and leukemic cells results in virtually complete inhibition of normal granulocyte growth. These experiments provide a means of studying malignant growth of leukemic cells, as compared to the controlled growth and differentiation of normal granulocytes, and mechanisms by which leukemic cells suppress normal granulocyte development.


Isolation and in vitro differentiation of human erythroid precursor cells. There is decreased beta-globin production in beta-thalassemic reticulocytes and nucleated erythroid cells. In this study, we have examined whether unbalanced globin synthesis is expressed at all stages of human erythroid cell maturation. In order to determine the pattern of globin synthesis in early erythroid cells during erythroid cell maturation, an in vitro culture system using human bone marrow erythroid precursor cells has been developed. Early erythroid precursor cells (proerythroblasts and basophilic erythroblasts) have been isolated from nonthalassemic and thalassemic human bone marrows by lysing more mature erythroid cells, using complement and a rabbit antiserum prepared against normal human red cells. In the presence of erythropoietin, differentiation and proliferation of erythroid cells in demonstrable in liquid suspension culture for 24-48 hr, as determined by morphological criteria and by an increase in globin synthesis. The ratio of alpha- to beta-globin chain synthesis in nonthalassemic cells in approximately 1 at all stages of erythroid cell differentiation during culture. In cells from four patients with homozygous beta- thalassemia there is decreased beta-globin synthesis compared to alpha-globin synthesis, both in early erythroid precursor cells and during their maturation in culture. These findings indicate that unbalanced globin chain synthesis is expressed at all stages of red cell maturation in homozygous beta-thalassemia.


Separation of the erythropoietin-responsive progenitors BFU-E and CFU-E in mouse bone marrow by unit gravity sedimentation. The sedimentation velocity profiles of the entities in mouse bone marrow responsible for erythropoietic burst formation (BFU-E) and for erythrocytic colony formation (CFU-E) have been studied under conditions designed to determine whether the values observed are real or result from cell interactions occurring during culture of the fractions. Bone marrow cells of adult C3Hf/Bi mice were subjected to unit gravity sedimentation in a bovine serum albumin gradient, and fractions were assayed in plasma culture. Because it was found that cell concentration affected the efficiency of erythropoietic burst formation in culture, aliquots were plated at two different cell concentrations, as well as at a fixed proportion of each fraction. The modal sedimentation velocity of the BFU-E population averaged 3.9 mm/hr and that of the CFU-E population, 6.4 mm/hr; both were found to be independent of cell concentration or method of dividing the fractions. Cells from fractions of different sedimentation velocity were mixed with one another or with unfractionated cells. No significant inhibition or stimulation of erythropoietic burst formation was seen. We concluded that the observed values represented the true modal sedimentation velocities of BFU-E and cfu-e in normal mice. To determine whether a change in the physiologic state of the animals affected the sedimentation velocities of BFU-E or CFU-E, marrow cells from mice hypertransfused with red cells were compared with those from controls. The modal sedimentation velocity of BFU-E was unaffected by hypertransfusion, nor was there any change in the number of BFU-E under these conditions. The number of CFU-E was substantially reduced without a significant change in modal sedimentation velocity.


Effect of vitamin B12 and folic acid deficiencies on neutrophil function. Morphological and quantitative neutrophil abnormalities are common in the megaloblastic anemias of vitamin B12 and folic acid deficiency. Little is known, however, about the role of these vitamins in normal leukocyte function. Seven patients with megaloblastic bone marrows, four with vitamin B12 deficiency and three with folic acid deficiency, were studied to determine the effect, if any, of these deficiencies on leukocyte function. Phagocytosis of staphylococci, hexose monophosphate shunt activation with phagocytosis, and microbicidal capacity against Staphylococcus aureus were determined prior to the institution of specific therapy. In two instances, these studies were repeated following treatment. There was no impairment of phagocytosis per se, and resting metabolism was not significantly decreased. With phagocytosis, however, metabolic activation was decreased to 35%-36% of control values in the leukocytes of patients with vitamin B12 deficiency but not in the leukocytes of patients with folic acid deficiency. Bacterial killing was slightly decreased in vitamin B12 but not in folic acid deficiency. These abnormalities of function were reversed after specific therapy. These findings suggested a specific role for vitamin B12 in the production of intermediates necessary for normal cell function.


Pyruvate kinase deficiency and leg ulcers. We report a family with a new pyruvate kinase (PK) variant in which leg ulcers have been present in four of the five affected homozygous family members, but not in any of the unaffected individuals. The propositus, an 18-yr-old boy, suffered from recurrent crises of hemolytic anemia and leg ulcers. A splenectomy was performed and the leg ulcer was treated un-successfully with a pinch graft. Studies ondialyzed hemolysates showed that the enzyme was kinetically abnorma, being almost entirely resistant to activation by fructose diphosphate. THE THERMOSTABILITY OF THE ENZYME WAS MODERATELY DECREASED, AND THE ELECTROPHORETIC MOBILITY WAS NORMAL. One may speculate that the development of leg ulcers in some kinships with PK deficiency may be related to variants of PK which exert unusual effects on the rheologic properties of the red cell in vivo.


Hemoglobin pyrgos alpha2 beta2 83 (EF7) Gly leads to Asp: a new hemoglobin variant in double heterozygosity with hemoglobin S. An electrophoretically fast-moving hemoglobin variant was found to be present together with hemoglobin S, in the hemolysate of the rythrocytes of at 3-yr-old Greek boy. Electrophoresis of the parents' erythrocyte hemolysates revealed that the father was an AS heterozygote, while the mother was a carrier of the variant hemoglobin. A sibling was also found to be a carrier. The amount of the mutant hemoglobin in the peripheral blood of the propositus, his mother, and his brother was 62.2%, 52.5%, and 51.1%, respectively, as determined by column chromatography. The patients peripheral blood smear showed mild anisocytosis, microcytosis, and hypochromia. Similar but less pronounced red cell abnormalities were found in the other two carriers. Structural analysis of the variant hemoglobin revealed substitution of an aspartic acid for the glycine residue at the beta83 (EF7) position. This new hemoglobin was named hemoglobin Pyrgos. All the carriers of hemoglobin Pyrgos are clinically healthy, and there seems to be no interaction between hemoglobin Pyrgos and hemoglobin S as manifested clinically.


The effect of experimental hematoma on serum levels of fibrinogen-related antigen. The effect of experimental hematomas on serum levels of fibrinogen-related antigen (FRA) was studied in rabbits. Homologous blood used for production of hematomas was mixed with 131I-fibrinogen, and the measurement of FRA was made using a radioactive technique (representing FRA from hematoma) and immunologically (representing total FRA). Total body radiation of animals bearing hematomas containing 131I-fibrinogen decayed slowly (mean t 1/2 = 189 hr) over the first 2-3 days and then rapidly (mean t 1/2 = 43 hr) during the subsequent days. Serum FRA levels measured immunologically rose transiently from 4 to 11 mug/ml during the slow phase of hematoma resolution, and returned to baseline levels during the rapid phase of resolution. The appearance of a small amount of protein-bound radioactivity in the blood of animals with hematomas paralleled the time course of the changes in immunologically determined FRA, but, even at its peak, circulating levels only averaged 0.36% of the administered tracer. From these observations, it seemed unlikely that the dissolution of fibrin which may form as the result of bleeding into tissues would significatnly contribute to levels of circulating FRA.


Studies on the erythropoietic cell system in CBA mice after Rauscher virus infection. Erythropoiesis in CBA mice was studied in Rauscher leukemia virus infected mice using the incorporation of 59Fe into spleen, bone marrow and peripheral blood. Beginning at day 4 an increased uptake into the spleen and a decrease in the bone marrow and the peripheral blood was observed. The increased uptake by the spleen was also found in plethoric mice. The erythropoietin responsive compartment was also enlarged in the spleen of these mice. The The dose-response-curve for erythropoietin was altered 4 days after infection, there was a higher background level of 59Fe incorporation and the response to low doses was better in infected animals. The reticulocytopenia which is usually seen in these mice, was overcome by administration of high doses of erythropoietin. It is concluded that the Rauscher virus acts in a similar manner to erythropoietin, but the erythropoiesis induced is ineffective since the cells do not mature. This maturation deficiency is influenced by administration of exogenous erythropoietin.


Iron storage in macrophages and endothelial cells. Histochemistry, ultrastructure, and clinical significance. 1 hour after  i. v. infusion of colloidal iron in iron deficient subjects uniform phagosomal iron granules were observed in macrophages and endothelial cells of several organs. 7 to 10 days later transformation into ferritin coould be visualized in macrophages only. Now, these cells showed diffuse iron staining of the cytoplasm due to dispersed ferritin molecules. Polymorphous lysosomes contained densely packed particles from still unchanged ferric hydroxide to paracristalline ferritin. The macrophageal iron was mobilizable in few days to several weeks. The univorm lysosomal iron granules of endothelial cells disappeared after 1 to 2 years. Endothelial iron siderosis without previous i. v. iron application was a frequent finding in pernicious anaemia and iron overload of diverse origin.


[Detection of reagent errors by internal quality control of the Coulter counter S]. By a simple program of quality control for the Coulter counter model S two deficient reagents could be detected. To high values of PCV associated with a decrease of MCHC were caused by a faulty Isoton batch. This error was revealed by native blood samples but not by the stabilized 4 C standard. Falsely elevated leukocyte counts due to insufficiently lysed giant platelets and platelet aggregates were produced by modified Lyse-S batches. Comparisons made with a Coulter counter model F using Zaponin and with a counting chamber yielded values at lower levels.


The response of dietary stressed Periplaneta americana to chronic intake of pure aflatoxin B. In general these studies seem to indicate that adult male P. americana are not particularly sensitive, toxicologically, to aflatoxin B1, even when maintained on a marginally inadequate diet containing a low level of sucrose and no protein. Also they may be capable of detecting low levels of aflatoxin B1 in their diet (12 mug/ml) and seem not to concentrate aflatoxin B1 in their bodies. Even in dietary stressed conditions adult male American cockroaches showed a very limited potential as a bioassay organism for this toxin. Actually it appears that they may be quite resistant to the toxin. Currently there is no definite answer as to the advantages or disadvantages of insufficient dietary proteins or even carbohydrates providing protection against this toxin. The results show that the toxin would not be an effective cockroach-killing agent and thus could not serve as a bioassay system. However, this insect could serve as a model system in further investigating the mode of action and possible detoxification of aflatoxin B1.


Uptake and persistence of pesticides in cultured human cells. The uptake and persistence of 14C-labeled pesticides in cultur-s of human embryonic lung diploid cells were studied. Chlordimeform, DDT, parathion, aldrin and dieldrin were selected as test compounds. Results obtained from these experiments divided the chemical into two groups. The first group consisted of three chemical DDT, aldrin and dieldrin which are generally classified as persistent insecticides while the second group was composed of chlordimeform and parathion, generally considered to be non-persistent insecticides. The rate of initial cellular incorporation of first group was approximately 20 to 70 times greater than the non-persistent insecticides. During the course of an incubation, the amounts of pesticide taken up by the cells decreased gradually.


Effect of some inhibitors on aflatoxin-production in a synthetic medium and on the incorporation of acetate-1- 14C into aflatoxins by resting mycelia of Aspergillus parasiticus. The effect of a number of metabolic inhibitors on the incorporation of acetate-1-14C into aflatoxins was investigated, using resting mycelia of Aspergillus parasiticus suspended in phosphate buffer. Malonate, iodoacetate, sodium arsenite, 2:4 dinitrophenol, sodium fluoride and p-aminosalicylate stimulated the incorporation at low concentrations and inhibited the same at high concentrations. p-Nitrobenzoic acid was inhibitory at all the concentrations tried. Fluoride, arsenite, arsenate and iodoacetate inhibited both growth and aflatoxin production when added directly to the growth medium. In general, there was a greater inhibition in growth medium than with the suspended mycelia.


Damage to spermatogenesis in juvenile rat treated with DDVP and malathion. Juvenile male rats received either 20 mg DDVP or 40 mg malathion/kg on the 4th and 5th day of life, and either 10 mg DDVP or 20 mg/kg malathion daily from the 4th to the 23rd day of life. The histological examination of the testes showed slight reductions of the spermatogentic cells and Leydig cells. Therefore, it is assumed that testosterone synthesis is reduced, followed by damage to spermatogentic cells. All disturbances return by normal by the 50th day of life.


A study of inhalation of pentachlorophenol by rats III. Inhalation toxicity study. An LD50 study of inhaled pentachlorophenol has been conducted. Seven groups of rats, consisting of 12 animals each, were exposed to the aerosol of sodium pentachlorophenate. The LD50 was 11.7 mg/kg body weight as shown on a probit curve.


A study of inhalation of pentachlorophenol by rats. IV. Distribution and excretion of inhaled pentachlorophenol. It appears that in the rat repeated respiratory exposures to PCP do not result in an increase in the body burden of this compound as would be suspected from the 24 hour half-life determined from a single inhalation exposure. These results suggest some mechanism induced by prior exposure to PCP that increases the ability of the animals to remove this compound from its body. Increased excretion may be a factor in this activity, however, it cannot account for the total effect. Storage appears unlikely, since the elimination rate and time period remain unchanged after five doses as compared to after one. Increased matebolism may be the explanation, although this mechanism can only be inferred from these data. Quantitative metabolic results will be necessary to support this hypothesis.


Reflex bradycardia and hypotension produced by prostaglandin F2alpha in the cat. 1 Intravenous administration of prostaglandin F2alpha results in a dose-dependent increase in pulmonary arterial pressure, decrease in systemic arterial pressure and a delayed bradycardia. Pulmonary vasoconstriction was observed at doses as low as 0.1 and 0.3 mug/kg. The systemic depressor and heart rate lowering effects were observed at 1 mug/kg doses and above. 2 A moderate bradycardia was still observed after atropine blockade but was abolished following bilateral vagotomy. Neither of these procedures affected the pulmonary vascular response. 3 Injections of submaximal doses of prostaglandin F2alpha (1--4 mug/kg) produced a greater and longer lasting bradycardia when injected into the left atrium than was observed following intravenous administration. In addition the latency of onset was much shorter following left atrial injection. These doses resulted in no change in heart rate and a minimal hypotension when injected into the brachiocephalic artery or into the aortic arch. 4 Small doses of prostaglandin F2alpha administered at the level of the origin of the coronary arteries produced marked decreases in heart rate and blood pressure whereas no change occurred following injection of the same amount into the ascending aorta at more distal sites. 5 These results suggest that prostaglandin F2alpha produces bradycardia and hypotension in the cat by activating 'receptors' located in the left heart or by acting on structures perfused by means of the coronary arteries.


The effects of intra-amygdaloid injections of 6-hydroxy-dopamine on avoidance responding in rats. 1 The effects of bilateral intra-amygdaloid injections of 6-hydroxydopamine (6-OHDA) on shuttle box avoidance acquisition, retention, and extinction, and passive avoidance acquisition were examined in rats. 2 Intra amygdaloid 6-OHDA injections produced catecholamine depletion in and around the amygdalae but failed to reduce striatal dopamine concentrations. 3 Conditioned avoidance acquisition was markedly inhibited in 6-OHDA-treated rats whereas retention and extinction were only slightly impaired. 4 Passive avoidance acquisition was slightly but significantly improved in rats with amygdaloid 6-OHDA lesions. 5 Treated rats showed no motor abnormalities, they were not hypoactive in a photocell activity cage and they performed as well as controls on a rotating rod. 6 It is suggested that the conditioned avoidance acquisition deficit in rats with amygdaloid 6-OHDA lesions may be related to an impairment of associative learning rather than to perceptual or motor disturbances.


Effects of azaperone on cardiovascular and respiratory functions in the horse. 1 The butyrophenone tranquilizer, azaperone, was administered intramuscularly, at dose levels of 0.4 and 0.8 mg/kg, to ponies and its effects on cardiovascular and respiratory functions assessed. 2 Arterial blood pH, CO2 tension (PaCO2) and O2 tension (PaO2) remained relatively constant throughout the course of action of azaperone. 3 Azaperone did not modify plasma protein concentration but venous blood packed cell volume and haemoglobin concentration were reduced by 5 to 10% for at least 4 hours. These changes were probably caused by uptake of erythrocytes into the splenic reservoir. 4 Small increases in heart rate occurred for up to 60 min after administration of the drug, and this was followed by a slight bradycardia in some ponies. 5 Azaperone reduced mean arterial blood pressure (MAP) for at least 4 h, by which time its ataractic action was generally no longer apparent. The hypotension was caused, during the early phase of action at least, by a reduction in peripheral resistance, since cardiac output was increased slightly 20 min after its administration. Possible mechanisms underlying the cardiovascular changes are discussed. 6 In spite of reductions in arterial blood O2 content and MAP produced by azaperone, it is likely that tissue oxygenation was adequate, since arterial blood lactate concentrations were not increased.


Blood pressure responses to adrenal field stimulation as a measure of adrenal catecholamine release. 1 A new method for studying adrenal medullary release is described in pithed rats using field stimulation of an entire adrenal gland. 2 The increases in blood pressure in response to field stimulation of the gland consisted of an initial short, variable component, due to stimulation of adrenergic vasomotor neurones and a secondary, longer lasting component, due to medullary catecholamine release. 3 Removal of the initial component by drugs or cardiac/coeliac ganglionectomy did not affect the magnitude of the secondary pressor component. 4 The secondary pressor component was frequency-dependent, reproducible and stable with time. The extent of medullary catecholamine release could be assessed by comparing the blood pressure rise with those obtained after adrenaline injections. 5 The method appears to provide a reliable means by which adrenal medullary catecholamine release may be assessed without significant interference from vasomotor nerves.


Rat uterus renin-like activity: effect of stimuli and hormones. 1 The characteristics of renin-like activity in rat uterus were studied. The optimum temperature was 50 degrees C and optimum pH 4.0. Potassium (100 mM) enhanced this activity but sodium or calcium had no effect. 2 Uterine renin-like activity was unchanged 24 h after bilateral nephrectomy. 3 Renin-like activity in the uterus increased slowly from birth to 4 weeks of age and faster between the 4th and 8th week. 4 Ovariectomy caused a considerable fall in uterine renin-like activity. 5 The following factors, known to affect renin secretion in the kidney, i.e., hypovolaemia, sodium loading, adrenalectomy, administration of desoxycorticosterone acetate and injection of isoprenaline, had no effect on uterine renin-like activity. 6 Stilboestrol, an oestrogen, caused a significant increase of uterine renin-like activity. Progesterone and testosterone had no significant effect on this activity but blocked the increase caused by stilboestrol. 7 During pregnancy there was a small but significant fall of renin-like activity in the uterus in the first week and a continuous increase throughout the later period of pregnancy. 8 It is concluded that uterine renin-like activity is independent of kidney renin and does not respond to stimuli  affecting kidney renin. Uterine renin activity is hormone-dependent and may be governed by the ratio, oestrogen : progesterone.


A method for recording smooth muscle and vascular responses of the blood-perfused dog trachea in situ. 1 A method is described for measuring responses of dog tracheal musculature and vasculature in situ. 2 The upper two thirds of the trachea was perfused with blood through both cranial thyroid arteries at a constant pressure. The blood flow through the arteries was measured with an electromagnetic flowmeter. The response of the tracheal musculature was measured as a change in pressure in a water-filled cuff inserted into the trachea via the mouth. Drugs were injected close-arterially. 3 Acetylcholine produced dose-dependent increases in blood flow rate (vasodilatation) and in tracheal intraluminal pressure (tracheal constriction). These responses were antagonized by atropine. 4 Isoprenaline produced vasodilatation which was blocked by propranolol. Adrenaline and noradrenaline caused vasocontriction which was blocked by phentolamine. 5 All three catecholamines produced a decrease in tracheal intraluminal pressure (tracheal dilatation). The tracheal dilatation in response to adrenaline and noradrenaline was converted to constriction by propranolol. The tracheal constriction thus unmasked was abolished specifically by phentolamine. 6 From these results it is concluded that the tracheal musculature and vasculature contain muscarinic receptors, and excitatory alpha- and inhibitory beta-adrenoceptors. In the tracheal musculature beta-adrenoceptors predominate over alpha-adrenoceptors; the reverse is true in the tracheal vasculature.


Impaired absorption of chlorpromazine in rats given trihexyphenidyl. 1 The absorption and tissue distribution of orally administered [14C]-chlorpromazine (CPZ) were compared in trihexyphenidyl (THP; Artane)-treated and control rats. 2 Total radioactivity (CPZ) in the plasma and brain of rats treated with THP was significantly lower whereas total radioactivity in the stomach was significantly higher than in rats not previously treated with THP. 3 Gastric emptying in rats treated with THP was significantly delayed as measured by gastric clearance of a marker [14C]-polyethylene glycol. 4 Transport of [14C]-CPZ in everted sacs was not affected by treatment with THP. 5 Metabolism of [14C]-CPZ by liver homogenates was not affected by treatment with THP. 6 The relationship of delayed gastric emptying in THP-treated rats and their lower plasma and brain levels of [14C]-CPZ after oral administration is discussed.


Benzodiazepines and central glycine receptors. 1 In cats, anaesthetized with pentobarbitone, intravenous diazepam (minimum dose 3.0 mg/kg) enhanced dorsal root potentials but did not significantly diminish the reduction by electrophoretic strychnine of the inhibitory action of electrophoretic glycine on dorsal horn interneurones. 2 In mice, intraperitoneal diazepam (2.5 mg/kg) had no appreciable effect on the potency of strychnine as a convulsant, although providing some protection against bicuculline. 3 These observations, together with the failure of chlordiazepoxide to either inhibit the firing of spinal interneurones or reduce antagonism between strychnine and glycine when administered locally, provide no support for the interaction between benzodiazepines and mammalian central glycine receptors which has been proposed on the basis of in vitro studies of strychnine binding.


Studies on the relative effects of prostaglandins, bradykinin, 5-hydroxytryptamine and histamine on the synovial microcirculation in dogs. 1 The relative effects of prostaglandins E1, E2, F1alpha, F2alpha, bradykinin, histamine and 5-hydroxytryptamine (5-HT) on the canine synovial microcirculation were investigated using the rate of clearance of radioactive xenon (133Xe) as an index of synovial perfusion. 2 All the compounds tested, except prostaglandin F1alpha, produced a vasodilator effect. The descending order of potency of the active compounds was (i) prostaglandin E1, (ii) prostaglandin E2 and bradykinin, (iii) histamine and 5-HT, (iv) prostaglandin F2alpha. The most potent compound tested, prostaglandin E1 produced an effect in nanogram amounts in each joint. 3 Prostaglandin F2alpha has been reported to have an anti-inflammatory action; however no evidence was found of antagonism of prostaglandin E1 by two dose levels of prostaglandin F2alpha. 4 Preliminary studies showed that threshold doses of prostaglandin E1 did not potentiate the vasodilator action of threshold or sub-threshold doses of bradykinin in the dog synovium.


The effects of prostaglandins E1, E2 and F2alpha on the cutaneous vasculature of the rat. 1 The responses of the rat cutaneous vasculature to prostaglandins E1, E2 and F2alpha have been investigated by a photomicrographic technique. 2 Prostaglandin E1 produced transient arterial constriction which was blocked by local pretreatment of preparations with compound 48/80 or methysergide. It was concluded that prostaglandin E1 produced vasoconstriction by release of 5-hydroxytryptamine (5-HT) from mast cells. The magnitude of the vasoconstrictor response appeared to be subject to seasonal variation. 3 Prostaglandin F2alpha produced arterial constriction of longer duration which was not blocked by compound 48/80, methysergide or phenoxybenzamine. 4 Preparations pretreated with prostaglandin F2alpha were found to be more sensitive to the venous constrictor effect, and less sensitive to the arterial constrictor effect, of noradrenaline. 5 Prostaglandin E2 produced arterial constriction which was usually partially blocked by compound 48/80 and methysergide and it was concluded that a major component of the vasoconstrictor response to prostaglandin E2 was of the E1 type but some component was of the F2alpha type.


A comparison of gamma-aminobutyric acid and the semi-rigid analogues 4-aminotetrolic acid, 4-aminocrotonic acid and imidazole-4-acetic acid on the isolated superior cervical ganglion of the rat. 1 The rat superior cervical ganglion possesses receptors for gamma-aminobutyric acid (GABA). This can be demonstrated in vitro by recording the changes in ganglionic surface potential which occur after the addition of GABA to the bathing solution. 2 The action of three conformationally-restricted analogues of GABA namely 4-aminotetrolic acid (4-ATA), trans 4-aminocrotonic acid (4-ACA) and imidazole-4-acetic acid (IAA) have been examined for activity at this peripheral receptor. 3 All three analogues depolarized the ganglion in a manner similar to GABA. Their actions were transient and were 'occluded' by GABA; also the dose-response curve in each case was parallel to that of GABA. Molar potencies relative to GABA (= 1) were 4-ACA = 1.48, IAA = 0.100, 4-ATA = 0.0028. 4 The action of each analogue could be blocked by the GABA antagonists bicuculline and tetramethylenedisulphotetramine at doses which had relatively little effect on responses to the cholinomimetic carbachol. 5 4-ACA and IAA (1 mM) significantly reduced the ganglionic accumulation of [3H]-GABA (0.2 muM) by 88% and 58% respectively whereas 4-ATA (1 mM), caused no significant reduction in [3H]-GABA accumulation.


Investigation of occurrence of tolerance to bronchodilator drugs in chronically pretreated guinea-pigs. 1 The actions of sympathomimetic amines on isolated preparations of atria, trachea and ileum were studied in vitro in guinea-pigs, which had been pretreated for 5 or 12 days, by subcutaneous injection, with adrenaline (5 mug/kg), salbutamol (0.5 mug/kg), salbutamol (0.5 mug/kg), methoxamine (250 mug/kg) or saline (0.9% w/V NaCl solution). 2 In the trachea, a decrease in sensitivity (tolerance) to the relaxant effect of adrenaline was induced by pretreatment, for 12 but not for 5 days, with adrenaline. In these animals, cross-tolerance to isoprenaline or salbutamol was not observed. Tolerance to the relaxant actions of adrenaline isoprenaline or salbutamol was not observed after pretreatment with salbutamol. 3 In the trachea, pretreatment with methoxamine or adrenaline for 12 days did not change the sensitivity to the alpha-adrenoceptor-mediated contractor action of methoxamine. 4 In the atria from those guinea-pigs pretreated with adrenaline or salbutamol, there was no reduced sensitivity to the beta-adrenoceptor agonist actions of adrenaline, isoprenaline or salbutamol. In animals pretreated with methoxamine or adrenaline, there was no observable tolerance or cross tolerance to methoxamine with respect to its alpha-adrenoceptor-mediated positive inotropic action in the atria and no unequivocal evidence of a reduced sensitivity to that action of adrenaline. 5 It was confirmed that the twitch-like contractions of the longitudinal muscle of the electrically stimulated ileum were inhibited by sympatomimetic amines acting on alpha- and beta-adrenoceptors. There was no reduced sensitivity to the inhibitory actions of noradrenaline or isoprenaline on the twitch of ileum isolated from animals pretreated with adrenaline, salbutamol or methoxamine for 5 or 12 days. 6 From our results on these three preparations from the same animals, it is concluded that generalizations regarding changes in sensitivity to sympathomimetic amines following their prolonged administration should not be made in any one species.


Lithium orotate, carbonate and chloride: pharmacokinetics, polyuria in rats. 1 The pharmacokinetics of the lithium ion administered as lithium orotate were studied in rats. Parallel studies were carried out with lithium carbonate and lithium chloride. 2 No differences in the uptake, distribution and excretion of the lithium ion were observed between lithium orotate, lithium carbonate and lithium chloride after single intraperitoneal, subcutaneous or intragastric injections (0.5-1.0 mEq lithium/kg) or after administration of the lithium salts for 20 days in the food. 3 The findings oppose the notion that the pharmacokinetics of the lithium ion given as lithium orotate differ from lithium chloride or lithium carbonate. 4 Polyuria and polydipsia developed more slowly in rats given lithium orotate than in those given lithium carbonate or lithium chloride, perhaps due to an effect of the orotate anion.


The uptake of tritiated delta 1-tetrahydrocannabinol by the isolated vas deferens of the rat. 1 Weighed stripped vasa deferentia were incubated in Holman's solution containing (a) [14C]-sorbitol 0.014 mm, (b) [3H]-noradrenaline ([3H]-NA) 12.31 nM, (c) [3H]-tetrahydrocannabinol ([3H]-delta1-THC) 1 mug/ml for 5, 10, 20 and 30 minutes. 2 Tissues were washed, dissolved in Protosol, counted by standard scintillation counting technique and 'drug space' expressed as ct min-1 mg-1 tissue/ct min-l mul-1 bathing fluid. 3 Vasa incubated for 30 min with [14C]-sorbitol were washed for varying lengths of time; 82% clearance had taken place after 2 washes of 5 minutes. 4 The uptake of [3H]-NA was inhibited by the presence of desmethylimipramine (DMI) 10 nM in the bath or by pretreatment of rats with 6-hydroxydopamine (6-OHDA). 5 The uptake of [3H]-delta 1-THC was not inhibited by the presence of DMI. It was reduced but not abolished by 6-OHDA pretreatment.


Uptake of 5-hydroxytryptamine by rat blood platelets and its inhibition by adenosine 5'-diphosphate. 1 The uptake of 5-hydroxytryptamine (5-HT) by rat blood platelets in citrated plasma was linear for at most 10 s and was substantially complete within 3 minutes. 2 Adenosine 5'-diphosphate (ADP) was a potent inhibitor of 5-HT uptake (Ki=0.38 muM) and kinetic analysis revealed that the inhibition was not competitive. 3 Inhibition of 5-HT uptake by ADP was abolished in the presence of prostaglandin E1 and 2-n-amylthio-AMP, which also inhibit the stimulant actions of ADP on blood platelets. 4 It is concluded that ADP could inhibit 5-HT uptake by changing the Na+/K+ distribution across the cell membrane, and the biological significance of this is discussed.


The distribution and kinetics of sulphacetamide in leukaemic mice. 1 During the first 90 min following oral administration of sulphacetamide, there was a rapid decline in plasma drug concentration in control mice whereas a progressive increase in sulphacetamide concentration was observed in leukaemic mice. 2 Similar changes in the kinetics of sulphacetamide distribution were observed in the liver, spleen and muscle. 3 While the concentration of sulphacetamide remained quite constant in the brain and fat tissue of control mice, a progressive increase in drug concentration was observed in the brain and fat tissue of leukaemic mice. 4 Some of these changes in the kinetics of sulphacetamide tissue distribution are compatible with delay in gastrointestinal absorption of the drug and its accumulation in the ascitic fluid.


Effects of mazindol, a non-phenylethylamine anorexigenic agent, on biogenic amine levels and turnover rate. 1 Mazindol is a new anorexigenic agent which possesses a different chemical structure from that of phenylethylamines, but shows a pharmacological profile similar to that of (+)-amphetamine. 2 Mazindol neither altered whole brain monoamine levels (noradrenaline (NA), dopamine, 5-hydroxytryptamine (5-HT)) nor changed NA levels in the hypothalamus or dopamine levels in the caudate nucleus. 3 Mazindol enhanced dopamine turnover rate in the caudate nucleus, as shown by the increased rate of dopamine decline after blockade of catecholamine synthesis by alpha-methyl-p-tyrosine and decreased the conversion index of (3H)-tyrosine into brain NA. 4 Mazindol administration did not modify pargyline-induced decline of 5-hydroxyindoleacetic acid suggesting that 5-HT turnover is not altered by this drug.


The uptake and subcellular distribution of radio-labelled metabolites of digitoxin in the guinea-pig isolated perfused heart. 1 Comparisons were made of the uptake and inotropic effects of concentrations of 0.1 muM of digitoxin and its cleavage products digitoxigenin-bis-digitoxoside, digitoxigenin-mono-digitoxoside and digitoxigenin in the isolated perfused hearts of guinea-pigs. 2 Digitoxin produced the greatest inotropic responses in this series, while the sequence of cleavage products produced progressively smaller responses. 3 The uptake of digitoxin was significantly higher than that of the three metabolites, and the uptake of metabolites became progressively less with cleavage. The highest binding in each case was found in the microsomal fraction. 4 The uptake of all four digitaloids was reduced when the potassium in the perfusion medium was increased.


Uptake of 5-hydroxytryptamine in different parts of the brain of the rabbit after intraventricular injection. 1 The uptake of 5-hydroxytryptamine (5-HT) was investigated in different areas of the rabbit brain (anterior hypothalamus, the raphe, the region of the substantia nigra, several cortical areas and the medulla oblongata) after intraventricular injection in pargyline pretreated animals by the formaldehyde-induced histochemical fluorescence method. 2 The distribution of fluorescence showed that the uptake of 5-HT, after circulation in the cerebrospinal fluid, caused a general increase in intensity of green yellow to yellow background fluorescence. There was an increased fluorescence in the nerve terminals, but no uptake occurred either in the cell bodies of neurones or in the glial cells.


The relationship between calcium and increased sensitivity of rabbit aortae four hours after reserpine. 1 Four hours after reserpine, rabbit aortic strips were supersensitive to acetylcholine, isoprenaline and noradrenaline. The threshold concentration of the drugs necessary to induce a response was less and the maximum tension developed by the tissues was greater than in control strips. 2 Reserpine-treatment potentiated the contractile responses to CaCl2. 3 Reserpine-treatment resulted in an increase in calcium uptake and an increase in the slow component of 45Ca2+ efflux. 4 After resperine-treatment, the rate of relaxation from a potassium-induced contraction was decreased. 5 It is concluded that reserpine-induced supersensitivity is related to an enhanced ability of the tissue to retain and utilize calcium.


Prostaglandin production by rabbit isolated jejunum and its relationship to the inherent tone of the preparation. 1 Pieces of rabbit jejunum were bathed in Krebs solution at 37 degrees C in an isolated organ bath bubbled with O2 and 5% CO2. The bathing fluid was collected regularly and assayed for prostaglandins. 2 The preparations maintained a continuous sub-maximal muscle contraction, referred to as inherent 'tone'. Prostaglandins E2 and F2alpha were continuously generated by the intestine and released into the bathing fluid. The amounts released first declined over 2 h and then steadily increased. The release was also greater after 48 h storage in the refrigerator and after mechanical damage. 3 There was no change in prostaglandin release when the rabbit jejunum was contractd by acetylcholine or physostigmine or relaxed by adrenaline, hyoscine, papaverine, dinitrophenol, or calcium-free Krebs solution. 4 Addition to the bathing fluid of the prostaglandin precursor, arachidonic acid, did not increase the release of prostaglandins although it contracted the tissue. Thus, output of prostaglandins from the tissue was not limited by substrate concentration but more probably by the capacity of the prostaglandin synthetase. 5 Prostaglandin output was decreased by bubbling the bathing fluid with N2 rather than O2; at the same time the preparation relaxed. 6 Aspirin-like drugs such as indomethacin also decreased or abolished prostaglandin formation and this, too, was accompanied by loss of tone of the isolated preparation. 7 Pieces of rabbit jejunum stored in Krebs solution containing indomethacin initially released little or no prostaglandin into the bathing fluid. However, prostaglandin release increased with repeated washing of the preparation. 8 The results suggest that intra-mural prostaglandin production contributes to the inherent tone of the rabbit jejunum, that trauma increases prostaglandin production and that the inhibitory effects of anoxia are linked with the lack of prostaglandin production and activity. The relevance of these findings to intestinal activity in vivo is discussed.


The effects of dimercaptosuccinic acid on the excretion and distribution of mercury in rats and mice treated with mercuric chloride and methylmercury chloride. 1 All five rats in a group survived if dimercaptosuccinic acid (DMSA), a water soluble derivative of 2,3-dimercaptopropanol (BAL), was given in doses of 10-40 mg/kg intraperitoneally 30 min, 4 and 24 h after administration of 2.4 mg/kg Hg as HgCl2, whereas three out of a group of five died if DMSA was not given. DMSA 20 mg/kg increased urinary excretion and decreased the body burden significantly more than 10 mg/kg DMSA, but further doubling of the dose had only marginal effects. 2 DMSA was able to reduce body burden and increase urinary excretion of Hg when intraperitoneal treatment started eight days after the subcutaneous administration of HgCl2. 3 DMSA was effective in decreasing body burden and the brain concentration of Hg in rats dosed orally with methylmercury (MeHgCl) when intraperitoneal treatment started with 40 mg/kg DMSA 24 h after Hg. Increase in the urinary excretion of mercury was responsible for the decrease in body burden. 4 DMSA was effective when given in the drinking water of rats or mice both against inorganic Hg and MeHgCl. In mice treated intraperitoneally with MeHgCl, DMSA 19.5 mug/ml in the drinking water caused a significant decrease in the body burden and increase in the excretion of Hg. 5 DMSA was about four times more efficient than D-penicillamine in decreasing the body burden of Hg. As their toxicity is in the same range, the higher efficiency of DMSA offers a larger margin of safety for the mobilization of Hg.


Where do psychiatrists come from? The influence of United Kingdom medical schools on the choice of psychiatry as a career. The medical schools of origin of 531 psychiatrists who had qualified in the U.K. in the period of 1961-1970 were ascertained. Psychiatrists were for the purpose of the study operationally defined as those who had taken the Royal College of Psychiatrists' Membership examinations since its inception. There were large discrepancies, as much as five-fold, between different medical schools, and no ready explanation is forthcoming. There were also discrepancies in the proportion of women graduates opting for psychiatry.


Stereoselective binding in cardiac tissue of the enatiomers of benzetimide, and antimuscarinic drug. 1 Benzetimide, possessing two stable enantiomers, dexetimide and levetimide, has been investigated in guinea-pig atria with respect to its atropine-like action and its tissue distribution. 2 The antagonistic potency of dexetimide was found to be over 6000 times higher than that of levetimide, the pA2 values being 9.82 and 6.0 respectively. 3 The tissue accumulation was investigated for both isomers in the concentration range from 1.5 X 10(-9) M to 10(-6) M yielding tissue to medium ratios (T/M) of between approximately 50 and 10. The highest values were found for the lowest concentrations. At any concentration investigated, dexetimide exhibited a higher uptake than the levoisomer. 4 The rate of uptake and washout of dexetimide was extremely slow, that of levetimide being considerably faster at equimolar concentrations. The same pattern held true for the onset and decline of the antagonistic action. 5 The high accumulation was found to be almost entirely due to unspecific binding. Even in the case of dexetimide the relative size of the receptor compartment could not be determined. The unspecific binding sites displayed a certain stereoselectivity but to a much lesser extent than the specific receptor binding sites.


The cohesiveness of alcoholism-complicated marriages and its influence on treatment outcome. One-hundred husbands, diagnosed as suffering from alcoholism, and their wives, were followed up twelve months after initial consultation and assessment. Follow-up information was complete in 89 cases. On the basis of both husband and wife accounts of the husband's drinking behaviour during the follow-up period, and their assessment of the drinking problem at twelve-months follow-up, 28 were classified as having a 'good' outcome and 29 as having a 'bad' outcome. In the remaining 32 cases outcome was considered 'equivocal'. A composite measure of marital cohesion was predictive of twelve-month outcome classification, cohesive marriages being significantly more likely to have a good outcome. The measure of marital cohesion was based upon husband and wife reports of mutual affection and of husband involvement in family tasks, favourable spouse perceptions and meta-perceptions, and optimism about the future of the marriage. Composite measures of dominance balance within the marriage were not predictive of outcome. Husband's job status, husband's self-esteem, and wife's reported hardship were not independent of marital cohesion, and were themseleves predictive of twelve-months outcome. When these variables were partially controlled it was found that marital cohesion remained predictive for husbands with relatively low status jobs and husbands with relatively low levels of self-esteem. It is an over-simplification to state that either the marriage, the spouse, or the severity of the patient's condition is alone the cause of variation in outcome. It is possible to integrate these findings with those of other studies on the influence of family variables on the outcom of conditions other than alcoholism. Together these studies suggest a general hypothesis linking a breakdown in the cohesiveness, or mutual rewardingness, of family relationships and unfavourable outcomes following treatment or consultation for psychological disorder.


Certificated incapacity and unemployment in alcoholics. Seventy-three male alcoholics permitted information to be obtained from official sources about time recorded as lost from work in receipt of sickness or unemployment benefits and about their weekly state insurance contributions. The average yearly time loss was 121-7 working days per person, comprising an average yearly loss through sickness of 86-1 and through unemployment of 35-6 working days respectively. By contrast the recorded national sickness loss for men in a comparable twelve months period averaged 15-9 working days per person. Thirteen alcoholics showed over five years, prolonged deficiency in work attendance. State benefits to the subjects, over twelve months during the early 1970s, totalled pounds 18,434.80. Diagnoses on their medical certificates underestimated incapacity from alcoholism.


Deliberate self-harm: a follow-up study of 279 patients. Two-hundred-and-seventy-nine patients (103 men, 176 women) were followed-up 1-2 years after an act of non-fatal deliberate self-harm. Of 155 patients offered a psychiatric out-patient appointment at the time, only 68 completed the treatment. A further act of deliberate self-harm was committed by 26 men and 41 women within twelve months. The factors most highly associated with repetition were previous psychiatric treatment, a previous act of deliberate self-harm, and a criminal record. These factors held good for a separate series of patients. Significantly more repeaters received prolonged psychiatric care after the initial episode of deliberate self-harm. The implications of these findings for the clinical management of such patients are discussed.


Temporal stability of symptom patterns in depression. Temporal stability of symptom patterns was examined in 33 depressives studied initially at the height of illness and again some months later in a relapse following earlier recovery. Relapse symptoms were significantly less severe at the time of rating, and initial and relapse severity were not significantly related. Neverthless there were significant correlations between initial and relapse scores on two factors orthogonal to severity. One of these reflected symptom patterns important to the endogenous-neurotic distinction, the other a contrast between depression and anxiety. These findings indicate some consistency in symptom patterns in successive episodes of depression, and thereby support the value of clinical classifications depending on symptom patterns.


Physiological dependence on, and symptoms of withdrawal from, chlormethiazole. The uses of chlormethiazole (Heminevrin) are briefly mentioned. Differing views of its potential for producing dependence are discussed. The consensus opinion is taken to be that a risk of psychological dependence does exist, but only one case has appeared in the medical literature to date of physiological dependence on chlormethiazole, with withdrawal symptoms. This case is re-examined. A second case is described in which the features of increasing dosage and withdrawal were followed by confusion, disorientation, delusions, hallucinations and muscular spasm and coarse jerking. This is taken as confirmation of the potential of chlormethiazole to produce physiological dependence. Some personal opinions of the author regarding indications for use and incidence of abuse are briefly mentioned.


Plasma concentrations of protriptyline and clinical effects in depressed women. We studied the relationship between side effects, clinical outcome and the drug plasma levels in 28 female depressed patients treated with protriptyline. After 3 1/2 weeks treatment, patients with plasma levels within a median range (630 to 900 nmol/l) showed better responses to the drug than patients with plasma levels outside this range. There were no statistically signficant correlations between plasma levels and side effect scores or 'corrected' side effect scores (scores after subtracting pretreatment values) for the group at any time after starting the treatment. But we found positive correlations between plasma levels and 'corrected' side effect scores for the neurotic subgroup after 14 and 21 days of treatment. Other correlations between plasma levels and side effect scores were non-significant.


Childhood separation experiences and psycho-social status in primiparous women: preliminary findings. In a group of British-born primiparous women, admission of a separation experience from parents in childhood was found to be associated with unmarried status, teenage pregnancy, having had psychiatric treatment, housing problems and a high score on a 'Malaise' inventory. Within the separated group the unmarried and teenage status were associated only with separations occurring in the context of a disrupted childhood, but were not related to the age of the separations. The Malaise score, however, was raised both for disrupted separations and for those occurring below the age of 5. It is noted that the factors associated with the separation in the mothers are those which have been found to be more common in the mothers of children with behaviour disorders.


Multivariate analysis: data reduction and treatment evaluation. In a recent article, Everitt (1975) discussed several problems with multivariate techniques. However, two useful applications of multivariate techniques were not covered. The present paper describes the use of factor analysis to reduce a large array of outcome variables to a statistically manageable number, and multivariate analysis of variance to determine the relative effectiveness of several treatment regimes where a single outcome variable cannot be specified. It is concluded that the advantages of a multivariate approach out-weigh the disadvantages, provided the researcher is careful in interpreting and reporting his results.


Responsiveness of delinquents and non-delinquents to social reinforcement. A series of six experiments, involving 198 subjects, examined the hypothesis that delinquents are less responsive than non-delinquents to social reinforcement and punishment. The hypothesis received support (a) using two different experimental techniques, one in which the subjects' judgements of autokinetic movement were modified and one using the Taffel (1955) verbal conditioning paradigm; (b) with the female adult administering the reinforcement and with a peer; (c) when the contingent social cues were rewarding (Good or Fine) and when they were punishing ('No'). The hypothesis was not supported when the verbal reinforcement was varied. Control studies using no reinforcement and money reinforcement indicated that the social reinforcement did indeed have a specific reinforcement effect and that delinquents did not show a general learning deficiency.


Language behaviour in acute and chronic schizophrenia. A predicition made by Broen (1968) regarding the performance of acute and chronic non-paranoid schizophrenics on measures of dominant verbal response bias was tested in a group of 40 hospitalized schizophrenic patients. A subgroup of 10 chronic patients were found to show an abnormal dominant response bias on two different language tasks and on one task showed a bias significantly greater than that shown by a group of 10 acute patients matched on verbal IQ and rated symptomatology. A correlational analysis of the bias scores of the total sample in relation to three indices of chronicity also showed a trend in the predicted direction of a greater dominant response bias with increasing chronicity. The data are consistent with Broen's (1968) theory of dominant response bias as a learned defence against aversive response interference in acute schizophrenia.


Relationship between conceptual judgements and stimulus dimensions among schizophrenics and normals. Eighteen paranoid schizophrenics, 18 non-paranoid schizophrenics and 18 normal subjects were shown a set of 36 schematic drawings of human faces. The faces varied along four dimensions: nose length, chin length, distance between eyes, and forehead height. Subjects were asked to rate each face as either 'intelligent' or 'unintelligent' and then as either 'contented' or 'discontented'. The paranoid schizophrenics were less systematic than both the normals and non-paranoid schizophrenics in their use of the stimulus dimensions in the judgements, the latter two groups not significantly differing in this respect. It was also found that there were significant differences among the groups regarding the average importance given to the different physical features, the profiles for the two schizophrenic groups being flatter than that of the non-schizophrenics. The results suggested there were two aspects of consistency in dimension utilization involved in the overall group differences-between-subject and within-subject consistency. The paranoid schizophrenics displayed low within-subject consistency, the non-paranoid schizophrenics displayed a high within-subject consistency but low between-subject consistency (i.e. an idiosyncratic weighting of dimensions in their judgements), and the non-schizophrenics displayed high within- and between-subject consistency.


Temporal lobe swelling: a common treatable complication of head injury. Four cases are described of focal contusion and swelling of the temporal lobe after head injury, giving rise to acute cerebral compression. The clinical features, pathology and treatment of this condition are discussed. It is suggested that this occurrence may be a common treatable complication of closed head injuries which may easily be overlooked, with fatal results, if exploratory cranial surgery is undertaken without preliminary cerebral angiography.


Primary malignant tumours of the thyroid: the relationship between histological classification and clinical behaviour. One hundred and seventy-nine primary malignant tumours of the thyroid seen at The London Hospital between 1945 and 1972 were classified by the system of Woolner et al. (1961) and Hazard (1964). The distinct pathological and clinical features of the differentiated primary carcinomas and the similarities and differences between malignant lymphoma and anaplastic carcinoma were confirmed. This study showed the 'benign' behaviour of more than half the 'differentiated' papillary and follicular carcinomas when treated by thyroid lobectomy and the very malignant nature of anaplastic carcinomas and lymphomas whatever their treatment. The behaviour of medullary carcinoma was closer to that of the other differentiated tumours than to the undifferentiated varieties. Our patients were not thought to have been exposed to known goitrogens or previous thyroid irradiation.


Paraganglionomas in the neck.

Paraganglionomas in the neck. Three paraganglionomas in the neck investigated by angiography are presented. The value of angiography in these tumours is stressed, and one case showed distinctive radiological features hitherto undescribed which probably constitute a basis for the definitive preoperative diagnosis of malignant lesions.


Experimental carotid-basilar bypass.

Experimental carotid-basilar bypass. A procedure for anastomosing the carotid to the vertebrobasilar circulation in the dog is described. A total of 20 experiments (10 acute and 10 chronic) were performed on dogs. The grafted vessel was found to be patent in 2 out of 4 dogs at 3 months after operation. The flow through the grafts, recorded by electromagnetic flowmeter, was 5-9 ml/min.


Grafting of the major veins: the value of anti-thrombotic drugs to maintain patency. The value of anti-thrombotic drugs to maintain the patency of grafts into the central venous system is described. The infrarenal portion of the inferior vena cava in mongrel dogs was used as the test bed. Two autologous graft materials were used: first, the tissue reaction to implanted silicone rubber, and, secondly, free peritoneum. Phenylbutazone was the drug administered to inhibit the aggregation of platelets at the bloodgraft interface. The low patency rate of the control group of animals conformed with previous experimental studies. The patency of grafts in the phenylbutazone-treated animals (up to 92%) was predictable after studying the in vitro behaviour of their platelets preoperatively.


Peripheral aneurysms in Behĉet's disease. Two patients with Behĉet's disease are reported, both of whom had aneurysms of peripheral arteries. In one the aneurysms were multiple. The aneurysm was replaced with a Terylene prosthesis in one patient, and in the other an autogenous vein bypass was used. In each case a further aneurysm developed adjacent to the vascular anastomosis. Severe ischaemia of the affected limbs subsequently developed in both patients.


Parietal pleurectomy for recurrent pneumothorax. One hundred patients with persistent or recurrent pneumothorax treated by parietal pleurectomy are described. There was one known recurrence and no postoperative deaths. Six patients required further surgery for complications. In the uncomplicated cases the average stay in hospital following operation was 11-5 days. Parietal pleurectomy should be regarded as the treatment of choice for patients with recurrent pneumothorax who are fit to undergo surgery.


Resection and reconstruction for carcinoma of the thoracic oesophagus. The technique and results of oesophageal resection through a right thoracotomy and laparotomy with reconstruction utilizing the stomach via a retrosternal route are reported. Forty patients underwent this procedure, with no mortality. The average blood loss during operation was 424 ml, and 72% of this series underwent the operation without blood transfusion. It is believed that this type of one-stage operation for carcinoma of the oesophagus is reasonable from the viewpoint of adequate resection of malignancies, and it can be performed with minimal surgical risk. With experience, perhaps it will become a standard method such as the Billroth I method in gastric surgery.


Kinin levels in the peripheral venous blood of patients with severe vasomotor dumping before and after revisional surgery. The kinin activity in peripheral venous blood was estimated before and after jejunal interposition in 17 patients with severe vasomotor dumpling. In each case the kinin activity was assayed both under fasting conditions and after the oral administration of a liquid hypertonic glucose meal (100 g). No significant difference in the preoperative fasting kinin values was found between patients who were improved of their symptoms (11 cases) as distinct from those who did not derive any benefit from jejunal interposition (6 cases). However, in patients who obtained relief after revisional surgery, the kinin level after glucose administration (56-15 +/- 11-19 ng/ml) was significantly higher (P less than 0-01) than the release obtained in patients who were not improved by surgery (3-65 +/- 2-33 ng/ml). Furthermore, the kinin release was reduced to near normal levels on re-challenge with glucose 3 months after jejunal interposition in patients who were cured or improved of their symptoms.


Lobar dearterialization in liver trauma. Two cases of blunt liver trauma managed by hepatic artery ligation are reported. Lobar dearterialization is a simple and effective method of achieving haemostasis in exsanguinating wounds of the liver. The postoperative management and scope of this procedure are discussed.


The clinical presentation of pyogenic liver abscess. The high mortality rate from pyogenic liver abscess is contributed to by delay in diagnosis. The widespread availability of radio-isotope liver scanning facilitates diagnosis once a hepatic abscess is suspected. This retrospective study identifies diagnostic features present at the time of admission to hospital in 28 patients who were subsequently found to have a hepatic abscess.


Syndromes in amoebic liver abscess.

Syndromes in amoebic liver abscess. A series of 137 patients with amoebic liver abscess has been studied. Recognition of clearly defined but diverse clinical syndromes was found to be necessary not only in diagnosis but also in planned surgical management. The majority of patients had the classic syndrome of fever, right abdominal or chest pain, hepatomegaly, hepatic tenderness and radiological abnormalities. Other syndromes of presentation included the silent abscess, acute amoebic colitis, the acute abdomen, the intraabdominal lump, the external sinus, pyrexia of obscure origin, obstructive jaundice and renal, pleuro-pulmonary and cardiac symptoms. The syndromes due to an abscess in different parts of the right lobe and in the left lobe of the liver are to some extent distinct. In spite of the varied modes of presentation of amoebic liver abscess, the key to diagnosis is an understanding of the chronological sequence of the disease and its progression from one syndrome to another. Diagnostic methods of value and the mortality are discussed.


Blunt pancreatic and pancreaticoduodenal trauma. Three cases of pancreatic injury and 1 case of pancreaticoduodenal injury caused by blunt trauma are reported. The literature is reviewed with reference to these cases in respect of incidence, mortality, complications, diagnosis and treatment.


Septic complications of pancreatitis.

Septic complications of pancreatitis. Over an 11-year period 693 patients with acute pancreatitis and 317 with chronic pancreatitis were seen at the Harbor General Hospital. Review of these cases revealed 9 patients with primary pancreatic lesser sac abscess and 11 with secondary abscess. The appropriate management for pancreatic abscess, whether primary or secondary, is early recognition and drainage; multiple drainage procedures may be necessary. Broad spectrum antibodies appear to be helpful and should be used until cultures indicate more appropriate antibiotic therapy. Successful management involves prolonged hospitalization, but contrary to previous reports the success rate is surprisingly high. Eight out of 9 patients with primary abscess and 8 out of 11 patients with secondary abscess survived.


Fistula formation complicating pancreatic abscess. Internal fistula formation is a rare complication of pancreatic abscess or pseudocyst; a fairly extensive search of the literature has produced only 47 cases. Common factors in the aetiology, presentation and management are discussed, and a further case is reported which demonstrates many features of this unusual condition.


Carcinoids of the first part of the duodenum. Three cases of duodenal carcinoid tumour are described and the histology of this type of tumour is discussed. Two of the patients have been followed up for 8 years. No further complications related to the tumours have been observed.


The effect of methionine on colonic wound healing in malnourished rats. Recent studies have suggested that the healing of colonic anastomoses is impaired in malnourished subjects. It has been claimed that the healing of skin and abdominal wounds in experimental animals is improved by the administration of the essential amino acid methionine, and in the present study the effects of methionine on colonic wound healing were studied in malnourished rats. Test animals were fed a protein-free diet for 7 weeks before surgery. Methionine-treated animals received the amino acid by subcutaneous injection during the seventh week of protein deprivation and throughout the postoperative period. Anastomoses were made in the left colon, and colonic wound healing was assessed by measurements of the bursting wall tension and collagen content of anastomoses. The results were compared with those of control animals fed a normal rat diet. Protein deprivation for 7 weeks resulted in a 34% reduction in body weight, and a significant reduction in the tensile strength and collagen content of colonic anastomoses was observed. Methionine supplements had no apparent effect on these parameters of wound healing. The concept of single amino acid supplementation in cachetic patients undergoing surgery is an attractive one, but it has yet to be established that methionine supplements alone can alter the course of wound healing in such cases.


Open pedicle grafts of ileum for the repair of large duodenal defects: an experimental study. An experimental study of open pedicle grafts of ileum for the repair of large duodenal defects is presented. All the grafts survived and functioned well. No shrinkage  occurred. The results are extremely encouraging for the clinical application of this technique.


Tension pneumothorax from a perforated gastric ulcer. A case of tension pneumothorax from a perforated gastric ulcer is reported and the pathogenesis and management of this rare complication are discussed.


An unusual presentation of carcinoma of the rectum. The case is described of a middle-aged man whose rectal carcinoma presented with meningitis, due to a fistula into the spinal theca.


Cellular immunity to Hodgkin's splenic tissue measured by leucocyte migration inhibition. Patients with lymphoreticular malignancy were shown by a leucocyte migration inhibition technique to have cellular immunity to Hodgkin's splenic tissue. Migration was significantly inhibited in 31 out of 55 patients with Hodgkin's lymphoma and 19 out of 39 patients with other types of lymphoma. Inhibition was also shown in only three out of 29 patients with other malignancy, one out of 23 normal volunteers, and one out of 25 patients with non-malignant disease. The splenic factor that inhibits leucocyte migration, which has yet to be isolated and identified, may be a helpful diagnostic tool in patients with suspected lymphoma.