Clinical trials with bis-dioxopiperazine propane (ICRF 159; NSC 129, 943) in acute leukaemias.

Clinical experience is reported with bis-dioxopiperazine propane (ICRF 159) in 20 children with acute leukaemia in relapse. They were resistant to most of the generally used cytotoxic drugs. Despite the unfavourable selection of cases, two complete and seven incomplete remissions lasting from 1 to 6 months were obtained.


Transfer of drug resistance factor in Shigella sonnei isolated in Iran.

The pattern of drug resistance and incidence of R-factors were studied in Shigella sonnei strains isolated in Iran. Eighty-nine out of 172 strains (51.7%) were resistant to one or more drugs and multiple drug resistance was more common than single drug resistance. The most predominant pattern of resistance observed was (Tc, Cm, Sm, Su). By mixed cultivation, 85.7% of Shigella sonnei resistant strains isolated on the Central Plateau and 100% of the strains from the caspian littoral transferred at least a part of their resistance pattern to sensitive E. coli K12 F- (gamma). In this experiment, 67.1% of our resistant and 17% of our sensitive strains had colicinogenic properties. No such difference could be observed between R+ and sensitive strains isolated in the Caspian littoral.


[Radioimmunoassay of human prolactin].

The radioimmunological dosage of human prolactin using the hormone as tracer and reference and an anti-prolactin antiserum is described. The labeling of human prolactin is carried out in the presence of a small quantity of chloramine T (10 mug). The purification of the labeled hormone is carried out by gel filtration on Sephadex G-75 or by polyacrylamide gel electrophoresis. The optimal incubation conditions were found using a first incubation of 40-48 hours at room temperatures followed by an incubation of 4 to 6 hours with cellulose-bound second antibody. The interference of serum proteins is small. There is no cross reaction with follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), human chorionic gonadotrophin (HCG), human placental lactogen (HPL) and human growth hormone (HGH). However, cross reaction with ovine, bovine and rat prolactin is found. These cross reactions are complete with endogenous human prolactin and hormone of different origin. Serum prolactin was determined in normal subjects and subjects treated with TRH and bromoergocryptine.


[Prolactin and breast cancer].

In the animal, prolactin favours growth of breast tumours. Prolonged hyperprolactinemia occurring after the action of a carcinogenic agent increases the incidence of these tumours, but hyperprolactinemia, induced before the application of such an agent, reduces it. In women, there is also evidence in favour of the influence of prolactin on growth and on the incidence of breast carcinomas, but this evidence is still very indirect and sometimes contradictory. Serum levels of prolactin in women with carcinoma of the breast are identical to those observed in a female population of comparable age. In cases of generalised carcinoma, hysterectomy and ovariectomy induce remissions. These operations should be followed by a fall in prolactinemia. They also reduce the incidence of carcinoma of the breast in women. A full term pregnancy before the age of thirty years, apparently protects the mammary gland from the etiological agent. Now, in women, the secretion of prolactin is considerably increased during pregnancy.


[Application of affinity chromatography to the study of renin].

Hog renal renin was measured by a radioimmunoassay of angiotensin I generated during the incubation of the enzyme with an excess of angiotensinogen. The fixation of renin on a sepharose-hexamethylenediamine-pepstatin gel has been studied: the saturation of a 1 ml column of gel is obtained with 900 Goldblatt units of renin. A 70 ml column processing several grams of protein has been used to purify renin by affinity chromatography: a 100 fold purification of renin is achieved in one step. Renin, before and after affinity chromatography, has been analysed by electrofocusing with a pH gradient from 3 to 10; the isoelectric points obtained are respectively 4.8 and 5.0.


[Heterogeneity of immunoreactive calcitonin in the plasma of patients with bone marrow cancer].

Plasma from patients with medullary carcinoma containing very high levels of immunoreactive calcitonin were fractionated by filtration on Sephadex gel. In all cases the elution gave four immunoreactive fractions. Two of these fractions correspond to the volume of elution of the monomere and of the dimere of human calcitonin. The two other fractions emerge at an elution volume corresponding to much higher molecular weights. After stimulation of calcitonin secretion in vivo, by dynamic tests, the fractions corresponding to the monomere and dimere increase more strongly than the two other fractions. Preliminary studies of secretion, in vitro, of calcitonin by medullary carcinoma tissue, show the presence in the incubate of four immunoreactive forms having the same elution characteristics as those found in the plasma. The significance of these results is discussed.


[The circulating forms of human calcitonin].

It is demonstrated for the first time that there are at least two forms of immunoreactive CT in serum: the first has the same physico-chemical properties as synthetic CT whereas the second one has a higher molecular weight than synthetic CT, close to the molecular weight of serum albumin. Such heterogeneity was found in the sera of normal subjects and in the sera of patients suffering from several diseases. Results suggest that the percentages of these two forms vary from one serum to another.


[Heterogeneity of human plasma parathormone].

The heterogeneity in the plasma of peptide hormones has been known for some time. The demonstration of various fragments of circulating parathormone was undertaken using two antisera, which permitted the authors to study: -- the plasma half-life of parathormone; -- the variations in parathormone levels during dynamic tests; -- the limits between normal and pathological levels. It was thus demonstrated that the antisera recognised, in one case, the terminal carboxyl fragment, in the other case, the terminal amino fragment.


[Radiolabeling (125I) with high specific activity of the 1-34 N-terminal derivative of bovine parathormone without loss of biological activity].

Radiolabelling of 1-34 N terminal synthetic biological active fragment of bovine parathormone (1-34 bPTH) with high specific activity and without loss of biological activity was studied. Chloramine T and lactoperoxydase methods were used. To assess biological activity of 125I 1-34 bPTH labelled fragment, we use their ability to activate renal cortical adenylate cyclase. Our results show that enzymatic labelling method preserved the biological activity. With the chloramine T method it is possible to keep the biological activity by using DMSO.


[Heterogeneity of human growth hormone in cultures of pituitary adenomas].

Human growth hormone obtained from cell culture of pituitary adenomas cannot be distinguished from hormone extracted from normal pituitaries as far as the physical, chemical and immunologic characteristics are concerned. From a quantitative point of view the proportion of high molecular weight forms seems greater in the case of the extracted hormone and the intra-cellular hormone than in the case of the hormone secreted in the culture medium. From the biological point of view the hormone obtained from the culture medium seems more active "in vivo" than the extracted hormone. The preliminary results of a compartimental kinetic study suggest a system of two pools of growth hormone with different rates of use.


[Immuno-reactive insulin-like substances in the rat].

Chromatography on G50 or G100 sephadex column of rat plasma or serum divides up the insulin-like immunoreactive material into three peaks: monomere insulin, proinsulin and a fraction of molecular weight between 50 and 100,000. This fraction is virtually absent (less than 1%) from immunoreactive material extracted from the pancreas. Comparison of the results obtained by methods using double or simple antibodies (charcoal dextran) and study of fixation in vitro of labelled insulin, taken up by various plasma proteins, suggest that the high molecular weight material includes insulin more or less broken down and linked to proteins. Furthermore, when one uses a double antibody method, the alpha globulins and albumin in the rat present also an insulin-like reactivity. This disadvantage does not occur with the charcoal dextran method which is more specific.


[Chains A and B, circulating fractions of insulin].

Experimental hyperthyroidism in the dog, and clinical hyperthyroidism in man, were studied as activation models of insulin catabolism. Plasma insulin and its A and B chains, were estimated by radioimmunoassay in 8 dogs, before and after daily administration of 1 mg of thyroxine per animal. A and B chains rose quite definitely under treatment, whereas the increase in blood insulin was only slight. Blood sugar did not vary. Glucose tolerance tests during treatment, showed that A and B chains did not follow a curve parallel to insulin were situated during the test, at a higher level in dogs treated with thyroxine than in controls. The estimations carried out in man, confirmed the high levels of the A and B chains in hyperthyroidism. The use of certain anti-insulin antisera for radioimmunoassay of insulin demonstrated cross reactions with A or B chains. This phenomenon may be the cause of excessive evaluation of plasma insulin in subjects with levels of circulating chains A and B. Chains A and B in the blood seem to be a sign of the level of metabolic destruction of the insulin and not that of secretion.


[Preparation, characterization and control of antiserums].

The development of radio immunoassay and its application to the estimation of new substances (e.g. drugs, enzymes, viral antigens, etc.) will shed further light on the various problems which we have discussed in this introductory report. For each group of substances there will no doubt be special difficulties. If these technics have become very popular, this seems to be for two main reasons: the potential selection of individual immune response, and better understanding of the role of the parameters which control the various stages of radio-immunoassay. I am sure that the reports programmed here will provide an important contribution to advances in our knowledge in this promising field.


The production of antibodies for radioimmunoassay.

Three factors which affect the outcome of any immunisation schedule designed to produce antisera for radio-immunoassay, the antigen, the method of immunisation and the choice of animal are considered. Several factors concerning the nature of the antigen are dealt with, for example, the molecular size and immunogenicity of the antigen. It is noted that the larger polypeptide and proteins are sufficiently immunogenic to elicit a useful antibody response alone and that whilst substances with molecular weights of less than 2000 may produce a response alone they will probably produce a better one if they are conjugated (chemically coupled) to a much larger molecule. With the low molecular weight substances such as the thyroxine, steroid hormones, and drugs which are of much clinical interest to many people conjugation is essential. The availability and purity of the immunogen are considered, especially in cases where a minute amount of material has been produced following a long and tedious purification procedure. The necessity in such instances that workers are aware of the smallest amount of material that will produce a useful antibody response and also of the most effective method of immunisation is stressed. The method of immunisation is discussed including a consideration of the use of adjuvant and the route and timing of injections. It is noted that antisera showing the relevant properties for radio-immunoassay are rarely produced without emulsification of the immunogen in Freund's adjuvant although this is not an absolute requirement for antibody production. Data are presented comparing the intramuscular and multiple intradermal routes of injection. The results, however, fail to demonstrate any major advantage for either method although the latter may be more economical, producing high titre antisera with relatively small amounts of immunogen. Because of their convenience rabbits are generally the first choice of animal for raising antisera for radioimmunoassay although guinea pigs, chickens and sheep have been used successfully in many cases.


Antiserum characteristics and assay quality.

On the basis of the experience derived from the setting up and standardization of different radioimmunoassay systems, this paper attempts to point out the role played by the characteristics of the antiserum in the optimization of the assay. In particular the antiserum heterogeneity, the rates of formation and dissociation of immunecomplexes, and the nature of the antigen-antibody bonds are taken into consideration as regards some implications on the extent of blank, the effect of separation procedures and the adequacy of preincubation techniques.


[Effect of the conditions of coupling in testosterone-albumine conjugates on the quality of the antibodies produced in the rabbit].

In order to produce antibodies against small molecules as steroid hormones a necessary step in the preparation of the antigen includes a covalent linkage of the hapten to a "carrier" protein. Two coupling procedures (mixed anhydrid method and carbodiimide method) have been utilized in the preparation of testosterone conjugate linked in the C3 position. The same batches of testosterone (o-carboxy methyl) oxime and crystallized bovine serum albumine have been used. In the 2 different antigens the steroid/BSA molar ratio was identical (30). Antibodies have been raised in female New-Zealand rabbits. It is concluded that experimental conditions of covalent linkage influenced the antigenic potency of the conjugate used. Antibodies of considerably higher titer, capacity and affinity were obtained when the mixed anhydrid method was used. However the specificity of these antibodies did not appear to be influenced by the type of antigen used.


Results of a comparative study on insulin radioimmunoassay in 36 Italian laboratories.

An interlaboratory study in which the insulin contents of five plasma samples were estimated in 36 italian laboratories was coordinated by the Istituto Superiore di Sanità (National Institute of Health) and the Consiglio Nazionale delle Ricerche (National Research Council). A rather large between-laboratory variability resulted, though the ranking of samples according to their insulin concentrations was practically the same. A significant dependence of estimates on the method used was established. The analysis of data, aimed at defining the possible reasons of the assay variability, is reported and discussed.


Reliability criteria for steroid radioimmunoassay.

The principle of radioimmunoassay has been applied to every hormonal steroid and many steroids without known biological activity. The validation of steroid radioimmunoassay requires the evaluation of reliability criteria. These criteria involve the degree of relative specificity of the assay, the sensitivity which dictates the volume of biological fluid required for accurate and precise measurement, and the precision and accuracy of the assay which should be evaluated in every batch of assays as quality control. The use of steroid radioimmunoassay in physiological and clinical studies requires prior validation of these assays by proper evaluation of the reliability criteria.


The use of diatomite microcolumns for the chromatographic separation of steroids prior to radioimmunoassay.

Since most anti-steroid antibodies are not usually specific enough to permit direct radioimmunoassay of these compounds, chromatographic purification is required to achieve reliability. We have used Celite microcolumns for the separation of a wide range of steroids prior to radioimmunoassay. Depending on the polarity of the steroids to be separated, various mixtures of solvents are used as stationary and mobile phases. This system is rapid, easy, economical, and reliable.


[Radioimmunoassay of synthetic steroids].

The sensitivity of a radioimmunoassay depends on the intrinsic association constant of the interaction between ligand and antibody. Its specificity depends on the position of the chain which forms the link with the antigen. Thus, an antibody specific of estradiol has been obtained by coupling estradiol to albumin via a chain at position 7. For synthetic steroids the structure of which is sufficiency different from that of natural hormones, the requirements for a sensitive assay method not involving chromatography are simply maximum affinity and positioning of the couple at a site which does not undergo metabolic attack. These criteria were used to develop assays for R 2858 and R 2453 which obviate the need to administer radioactive product in clinical pharmacology. Cross-reaction with structural analogs may be used to assay competitors. Thus, R 2323 antibody, highly specific for endogenous steroids, may be used to assay other trienes such as R 1697 (trenbolone) and R 2010 (norgestrienone).


Use of (3H) and (125I) tracers in steroid radioimmunoassays.

The comparative use of 3H and 125I tracers in steroid radioimmunoassays will be discussed around the following points: 1. 3H. a) they can be purchased commercially and have a long shelf-life. b) Disadvantages: they may have reduced affinity for antibodies due to "isotope effects"; the counting of beta-emitters is more expensive and difficult; 3H tracers are not available for all steroids. 2. 125I. a) gamma-counting is cheaper, simpler and more precise; 125I tracers may have higher affinity for antibodies than unlabelled steroids; 125I can be used to label any steroid. b) Disadvantages: 125I tracers have a limited shelf-life (n.b. six months for 125I histamine tracers). The high affinity of some tracers will be a big disadvantage if the unlabelled steroid cannot compete effectively.


[Radioimmunoassay of 18-hydroxy-11-desoxycorticosterone (18-OH-DOC). Preliminary studies].

An antiserum anti 18-OH-DOC-21-hemisuccinate-BSA was induced in the Rabbit. Its radioimmunological properties were studied. In this preliminary study, the classical reaction antigen-antibody was examined, principaly in the procedure for the separation of free antigen from antigen bound to antibody.


[A competitive radioisotope binding technic for the determination of prednisolone and of a new synthetic corticoid].

A competitive protein binding technique for the determination of plasma prednisolone in dexamethasone-treated men was found suitable for the estimation of plasma levels of a new non-steroidal compound having a chemical structure related to that of prednisolone. The method used allowed us to determine the time of appearance of this compound in the peripheral plasma after oral administration, the time of the peak and the apparent disappearance half-life which were comparable to that of prednisolone.


[Effect of the steroid sex hormones on the LH and FSH responses to LHRH in the normal subject].

In man both basal gonadotrophin levels and the pituitary responses to LHRH remained relatively constant throughout life. In women the pituitary sensitivity varied in the menstrual cycle due to the typical cyclic variation of oestradiol and progesterone. The max delta LH increase to 100 mug LHRH was observed in the periovulatory period (183 +/- 41 mU/ml); it was also significantly higher in the luteal (49 +/- 7 mu/ml) than in the early follicular phase (18 +/- 3 mU/ml). The effect of exogenous sex steroid hormones taken as contraceptive drugs was then studied in 15 women. Significantly lower LH and FSH basal values as well as responses to LHRH were observed in 8 normal women under oral combined contraceptives. Conversely, in 7 women under oral sequential contraceptives, basal LH and FSH remained in the normal range. The LH-FSH responses were increased and delayed when these tests were performed during the period of estrogen treatment. Thus, with combined oral contraceptives, constant and high levels of estrogens and progesterone not only inhibit the LH peak, but also decrease the basal LH-FSH levels and responses to releasing hormone. Conversely, with sequential oral contraceptives, the low level of estradiol does not inhibit these responses and even enhances them. In menopausal women both basal and gonadotrophin responses to LHRH were increased indicating an important pituitary reserve. In menstruating women a significant estradiol increase is observed 2 and 4 hours after a 100 mug LHRH injection, both during the follicular and the luteal phases whereas progesterone increases only in the luteal phase. In men, testosterone was found to increase 4 hours after a 100 mug LHRH injection. These studies show that in normal subjects, sex steroid hormones are important regulators of the sensitivity of the pituitary responsiveness to releasing hormone.


[Serum IgE Statistical study of 2000 measurements].

In a statistical analysis of more than 2000 IgE estimations, the authors corroborate the importance of this determination for diagnosis of asthma, eczema and rhinitis. Serum IgE levels are also elevated in parasitic diseases, and may be elevated in some other cases in which there are several disorders, such as cirrhosis and leukemia.


[The rat ventricular myocardium in chronic hypercapnia. Electron microscopic study].

An electron microscope study of the left ventricular myocardium from rat acclimatized to chronic hypercapnia was done in order to complete the preceding work concerning general effects of respiratory acidosis. After 15 and 30 days of the acclimatation to 8% CO2 no lesions of the myocardium could be found. The results of the morphometric analysis indicated, however, discrete modifications of heart ultrastructure similar to those found before in hypoxic and failing hearts: namely a decrease of mitochondrial mean diameter and a non significant decrease of mitochondrial fractional volume. The latter was accompanied by a significant decrease of myofibrillar mass. The presence of cellular oedema seems to be suggested by an increase of fractional volume of the cytosol. The mechanism of these changes is not easy to explain. Further work will be necessary to make a choice between two possibilities: (1) depressed contractility related to some direct effect of high pCO2 and (2) tissue hypoxia secondary to local effects of the former.


[An attempt at correlation between the numbers of intra-hepatic immunocytes and levels of serum immunoglobulins during the course of various liver diseases].

Liver samples from 71 patients with various liver diseases were obtained by needle-biopsy and examined by the direct fluorescent antibody technique. Immunocytes reacting with specific conjugated anti-IgG, A, M sera were counted. An attempt to correlate i-munocytochemical observations with Ig-levels was performed but remained statistically non valid. Nevertheless, graphic comparison of data in the three homogeneous investigated groups (steatosis, cirrhosis, hepatitis) might support the view that intra-hepatic immunocytes contribute partially to enhance the serum immunoglobulin levels in liver diseases.


[Contribution to the study of aortic hetero-transplants by means of electron microscopy].

In this study the ultrastructure of aortic valves of the pig, fixed immediately upon removal from the animal is compared with that of grafts treated to suppress immune responses as well as grafts treated to suppress immune responses as well as grafts which had to be replaced upon deterioration after implantation in humans. Fresh pig valves are lined by an endothelium forming a continuous barrier between the valvular tissue and the surrounding medium and which acts as a selective filter. Aortic valves consist essentially of bundles of collagen fibres interspersed with elastic fibres. They are synthesized by sever fibroblasts located in this connective tissue network. The agents used in treatment destroy the endothelial cells and fibroblasts. Furthermore, the connective network does not remain fully intact; modifications occur in both the collagen fibres and the "ground substance". Modifications observed in deteriorated implants, though of similar appearance, are more profound; collagen fibers are thus more or less calcified. Cells which sometimes invade the implanted tissues belong to the macrophagic series and they produce enzymes which contribute to the degradation of heterografts easily accessible to enzymatic attack. It therefore, seems that treatment of the aortic valves cannot prevent antigenic reactions in the host and, furthermore, cannot confer sufficient resistance on implants to protect them from degradation which are sometimes incompatible with their proper functioning.


[Effect of prostaglandin PGE1 on blood and tissue lipids in rabbit experimental arteriosclerosis].

Although the effects of prostaglandins (namely PGE) on lipolysis are well known, there are few data about their action on the various serum lipids (cholesterol, phospholipids, triglycerides). We have no information about the action of these products on experimental atherosclerosis and the arterial lipids. In the present work, we found in rabbits fed an hyperlipidemic diet, or receiving adrenalin injections, or a sequential atherogenic treatment for a long course, that the treatment by PGE1 induces a decrease of the serum lipids, mainly in animals fed an hyperlipidemic diet. In the same experiment, we found also a decrease of the cholesterol level in aorta and in the connective tissue of sub-cutaneous granulomas. The interest of these findings is discussed in the light of present known data about the effect of prostaglandins on lipid metabolism.


[Culture of human bone marrow. Counts of colony forming granulocytes and macrophages in 100 patients without hematologic diseases].

Bone marrow suspensions from non hematologic patients have been cultured in methyl cellulose, with conditioned medium prepared with normal peripheral blood cells. The granulocytic-monocytic colony forming cell (G-CFC) can give rise to colonies, which were counted on the 14th day. The mean G-CFC number is 38 +/- 26 when 2.10(5) cells are cultured. The striking disparity from one patient to an other cannot be explained by the culture conditions, nor by the clinical status. There is no sex difference; older patients have a significant reduction of the colony numbers compared to younger patients.


[Effect of minocycline on Candida albicans. "In vitro" study: comparison with tetracycline].

The action of minocycline has been studied in comparison with tetracycline on 52 strains of "C. albicans" by M.I.C. on Agar medium and by the dellophane transfer. A fungistatic activity was observed above 4 mug/ml, and a fungicidal activity above 1000 mug/ml, whereas tetracycline "in vitro" proved to be ineffective.


[Real time processing of data from a clinical biochemistry laboratory by means of a computer system].

Our experience on the use, for several years, of an off line data processing system, has permitted the development of a more advanced system. The basis of the new system is implantation in the laboratory of a minicomputer, linked secondarily to a large computer. The introduction of viewing apparatus favours the development of conversational procedures essential for this application. The organisation of work stands, which varies with the type of blood investigation carried out, whether automatic, semi-automatic or manual, and depends on the use of specialised terminal, e.g. key-board, screen or printing machine, was particularly studied. Simpler procedures were also fully studied, for a routine laboratory must continue to function if the computer breaks down.


[Molecular evolution].

The molecular evolution is considered in several protein families. It can be studied with the data of an entirely known structure, like in hemoglobin or cytochrome, or of only partial structural data, as for proteases or immunoglobulins. In the case of isozymes the study of physico-chemical and kinetic properties is more indirect. Finally, it is shown that the molecular mechanisms are always the same, happening probably at the same frequency, the differences being due to a variable selection by molecular constraints and adaptation to the environment.


[Continuous study of rapidly fluctuating parameters in the study of glucoregulation].

Continuous monitoring of a parameter is the more necessary the more fluctuant the studied parameter. Dosage upon discontinuously gained blood samples leads to a higher rate of interpretative errors. Our method of continuous investigation achieves a precise objectivation of the glycemia/insulinemia relationship; the automation assures a perfect comparability of the results.


The suppression of factor VIII antibodies in haemophilia.

Three severely affected haemophiliacs who had developed antibodies to factor VIII are described in whom the administration of cyclophosphamide was thought to have prevented reappearance of the antibody after factor VIII infusion. Some of the possible causes which might have led to the favourable outcome in these and three other, previously reported, patients in whom the antibody, which was raised at the time of IS therapy, dropped to zero and failed to reappear, are discussed. It is suggested that immunosuppressive therapy was effective in these patients as it was given during or soon after the primary immune response. As the antibody response becomes increasingly well established, so the chances of successful immunosuppressive therapy recede.


[Medical treatment of hemophilic hemarthrosis and surgical prospects].

The treatment of acute hemarthrosis as utilized by eighteen hemophilic centers in different towns from France was presented. The amount of F.VIII infused, the use of cortisone and analgesic drugs, immobilisation and rehabilitation were discussed by each center. Discrepancies from one center to another appeared except for one point: the amount of F.VIII to be infused and the interest of early infusion. The interest of orthopedic surgery in the evolution of hemophilic arthropathies was developed.


[Treatment of hemophilic arthropathies by medical synoviorthesis].

The effects of medical synoviorthesis were studied by the authors in the haemophiliac. The use of radioisotopes was limited in view of the young age of the patients but a good result was achieved for the 5 elbows treated and for the 4 knees (yttrium 90) the results were 2 good, 1 fair and 1 failure. Osmic acid was injected in 44 knees. The results were good and fair in 51% of 39 knees. The results can be improved by a second injection. Synoviorthesis should be kept for joints with very few destructions because of the danger of worsening the osteocartilaginous lesions, specially with osmic acid.


Interaction of platelets with purified macromolecules of the arterial wall.

A method is described for the study of the interaction between human blood platelets and intercellular matrix macromolecules of connective tissues such as those found in the sub-endothelium. The method is based on the qualitative and quantitative evaluation of the elution pattern of a platelet suspension from a mixed Sepharose 2B-fibrous protein column containing standardized amounts of fibrous proteins such as elastin or structural glycoprotein-microfibrils (SGP-MF). No interaction could be demonstrated with this method between platelets and SGP-MF but there was a very distinct interaction between platelets and elastin fibers. This could be confirmed by direct microscopical demonstration of platelet clusters around elastin fibers in cryostat sections of the affinity column.


Physical and chemical properties of normal and haemophilic factor VIII.

This review summarizes the physical and chemical properties of normal factor VIII (antihaemophilic factor). Special attention is given to the different subunits of this molecule, obtained after dissociation by beta-mercaptoethanol, high or low ionic strength. Present points of controversy are outlined. A description is given of the role of factor VIII in coagulation, as it is presently understood. The studies of the physical and chemical properties of haemophilic factor VIII also are reviewed; the molecular defect of haemophilic factor VIII remains to be identified.


Role of adrenergic stimulation in the fibrinolytic activation induced by histamine shock.

Comparison, in the dog, of the fibrinolytic response to adrenaline and histamine in presence of adrenergic blocking agents, suggests that adrenergic stimulation plays only a minor role in the mobilization of plasminogen activators during histamine shock.


High prekallikrein levels during pregnancy.

Prekallikrein levels are significantly increased during pregnancy. The increase is neither due to an excess of Hageman factor or of an activator, nor to the decrease of an inhibitor.


[Search for blast cells in the blood following transplantation (author's transl)].

The appearance of transformed lymphocytes in the circulating blood of transplanted patients may easily be followed by examination of blood smears. There is a significant relationship between the number of peripheral lymphoblasts and the course of the graft. The reliability and specificity of the test are discussed.


[Biliary elimination of metampicillin. Experimental and clinical study (author's transl)].

Under the conditions of the isolated rabbit liver perfusion, metampicillin was found to be excreted at a high rate in the biliary tract : bile contains 46,5% of the administered dose. Hepatic uptake of metampicillin seems to be early and marked. In man, the biliary elimination of this antibiotic varies according to the route of administration. Only moderate biliary levels of metampicillin were obtained after oral administration ; on the contrary, extremly high biliary concentrations were found when antibiotic was injected intravenously. When parenteraly administered, metampicillin appears to be a particularly suitable penicillin for the treatment of biliary tract infections.


[Swift preparation of hemoglobin free ghosts of human red cells (author's transl)].

Ghosts are adsorbed on extemporaneously formed tricalcium phosphate precipitate in lytic medium. They are free of hemoglobin and chemical characteristics are in good agreement with those obtained by Dodge (3) and Hanahan (5).


[Continuous photometric determination of total circulating blood saturation "in vitro" (author's transl)].

A methodology is described, entirely based on common commercial components with minor modifications, and allowing one to determine in vitro the saturation of whole blood in a photometric cell.


[Study of the radioimmunological and physicochemical properties of anti-aldosterone and anti-desoxycorticosterone antisera (author's transl)].

Study of the radioimmunological and physico-chemical properties of three anti-aldosterone antisera permitted practical conclusions to be drawn. By its high degree of specificity, anti-aldosterone-3-oxime-BSA is the most useful antiserum for the clinical assay of aldosterone. The principal advantage of this antiserum is that it allows both urinary and blood aldosterone radioimmunoassay without the necessity of including a chromatographic step. This work also includes the study of two anti-desoxy-cortico-sterone antisera.


[Iso-hormones : molecular forms of human chorionic somatomammotropin (HCS) (author's transl)].

The chorionic somatomammotropin hormone extracted from the human placenta exists in several molecular forms: Analytical electrophoresis on polyacrylamide gel permits separation of a highly anodic migration form : form 1 and another form migrating slightly faster than albumin : form 2. These two forms are active as measured by radioactive immunological analysis, form 2 being about 25 times more active than form 1. The two forms are mutually interconvertible. The two forms may also be separated by filtration on Sephadex G-50. However, they do not differ in molecular weight, they have the same coefficient of apparent diffusion, measured by analytic ultracentrifugation. Glutaraldehyde and 8 M urea do not modify their electrophoretic or chromatographic behaviour. On the other hand, the two forms differ in their tertiary structure, with the modification depending on the greater or lesser degree of oxidation of the intra-chain disulfide groups. The two forms also exist in placental culture media and the incorporation of tritiated leucine occurs preferably in form 1, The physiological significance of the two hormone pools is not clarified.


[Regulation mechanisms of the activity of T lymphocytes. Applications to infective and tumoral pathology. I. Delayed hypersensitivity and humoral response (author's transl)].

Delayed-type hypersensitivity (DTH) develops in the absence of an adjuvant when mice are injected with an apropriate dose of Sheep Red Blood Cells (SRBC). Increasing the dose of SRBC reduces and eventually abolished all evidence of DTH and no further sensitisation can be achieved even with the optimal subcutaneously injected dose, except in splenectomised mice in whom the development of DTH is not suppressed, even by massive doses of SRBC. This is also the case in mice treated with cyclophosphamide (CY) which suppresses selectively the antibody response. Hence the suppression of T cell activity measured as DTH cannot be due to antigen as such. The serum of blocked animals partially inhibits the induction and expression of DTH, and its blocking activity increase substantially after partial absorption. Absorbed serum did not inhibit in vivo the proliferative response nor the number of plaque forming cells to SRBC in peripheral lymph nodes, it increases the hemagglutinating titer of circulating specific antibody even though DTH is totally suppressed. It seems that the products of the interaction between antigens and antibodies block the activated T cells which mediate DTH without interfering with helper cells.


[Epoxy embedding of bone-marrow biopsies for light microscopy and histopathologic use (author's transl)].

A routine method of epoxy embedding of bone-marrow and other tissues for light microscopy is described. Undecalcified bone specimens obtained from the sternum or iliac crest using trephine biopsy are fixed in formalin, deshydrated in acetone, embedded in a Kushida's low-viscosity epoxy resin medium. The samples are cut using a carbide-edged knife in a rotary microtome or a glass knife in a Sorval JB4 microtome. After fixing sections to slide with Neoprene and removal of the embedding medium with sodium methoxide and acetone, the staining with usual histological procedures is quite easy. A simple and rapid technique is outlined for staining these sections with Giemsa. The resolution, compared with routine parafin sections, is improved.


[Presence of soluble red cell antigens in antilymphocyte serum or in serum of normal rabbits absorbed with sheep red cells (author's transl)].

The treatment of Wistar rats with normal rabbit sera or rabbit anti-Rat lymphocyte sera preabsorbed with sheep red blood cells induces variable degrees of immunisation against these erythrocytes. This phenomenon is due to transfer of soluble erythrocyte antigen released during the absorption procedure.


The effects of methylphenidate on the soft neurological signs of hyperactive children.

The neurological examination of many hyperactive children reveals the presence of abnormal neurological signs. Of 40 hyperactive children who had three or more neurological abnormalities on an initial neurological evaluation, 29 (72.5%) showed marked improvement or complete resolution of the neurological signs following treatment with methylphenidate hydrochloride (Ritalin) for 60 days. The administration of placebo did not change appreciably the neurological status of 20 hyperactive children. Improvement in behavior, which was ascertained by the use of Conners' Abbreviated Teacher Rating Scale, did not always correspond with resolution of the abnormal neurological signs. This finding suggests that methylphenidate affects behavioral and motoric functions separately and independently. Repeat neurological assessment, looking for resolution of abnormal neurological signs, should be included as part of the follow-up medical examination in treated hyperactive children. Coupled with other objective and subjective test information, improvement of the neurological status provides supportive evidence of overall improvement in the hyperactive child who is receiving drug therapy.


Echocardiography: its role in the severely ill infant.

Echocardiography is a noninvasive diagnostic tool which has the capacity to provide reliable information on cardiac anatomy and function  without risk or discomfort to the patient. The quality and quantity of information obtained in any given study is highly dependent upon the skill of the examiner. The anatomic and physiologic data obtained through its use in the severely ill infant allows immediate separation of infants with serious anatomic cardiovascular defects from those with conditions simulating heart disease. In some cardiac defects the echographic findings are specific enough to allow an accurate diagnosis.


Clinical features and pathophysiology of polycystic kidney disease in man.

Adult polycystic kidney disease is recognized as the traditional form of cystic kidney disease in man. It was the first described. It is the best studied. It is the most common among adults, affecting roughly one of every 500 persons. It accounts for renal failure in some 5% of patients coming to renal transplantation and ranks third as a cause of end-stage renal disease. Its cause(s) and prevention (other than genetic control through counseling) remain unknown, although some evidence of a preliminary nature is beginning to accumulate.


[The effects of somatostatin in acromegaly].

Somatostatine is the hypothalamic factor which inhibits the secretion of growth hormone. The administration of a synthetic form decreased growth hormone levels by 50 to 75% in 5 acromegalic patients. The action is rapid but the effect is not prolonged. Prolactin was reduced in only case with galactorrhea. Thyreostimulin, as well as gastrin, are unaffected. Plasma insulin levels, and to a lesser extent those of glucagon, are decreased by somatostatine which causes no variation in either cortisol or blood glucose. Somatostatine, by correcting the pathological secretion of hormone, opens the way to medical treatment of acromegaly.


[Objective results of lumbar sympathectomy. Statistical study, based on vascular function tests].

A series of 100 unselected patients who had undergone low lumbar sympathectomy were studied using vascular function tests (digital plethysmography, hyperaemia test, rheography, measurement of segmental pressures and dynamic tests, walking tolerance on a conveyor belt, Strandness test). Statistical study of the results obtained showed that, above all, isolated lesions of atherosclerotic origin gave excellent results. Increase in walking tolerance and circulatory flow (rheographic quotient) were the only statistically valid parameters. Prediction of the effects of lumbar sympathectomy by Hillestad's hyperaemia test was confirmed. There were many failures amongst the other cases (diffuse lesions, leg artery involvement, diabetic type lesions). Lumbar sympathectomy is hence justified only in the presence of femoral lesions and in association with reconstructive aorto-iliac surgery in all cases when the distal bed consists of the deep femoral only.


[Treatment of hyaline membrane disease with the plasminogen urokinase combination].

The authors present the results obtained using a therapeutic combinaison of plasminogen-urokinase in vivo in 14 premature infants suffering from respiratory distress. 86 % survived, a considerable improvement over classical survival rates. In addition it appeared that the duration of oxygen therapy was shorter, secondary to limitation of extension of the disease.


[Influence of the administration of levamisole on the reactivity of T-lymphocytes in advanced cancer patients].

The effects of levamisole were studied by evaluating T-cell responsiveness to a low dose of PHA on 31 advanced cancer volunteers. Treatment consisted in a 3-time a week oral administration of 150 mg of levamisole, actual time of observation is comprized between 10 and 31 months: 14 out of 31 treated metastatic cases of various solid tumours are still alive. In a group of 25 untreated patients, mean survival times were 65 days for men and 48 days for women. An increase of the responsiveness to a low dose of PHA was associated with survival, while death occurred when T-cells were unable to respond to the stimulatory activity of levamisole. These preliminary data confirm the paramount importance of cellular immunity in controlling neoplasias. They suggest a possibility to augment the life-span of cancer patients if an impaired cellular immunity machinery could be restored by the direct and indirect (hormonal) actions of levamisole, evidencing these mechanisms were still potentially functionning. They suggest also a monitoring of anti-tumoral immunity by evaluating the magnitude of T-cell response following levamisole administration.


Managing respiratory distress syndrome in adults.

Respiratory distress syndrome in adults may be produced by any of a number of causes resulting in similar pathophysiologic changes and having identical therapeutic implications. The most important factors in treatment are early recognition and early institution of therapy.


Intermittent positive-pressure breathing. A critical appraisal.

There are relatively few valid indications for the use of intermittent positive-pressure breathing (IPPB). It is of limited or no value as prophylaxis of postoperative pulmonary problems (pneumonia, atelectasis) or as a means of delivering aerosol medications or treating stable chronic obstructive pulmonary disease. In these situations, IPPB has few if any advantages over voluntary hyperventilation or deep breathing.


Secondary metabolic encephalopathy. Diagnosis and treatment.

Secondary metabolic encephalopathy is a diffuse disorder of the brain caused by an extracerebral process. Underlying causes include oxygen deprivation, systemic metabolic disease, and drug intoxication. Symptoms and signs usually suggest a generalized disturbance of brain function: alterations in the level of consciousness; diffuse and, occasionally, focal motor abnormalities; and seizures. Electroencephalography in most instances gives evidence of generalized neuronal disturbance. Early diagnosis is important because encephalopathy secondary to an extracerebral process is potentially reversible. Treatment is directed toward reversal or control of the underlying process, supportive care, and prevention of complications such as infection, electrolyte imbalance, and cerebral edema.


Preventing pulmonary embolism with heparin in low doses.

The introduction of low-dose heparin prophylaxis of thrombosis in deep leg veins represents a major advance in clinical medicine. It approaches an ideal form of prophylaxis in that it can be given easily to large numbers of patients at risk, requires no monitoring, is relatively safe, and, used widely, should save many lives. Conservative estimates are that 5,000 postoperative deaths and a comparable number of medical deaths can be avoided in the United States alone. Further inroads on this important problem will require additional developments, some of which are well under way.


[Pleural and pulmonary biopsies. Special morphologic technics].

Several special techniques can be fruitfully used but only in well defined cases by pathologists familiar with them and after a discussion with the clinician and the surgeon.


Deglycyrrhizinized liquorice in the treatment of chronic duodenal ulcer. A retrospective endoscopic survey of 32 patients.

Endoscopic examination in 32 cases of chronic duodenal ulceration treated with deglycyrrhizinized liquorice tablets showed that healing of the ulceration had occurred and in the majority the mucosa appeared normal. For optimum effect it appears to be important that the preparation in adequate dosage should be well chewed and swallowed on an empty stomach in the ambulant patient.


Xanthinol nicotinate in peripheral vascular disease.

In a double-blind control of xanthinol nicotinate ('Complamin'; 'Complamex') in patients with severe progressive obliterative vascular disease, 25 of 33 patients who completed the trial were helped significantly by the drug, as shown by both clinical and laboratory findings. Placebo helped in 4 of 33 patients. The difference is significant (p less than 0-001). These are the results for the trial period only. The results of follow-up for 6 to 30 months are available in 18 patients: 14 of these still had appreciable help from the drug, which was continued in maintenance doses. It should be noted that 3 of 6 diabetics were no longer helped after 6 months, and that only 3 of a total of 7 patients under the age of 50 were helped; however 3 of the 4 not helped were diabetics under the age of 50. Special caution was indicated in the use of the drug in patients who have ischaemic heart disease in addition to their peripheral arterial disease. Side-effects were common, particularly a severe prolonged flush shortly after taking a dose of the drug; many patients helped by it accepted this side-effect if it occurred. Xanthinol nicotinate reduced whole-blood viscosity and cholesterol and fibrinogen in about half of the patients helped. This is a useful drug for about half the patients in whom surgery is not indicated or is contraindicated.


Common problems in blood transfusion.

Prpgress and expansion in transfusion of blood and its products continue. Some common problems are discussed. Certain topical subjects are presented in detail and a new process is outlined for augmenting cryoprecipitate factor VIII activity which could ease the current short supply.


A new beta-adrenergic blocking drug in hypertension. A report from the General Practitioner Research Group.

It was concluded that acebutolol alone, in the doses given over the periods for which it was used, produced a modest hypotensive effect, which was not quite so great as that produced by bendrofluazide alone, although the differences are not statistically significant. On the other hand, the combination of the two drugs produced both a more rapid and more effective hypotensive action, which was more than might be expected by simple summation of the effects of the two drugs together. It would be seen that, in view of the virtual absence of side-effects, the combination of acebutolol with bendrofluazide may be particularly effective in the treatment of hypertension.


The objective measurement of mental performance in cerebrovascular disease. A double-blind controlled study, using a graded-release preparation of isoxsuprine.

An automatically controlled learned task was used to assess objectively the mental performance of a number of geriatric patients with cerebrovascular disease. The effect on the performance of the patients during treatment with isoxsuprine hydrochloride in a sustained-release presentation ("Duvadilan Retard") was measured during a double-blind, placebo-controlled trial of sixteen weeks' duration. There was a significant difference in the improvement in performance between the treated and untreated groups; by the end of the trial, the treated group having statistically significantly better scores (P = 0.047 two-tailed tests).


Trial of an oral antigen against upper respiratory-tract infection. Results in the second year (1973-74).

A double-blind trial in two randomly structured groups of boarders (44 girls and 66 boys) aged 7 to 13 years was undertaken in two Bristrol schools. Dosage was 1 ml a day of fluid (antigen or placebo) orally for the first four weeks of the autumn term, absenteeism being the main parameter measured, using a structured recording code. There was a highly significant difference in the number of days lost from upper respiratory-tract infection in the treated as opposed to the placebo group (x2 = 40-00 P less than 0-001 (v = 1). The number of colds was also significantly lower in the treated group (x2 = 8-05 P less than 0-005 (V less than i)).


[The development of pediatric gynaecology in Poland (author's transl)].

In view of the world-wide tendency to isolate adolescent medicine covering the period of puberty new problems arise for the gynaecologists. Pediatric gynaecology in Poland owes its growth to prof. Rudolf Peter from Prague (Tschechoslovakia), because it was under the guidance of prof. Peter and his followers at the clinic of Prague University that our gynaecologists extended their knowledge of the biological differences of the childhood. Since 1955 a regular gynaecological care for children and adolescence has been developed in Poland on the basis of general health care and MCH service. In Poland there are mainly out-patient departments of pediatric gynaecology, run by the gynaecological Clinics of Medical Academies and Hospitals. At the moment there are 52 pediatric gynaecological units in Poland. In the Medical Academies, Departments of Obstetrics and Gynaecology, research work on the physiology and pathology of puberty in girls is beeing carried out. The Pediatric Gynaecological Section of the National Gynaecological Society has organized two national symposia in 1969 and in 1972, devoted to gynaecological problems and functional disorders occuring during childhood and puberty. The last Symposium was attended by Professor Robert Contamin, the President of International Society of Pediatric and Adolescent Gynaecology. In June 1972 Polish gynaecologists attended the First International Symposium on Pediatric and Adolescent Gynaecology held in France (Bordeaux). The Polish translation of R. Peter and K. Vesely "Kindergyäkologie" was published in 1970. The Gynaecoligical Department of the Medical Academy in Lódź provides a training centre for gynaecologists in child and adolescent gynaecology.


Molecular structure of yeast RNA polymerase III: demonstration of the tripartite transcriptive system in lower eukaryotes.

Homogeneous RNA polymerase III (RNA nucleotidyltransferase III) has been obtained from yeast. The subunit composition of the enzyme was examined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The enzyme is composed of 12 putative subunits with molecular weights 160,000, 128,000, 82,000, 41,000, 40,500, 37,000, 34,000, 28,000, 24,000, 20,000, 14,500, and 11,000. The high-molecular-weight subunits and several of the smaller subunits of yeast RNA polymerase III are clearly different from those of enzymes I and II, indicating a distinct molecular structure. However, the molecular weights of some of the small subunits (41,000, 28,000, 24,000, and 14,500) appear to be identical to those of polymerases I and II. Thus, it is possible that the three classes of enzymes in yeast have some common subunits. As in other eukaryotes, yeast polymerase II is inhibited by relatively low concentrations of alpha-amanitin; however, contrary to what has been found in higher eukaryotes, yeast polymerase III is resistant (up to 2 mg/ml) to alpha-amanitin, while yeast polymerase I is sensitive to high concentrations of the drug (50% inhibition at 0.3 mg/ml). These results establish the existence of RNA polymerase III in yeast and provide a structural basis for the discrimination of the three functional polymerases in eukaryotes.


[Double blind crossover study of pseudoephedrine and triprolidine alone and in combination in the treatment of allergic rhinitis (author's transl)].

In a double-blind crossover trial of pseudoephedrine 60 mg. and triprolidine 2.5 mg. alone and in combination, on 40 volunteers suffering from allergic rhinitis, both drugs were found superior to placebo in reducing the effects of allergic rhinitis and were of equal efficacy. The combination tablet was consistently better than either drug in several of the assessments and was the treatment which the subjects, as a whole, preferred. Side effects were not a problem with any of the medications.


Transcription in yeast: alpha-amanitin sensitivity and other properties which distinguish between RNA polymerases I and III.

Three peaks of DNA-dependent RNA polymerase (RNA nucleotidyltransferase) activity are resolved by chromatography of a sonicated yeast cell extract on DEAE-Sephadex. The enzymes, which are named RNA polymerases I, II, and III in order of elution, show similar catalytic properties to the vertebrate class I, class II, and class III RNA polymerases, respectively. Yeast RNA polymerase III is readily distinguished from yeast polymerase I by its biphasic amnonium sulfate activation profile with native DNA templates, greater enzymatic activity with poly[d(I-C)] than with native salmon sperm DNA, and distinctive chromatographic elution positions from DEAE-cellulose (0.12 M ammonium sulfate) compared with DEAE-Sephadex (0.32 M ammonium sulfate). The three yeast RNA polymerases also show significant differences in alpha-amanitin inhibition. RNA polymerase II is the most sensitive (50% inhibition at 1.0 mug of alpha-amanitin per ml). Contrary to the results for vertebrate systems, yeast polymerase I can be completely inhibited by alpha-amanitin at high concentrations (50% inhibition at 600 mug/ml) while yeast RNA polymerase II BEGINS TO SHOW SIGNIFICANT INHIBITION ONLY AT CONCENTRATIONS EXCEEDING 1 MG/ML. Therefore, yeast RNA polymerases I and III show a pattern of alpha-amanitin sensitivity that is the reverse of that seen for the analogous vertebrate RNA polymerases.


Involvement of escherichia coli dnaZ gene product in DNA elongation in vitro.

E. coli dnaZ gene product is required for conversion of phiX174, fd, and ST-1 single-stranded phage DNAs to duplex DNAs in vitro. This protein has been purified about 5000-fold. It functions in the elongation of RNA- or DNA-primed single-stranded DNA that is catalyzed by DNA polymerase III(DNA nucleotidyltransferase; deoxynucleosidetriphosphate: DNA deoxynucleotidyltransferase; EC 2.7.7.7) in conjunctions with two other E. coli protein preparations referred to as DNA elongation factors I and III. It also functions in similar reactions catalyzed by DNA polymerase II in combination with E. coli DNA binding protein and DNA elongation factors I and III.


Variant forms of mitochondrial translation products in yeast: evidence for location of determinants on mitochondrial DNA.

Products of mitochondrial protein synthesis in yeast have been labeled in vivo with 35SO42-. More than 20 polypeptide species fulfilling the criteria of mitochondrial translation products have been detected by analysis on sodium dodecyl sulfate-exponential polyacrylamide slab gels. A comparison of mitochondrial translation products in two wild-type strains has revealed variant forms of some polypeptide species which show genetic behavior consistent with the location of their structural genes on mtDNA. Our results demonstrate the feasibility of performing genetic analysis on putative gene products of mtDNA in wild-type yeast by direct examination of the segregation and recombination behavior of specific polypeptide species.


Double-stranded RNA in chromatin transcripts formed by exogenous RNA polymerase.

RNA transcribed in vitro at low ionic strength, from either rat liver chromatin or DNA, contains a significant amount of structure resistant to RNase in high salt buffer. This is observed with rat liver (form B polymerase) as well as with Escherichia coli RNA polymerase (RNA nucleotidyltransferase; nucleoside triphosphate: RNA nucleotidyltransferase; EC 2.7.7.6). Treatment with RNases specific for either double-stranded or hybrid RNA indicates that resistance to RNase is due to the presence of double-stranded RNA sequences. Denaturation kinetics in the presence or absence of RNase suggest that these sequences are formed by intramolecular base pairing. Their mean length is about 20 to 30 nucleotides, but 15-20% are more than 100 nucleotides long. They contain 60-65% G-C base pairs. The proportion of double-stranded segments is higher in chromatin transcripts than in DNA-templated RNA, and is higher with homologous RNA polymerase than with the bacterial enzyme. On the other hand, chromatin endogenous RNA polymerase, which is unable to initiate transcription, does not synthesize double-stranded RNA. The problem of the location of these sequences is discussed; preliminary results suggest that the 5' end of the RNA transcripts could be enriched in complementary sequences.


Asymmetric orientation of phage M13 coat protein in Escherichia coli cytoplasmic membranes and in synthetic lipid vesicles.

At each stage of infection, the major coat protein of coliphage M13 binds to the E. coli cytoplasmic membrane with its antigenic site exposed to the cell exterior [Wickner, W. (1975) Proc. Nat. Acad. Sci. USA 72, 4749-4753]. This antigenic site is now shown to be at the amino-terminus of the protein. The amino-terminus of M13 coat protein is also found exclusively on the outside of dilauroyl or dimyristoyl lecithin vesicles, formed with coat protein by the cholate dilution technique [Racker, E., et al. (1975) FEBS Lett. 57, 14-18] near the lipid phase transition temperature. The basic carboxyterminus of the coat protein is exclusively on the inside of these vesicles. Vesicles of M13 coat protein and dimyristoyl lecithin when formed below the lipid phase transition temperature have both ends of the coat protein exposed to the vesicle exterior. The asymmetry of a membrane protein can, therefore, be established in the absence of other proteins and of lipid asymmetry; it depends on the physical state of the lipid phase. The factors which cause asymmetry in this model system may affect the distribution of proteins in biological membranes.


Effect of rifampin, clofazimine, and B1912 on the viability of Mycobacterium leprae in established mouse footpad infection.

Continuous dietary administration of rifampin to mice with an established Mycobacterium leprae footpad infection reduced the bacillary solid ratio, with an estimated survival half-life of 5-6 days. In rifampin-treated immunosuppressed animals the survival half-life of solid bacilli, in the absence of host immunity, was 12-13 days. Clofazimine and B1912 produced a significant effect on solid ratio only after a lag period of apparently 100 days. The rate of action was considerably slower than that of rifampin. Intermittent (once monthly) administration of both drugs produced effects similar to those of continuous administration.


Inhibition of macrophage migration by normal guinea pig intestinal secretions.

The incubation fluid from 24-hr cultures of normal guinea pig small intestines was found to contain activity capable of inhibiting the migration of normal guinea pig peritoneal macrophages. Each of three different culture fluids showed macrophage inhibitory activity in the 25,000-55,000 mol wt range when subjected to Sephadex G-100 gel filtration. One of these three preparations also contained inhibitory activity in the excluded volume. The low molecular weight activity was nondialyzable and heat stable to 56 degrees for 30 min. It was destroyed by boiling for 1 hr, and its activity was reversed by 10(-4)M epinephrine. Based upon these properties it is suggested that this activity was due to migration inhibitory factor (MIF). The high molecular weight inhibitor was stable to heating and its activity was not reversed by epinephrine. This material was most likely endotoxin. The presence of MIF, which may be associated with T-cell activity in the intestine, suggests that cell-mediated immunity (CMI) could play a role in local protection against gut infections. Furthermore, its presence in normal intestinal secretions suggests that some MIF-producing cells are always being stimulated by normal flora. The question is thus raised whether further specific stimulation of local CMI in the gut could be successful.


Adrenergic activity and gastric secretion.

Isoproterenol infusions depress pentagastrin (PG)-stimulated secretion of acid and pepsin from both gastric fistulae and denervated (Heidenhain) pouches in conscious dogs. It was not found to do so if methacholine replaced gastrin. Propranolol reversed the isoproterenol depression of PG stimulation but had no effect on isoproterenol plus methacholine except on the fistula where both acid and pepsin were depressed. It is felt that PG and methacholine act by differing mechanisms both on chief and parietal cells.


Effect of melatonin on the luteinizing hormone release induced by clomiphene and luteinizing hormone-releasing hormone.

The effect of melatonin on the LH-release response after the administration of synthetic LH-RH and clomiphene citrate was investigated in adult male rats. The sc administration of melatonin (1 mg/day) for 6 days produced a significant decrease in serum LH levels and in seminal vesicles and ventral prostate weights. On the other hand, the daily injection of 0.01 mg/100 g of body weight of clomiphene citrate during 6 days significantly stimulated LH levels and the weights of the accessory sex glands. Simultaneous treatment with melatonin and clomiphene produced an inhibitory effect similar to that obtained with melatonin alone. Neither pretreatment with melatonin alone. Neither pretreatment with melatonin (1 mg/day, sc for 6 days) nor its simultaneous iv administration (500 mug) with 75 ng of LH-RH modified the LH-release in response to the hypothalamic hormone. The fact that melatonin was able to suppress the effect of clomiphene, which is probably exerted at the hypothalamic level, but not the actiion of LH-RH on the pituitary, appears to indicate that the hypothalamus may be the site involved in the inhibitory effect of the pineal principle on the reproductive function.


Fast-neutron irradiation of mouse embryos in the pronuclear zygote stage: mortality curves and neoplastic diseases in 30-day postnatal survivors.

Mouse embryos in the pronuclear zygote stage were either irradiated in utero with a dose of 15 rad of fast neutrons or were sham-irradiated. Those animals that survived at least 30 days after birth were observed until their natural death. We investigated the percentage incidence and mean age at death for each of the principal neoplastic diseases seen on postmortem examination and also cumulative mortality distributions. No statistically significant differences were found between irradiated and sham-irradiated mice of the same sex.


Regression of corpora lutea in the rabbit after injection of a gonadotropin-releasing peptide.

We have shown that a potent agonist of the luteinizing hormone injected on either Day 11 of pseudopregnancy of Day 15 of pregnancy causes luteinization of ovarian follicles and a rapid regression of functional corpora lutea. Serum levels of progesterone declined markedly within 3 days of peptide injection in pregnant animals. In the presence of regressing corpora lutea, fetal resorption occurs which can be prevented by estradiol (500 ng, twice a day) or progesterone. Daily levels of estradiol below 4 mug did not maintain either corpora lutea weight or fetal survival, whereas 4 mug of the steroid maintained corpora lutea weight, but not pregnancy.


Impaired thymic regeneration in lethally irradiated mice given bone marrow from aged donors.

Mice were given a lethal dose of whole-body gamma radiation and injected with 10(5) or 10(6) marrow cells from 10- to 143-week-old syngeneic donors. Nine days later, colony-forming units (CFU) were counted in the spleens of mice given 10(5) cells, and 21 days after irradiation, spleen and thymus weights were determined in the recipients of 10(6) cells. It was found that there were no significant changes with age in marrow CFU or in the ability of marrow cells to repopulate host spleens. In contrast, thymic regeneration was significantly impaired when the recipients received marrow cells from donors 117 weeks of age or older. These observations suggest that with aging there is a decrease in marrow T-cell progenitors and/or a decline in their proliferative capacity.


Delayed implantation caused by administration of sheep immunogamma globulin against LHRH in the rat.

The effect of the administration of sheep anti-LHRH gamma globulin (anti-LHRH-G) on implantation of fertilized ova was investigated in rats. Daily injections of 1 ml of anti-LHRH-G from Days 1 through 7 of pregnancy uniformly inhibited implantation of fertilized ova on Day 8, but viable sites, though considerably smaller in size than in control rats, became distinguishable on Day 14 in most rats. In some of these rats resorption of fetuses occurred, and others delivered pups 7-8 days after term. When the rats were given anti-LHRH-G from Days 3 through 5, the implantation was delayed by 5 days, but the gestation was not terminated. A single injection of 1 ml of anti-LHRH-G on Day 4 inhibited implantation on Day 8, but injection on Day 3 or 5 did not. The delayed implantation by anti-LHRH-G injected on Day 4 was nullified by concomitant administration of 2 sc injections of 1 mug of LHRH, or a single dose of 1 mug of estradiol. The data indicate that the hypothalamic LHRH is essentail on Day 4 of pregnancy for timely implantation of fertilized ova, probably by maintaining LH and, consequently, estrogen secretion.


Use of the immobility reflex ("animal hypnosis") in neuropharmacological studies.

The immobility reflex (IR), a reversible, involuntary, immobility response in certain species is advocated as a uniquely useful assay system for testing of psychoactive drugs. One of the two potential areas of application is that measures of IR duration or arousal threshold serve to screen drugs to help establish drug classification, relative potency, and degree of extrapyramidal side effects. Drugs can also be tested for their neural target sites and modes of action of recording electrographic responses in various brain areas during IR. Electrographic activity (EEG, averaged evoked responses, multiple-unit activity) is relatively stable, artifact-free, and less influenced by behavioral feedback and other variables that are problems with alternative experimental preparations. The reversibility of the IR offers the advantages of chronic studies (evaluation of long-term effects, replication of results, and dose-response testing in which each animal can serve as his own control). Results from both areas of application would ultimately need cross-checking by other methods to rule out interactions of IR and the independent variable being tested. Further possible interactions in long-term studies include potential interactions between the degree of tolerance developed to repeated IR trials and to repeateddrug administration.


Body temperature responses at different ambient temperatures following injections of prostaglandin E1 and noradrenaline into the brain.

Since prostaglandins of the E series have been implicated in the production of fever by pyrogens, we have applied them directly to the anterior-hypothalamic preoptic area of uunanesthetized rats at various ambient temperatures. In this paper we have determined accurately the region of the brain of the rat from which temperature responses can be produced by local injection. In addition we present evidence to suggest that the responses to local injections of PGE1 are relatively unaffected by environmental temperatures, whereas those in response to injections of noradrenaline are influenced by ambient temperature. These results are discussed in light of similar findings with respect to the response to pyrogens in that it is relatively unaltered by ambient temperature. This work lends further support to the hypothesis that pyrogens act in the hypothalamus by releasing prostaglandins.


Effects of pemoline on hyperactive boys.

Thirty boys rated as hyperactive by their teachers and parents received penoline or placebo in a double blind design. A variety of measures were taken during the nine week blind period. Behavior ratings were made on the Conners scale at 4 time intervals showing that a significant improvement in the drug group was observed by the teachers, but no significant change occurred in the ratings by the parents and physician. No toxic or grossly abnormal results were obtained from pediatric examinations which included blood, urine and stool samples as well as height, weight and cardiovascular data. Psychological tests, including the WISC, yielded no significant findings over the 9 weeks although initial differences existed between the drug and placebo groups. These measures were also administered during the 18 month long-term phase for 14 of the children which led to the conclusion that penoline is an effective agent for improving the general behavior and school performance of some of the hyperactive boys.


[Space-occupying cerebral process as a clinical misdiagnosis in subacute spongioid encephalopathy (Jakob-Creutzfeldt syndrome). Clinical-morphological report on 3 cases].

This is a report on three cases of subacute spongioid encephalopathy (Jakob-Creutzfeldt syndrome) where an extended cerebral process had been diagnosed clinically. However, a final and correct diagnosis could not be established until after the postmortem examination. The patients were 1 woman and 2 men; the duration of disease was between 5 weeks and 2 1/2 years. In 2 of the patients, initial pseudoneurasthenic complaints were followed, in the further course of disease, by manifestations of an organic psychosyndrome accompanied by neurological and, moreparticularly, coordination disorders. The neuropathological conditions manifested themselves especially in the frontal and occipital cortices as spongioid states, astroglial changes, ganglion-cell failures and pathobioses.


[FSH, LH and testosterone evaluation in healthy males from pre-puberty to senile age. Study in basic conditions and after stimulation with Gn-RH].

The secretion values of the two seric gonadotropins and of plasmatic Testosterone have been estimated in a casuistry of normal males, 114 subjects, subdivided in groups of 8 to 95 years of age. Our investigation allowed to compare hormonal levels in the different ages; in particular, the pattern in senescence appeared greatly interesting. In one part of this casuistry, we have estimated the response to the intravenous administration of Gn-RH. The test showed a positive gonadotropic response in all ages, with some differences between FSH and LH, and induced no significant change in testosterone secretion. Among the results which have been obtained, it appears that physiologic hypogonadism of the elderly is a primary phenomenon, not hypophysodependent.


Computed tomography in the diagnosis of posterior fossa lesions.

A series of 3,500 cases examined by computed tomography (CT) of the head were reviewed to identify patients who had symptoms and signs suggestive of neurologic disease in the posterior fossa. Three hundred forty eight such cases (about 10%) were found, and the scans were reviewed to determine the character of lesions that could be detected and the accuracy of the neuroradiologic diagnosis. Overall, 16 errors were made (4.6%), of which 13 were false negatives and 3 were false positives. False negatives included nine tumors, two infarcts, and two arteriovenous malformations. Four of the tumors and the two arteriovenous malformations were small and caused no visible alterations in density even when analyzed retrospectively. In the remaining seven cases, specific findings either were overlooked or were obscured by artifacts, and, therefore, the diagnosis was not made. The three false positive diagnoses were made through a misinterpretation of density changes that were artifactual. No changes in the intracranial absorption coefficients were detected in 109 cases. Abnormal changes were evident in 226 cases in which structural lesions were subsequently found. Many of the lesions had a characteristic appearance, but in certain clinical situations, which include searches for metastatic disease, acoustic neuromas, meningiomas aneurysms of the basilar artery, and arteriovenous malformations, the injection of intravenous contrast medium was helpful, or even essential, for diagnostic success. The prominence of clinical signs and symptoms is not always an accurate index to the presence of structural alteration of the posterior fossa. We believe, therefore, that this portion of the cranium should be included in every CT study.


Initial clinical experience with computerized tomography of the body.

Computerized tomography of the body, now possible with an instrument that can complete a scan rapidly enough to permit patients to suspend respiration, adds an important new dimension to radiologic diagnosis. Cross-sectional antomy is uniquely reconstructed to provide accurate diagnostic information for various disorders throughout the body.


Urinary tract tomography.

The application of the priniciples of linear tomography to enhance the visualization of the kidneys during excretory urography represents a major advancement in the quality of excretory urography. The ability to visualize the renal parenchyma and renal outlines on tomograms has resulted in a significant increase in the detection of renal masses, parenchymal scars, and adrenal tumors. The use of tomography may also contribute significantly to the evaluation of patients with various other urinary tract diseases. It has been our practice during the past 5 years to obtain linear tomograms as a routine procedure during excretory urography in all adults and in selected pediatric patients. We believe that tomograms of the kidneys represent an important part of the excretory urogram and should be done as a routine procedure.


Physical and dosimetric aspects of diagnostic geometrical and computer-assisted tomographic procedures.

Tomographic systems offer potential for visualizing sections of the body that are ambiguously imaged by "flat" detection systems. Effective utilization involves the synergistic combining of various considerations, including appropriate motion, contrast, and extent of the anatomic region of interest; cost-benefit considerations; assurance of correct electromechanical operation; and benefit-risk analysis of patient exposure.


The Johns Hopkins radiology reporting system.

Radiologists can comprehensively report diagnostic radiographs by computer with a speed approaching that of dictation. This is the main mode of radiographic reporting used at the Johns Hopkins Hospital. Support functions include information storage, retrieval, statistics, and billing. Costs are comparable to stenography. The system can be run from a large time-sharing computer or dedicated minicomputer. A commercial stand-alone version will soon be available.


Dose-time fractionation study in patients with mycosis fungoides and lymphoma cutis.

Single and multiple dose-time fractionation schemes were investigated in patients with mycosis fungoides and lymphoma cutis. The single dose response shows that the disease-free interval is dose dependent. Remission rates are similar when the same total dose is given in either single treatments or multiple daily fractions. Weekly dose fractionation schemes are superior to daily regimes for lymphoma cutis. Changes in tumor volume reduction following single doses to lymphoma cutis indicate that the mean lethal dose (DO) is 90 rads and the extrapolation number (N) is less than 2. These findings are discussed in relation to the reoxygenation process and the cell cycle distribution of the tumor cell population.


Site of the in vivo stimulatory effect of prostaglandins on LH release.

A possible direct effect of prostaglandins E1 and E2 (PGE1 and PGE2) on luteinizing hormone (LH) release at the pituitary level was studied in vitro using anterior pituitary cells in primary culture, a system approximately 10-fold more sensitive to stimulation of LH release than previously used hemipituitaries. No effect of PGE1 or PGE2 could be detected on the time course of basal or LH-RH-stimulated LH release or on the LH responsiveness to LH-RH. This absence of a direct effect of PGEs at the pituitary level on LH release was confirmed by in vivo experiments using female rats under Surital anesthesia in the afternoon of proestrus. After intravenous injection, under these conditions, 15(S)-15-methyl PGE2 was 3-5 times more potent than PGE2 to increase plasma LH levels while PGE1 had about 50% the potency of PGE2. Injection of sheep anti-LH-RH serum one hour before PGE1 or PGE2 injection not only lowered basal plasma LH levels but prevented the rise induced by PGEs. These data indicate clearly that the increased plasma LH levels observed after in vivo PGE injection are secondary to a stimulation of LH-RH release while PGEs do not appear to have a significant effect on LH release at the pituitary level.


Quantifications of the major urinary metabolite of the E prostaglandins by mass spectrometry: evaluation of the method's application to clinical studies.

Measurement of 7alpha-hydroxy-5,11-diketotetranoprostane-1,16-dioic acid, (PGE-M), the major urinary metabolite of prostaglandin E1 and E2 in man provides a useful indicator to monitor prostaglandin biosynthesis. For quantitative analysis of this prostaglandin metabolite and the stable-isotope dilution techniqe of selected ion monitoring (SIM) is employed using gas-liquid chromatography-mass spectrometry. The preparation of the bis(D3-methyloxime), bis-methyl ester of PGE-M containing a tritium tracer in position 2 which was used as internal standard for the SIM method is described. The synthesis of this internal standard includes the biosynthetic conversion of 11-hydroxy-9,15-diketoprostanoic acid to PGE-M by the rabbit. The intra-assay coefficient of variation of this SIM method ranged between 4.0 to 6.7 percent. The recovery of authentic, underivatized PGE-M added to urine was 93 +/- 3% (mean +/- SEM, n=17). The levels of PGE-M excreted in urine were higher (p less than 0.001) in males than in females (15.2 +/- 1.9 mug/24 hours (n=24) and 3.3 +/- 0.3 mug/24 hours (n=17), respectively. These levels were in close agreement with values published previously. No significant difference in excretion of PGE-M between the sexes was observed in the pre-pubertal age-grou (male: 2.9 +/- 0.8 mug/24 hours, n=5; female: 3.1 +/- 0.9 mug/24 hours, n=5) or in the age-group of 45-80 years (male: 9.3 +/- 1.1 mug/24 hours, n=21; female: 7.3 +/- 0.9 mug/24 hours, n=12). The amount of PGE-M excreted decreased significantly after administration of indomethacin or acetyl salicylic acid in therapeutic doses. The concomitant reduction of the urinary excretion of PGE-M (68 to 85% decrease) and prostaglandin E (73 to 100% decrease) after indomethacin treatment in each case (n=8) is evidence that a diminished urinary PGE-M output reflects a decrease in prostaglandin E biosynthesis.


Spina bifida, exencephaly, and cranial bleb produced in hamsters by the solanum alkaloid solasodine.

Solasodine, one of the spirosolone structured solanum alkaloids, was gavaged to hamsters at 1184 - 1628 mg/kg once on the 7th or 8th day of gestation. About one-third of all litters from surviving, pregnant dams had one or more deformed offspring. There were 50 abnormals among 727 offspring from 84 dams at sacrifice. Abnormalities included 9 spina bifida, 13 major exencephaly, 25 cranial bleb, 2 hare lip, and 1 anophthalmic types. There were 5 abnormals among 1948 total offspring from 192 control dams. Malformation incidence in controls was 1/10 that in solasodine-gavaged animals. Solasodine gavage also resulted in a large increase in resorptions. Spina bifidas had a protuberance of the skin and other soft tissue in the dorsal mid-line of the lumbosacral region of the fetus. Exencephalics had a prominent dorsocranial defect that fully exposed the brain. Cranial blebs consisted of a soft protuberance of the skin in the mid-line of the interparietal region. The solasodine analogs tomatidine and diosgenin were not teratogenic at dose levels twice as high as the teratogenic dose of solasodine.


Laboratory trials with inactivated vaccines against Escherichia coli (O78 K80) infection in fowls.

Laboratory trials made with five inactivated (O78 K80) Escherichia coli vaccines showed that the greatest degree of protection against an intramuscular challenge with the homologous strain was obtained with an alum precipitated vaccine. This vaccine was equally effective when administered by the subcutaneous, intramuscular or intraperitoneal route. Maximal protection, persisting for at least six weeks, was obtained by inoculating chicks at three weeks of age with a dose of approximately 1-5 X 10(9) cells in 0.5 ml. Some degree of protection was obtained, however, in chicks vaccinated earlier. There was no evidence that this vaccine provided any cross protection against other pathogenic serotypes of E coli. No adverse effect was noted on growth rate or carcase quality in the chicks vaccinated. Immunological studies showed that protection was not related to the production of O and K serum agglutinins.


Comparative studies on the use of 5-fluorouracil in two different media as a selective agent for isolation of Leptospira.

Incorporation of 5-fluorouracil at concentrations of 100-150 mug/ml in Korthof's medium was found to be effective in inhibiting staphylococci and Escherichia coli without adversely affecting leptospiral growth when cultures were incubated at 30 degrees C or at room temperature (15-22 degrees C). No growth was detected in cultures incubated at 37 degrees C. it was concluded that Korthof's medium containing 5-fluorouracil at these concentrations forms a useful selective medium for the isolation of leptospires when incubated at appropriate temperatures.


Virulence of established vaccine strains and artificially passaged field strain of Mycoplasma mycoides subsp mycoides.

The virulence of Mycoplasma mycoides for mice, which appears to parallel virulence for cattle, was assessed in respect of four vaccine strains well known for their use in the control of contagious bovine pleuropneumonia. The T1 strain was slightly more virulent than V5, and both were much more virulent than F and KH3J, which could not be distinguished from each other. There was no significant difference between cultures of the T1 strain supplied by three different vaccine-producing laboratories, The mousevirulence test was also used to study the effect of serial passage in artificial systems on virulent field strains of M mycoides; two such strains underwent no appreciable change in virulence during many passages in chick embryos or in mice, although the same strains, and two others, were readily attenuated by repeated subculture in broth. With one strain of M mycoides there was evidence that the total number of subcultures in broth over a given period was more important than the duration of each subculture.


[Cyclical chemotherapy of myeloma with cell synchronization: therapeutic trial. Apropos of 13 cases].

The authors report the results obtained from the treatment of 13 cases of myeloma by cyclic chemotherapy (melphalan) applied after cellular synchronization with vincristine. The clinical results (maximum 2 years after treatment) were good in 11 cases out of 13. The following laboratory values quickly returned to normal: sedimentation and calcaemia, but there was little change in the immunoglobulins.


Properties, variants, and applications of the immunoradiometric assay method.

The immunoradiometric assay (IRMA) and 2-site IRMA techniques employ purified radioactive antibodies to convert soluble antigens into a directly detectable complex. Unreacted labelled antibody is discarded by reaction with solid-phase antigen (IRMA), or by a preliminary insolubilization of the unknown antigen using solid-phase antibody (2-site IRMA). The preparation and properties of antigen-immunoadsorbent, solid-phase antibody, and purified radioactive antibodies are discussed. Analysis of the dose-response curve and problems in dose-interpolation are similar in IRMA and 2-site IRMA, and different from radioimmunoassay and other competitive-binding assay systems. The most significant assay variables include: exchange of radioactive antibody in IRMA reaction 2, stability and reactivity of the solid-phase antibody, washing the solid-phase, non-specific interference by serum proteins, and a paradoxical fall in tube radioactivity at high dose (2-site IRMA) (the 'high-dose hook effect'). 2-site IRMA has advantages in specificity (by using separate antibodies directed to 2 different antigen sites), sensitivity and assay range (because of the low zero dose-response). Assay variants include: alternative antibody labels, various solid-phase antibody preparations (including immunological 'spacer-arms'), non-immunological insolubilization of antigen, univalent radioactive antibodies, repeated immunological extractions of unknown antigen, and non-immunological separations in IRMA reaction 2. Both IRMA and 2-site IRMA have been adapted to the use of labelled anti-IgG as an additional 'universal' reagent, thereby avoiding the necessity for the preparation of radioactive antibodies specific for the unknown antigen. These techniques have been applied to the assay of a great variety of antigens and will be especially appropriate for automation.


The role of immunological factors in the treatment of cancer.

Evidence has accumulated in the last 15 years that many experimentally-induced tumours in animals carry a tumour-specific transplantation-type antigen (TSTA) in their plasma membrane and that the tumour-bearing host responds to the TSTAs with the production of antibodies and cytotoxic mononuclear cells. In man the situation is not yet clear but there are indications that a similar situation may apply in many human malignancies. These findings have led to a resurgence in interest in the role of immunotherapy in the treatment of malignant disease, but as yet there is no clear evidence from properly controlled clinical trials that immunotherapy is the treatment of choice for any tumour. At present clinical immunotherapy constitutes a field for careful investigation but it cannot be considered a proven modality of treatment. At present its use must be confined to controlled studies in which benefit or possible harm can be determined. When giving immunotherapy it is necessary to monitor carefully the specific immune reaction of the host against the tumour. Further progress in immunotherapy requires a better understanding of why tumour cells succeed in vivo to escape destruction by the immune responses of the host. This review summarizes the current state of knowledge concerning the nature of TSTAs, the effect of the immune response to TSTAs on metastatic spread and the mechanisms of escape with special reference to the role which circulating soluble TSTA plays in 'neutralizing' the action of cytotoxic cells and antibodies. It is stressed that there is no support for the hypothesis of a 'blocking antibody'. Finally the different types of immunotherapy which have been developed in animal systems are described and possible clinical applications are discussed.


[Paget's disease and surgery].

Paget's disease may in some cases require recourse to surgery: (1) Fractures of bones in patients with the disease mend normally but slowly. Orthopaedic treatment is satisfactory, except for the femur where osteosynthesis is necessary. (2) Severe deformation of the lower limbs should be corrected by osteotomy when it is responsible for serious disablement. With a simple and sure technique functional improvement can be assured. (3) Coxopathy associated with Paget's disease sometimes involves sufficient invalidity to justify total arthroplasty. (4) Malignant degeneration, usually determined by biopsy, is beyond any therapeutic treatment.


The immunosuppressive effect of extracorporeal irradiation of the blood evaluated by blast transformation and membrane immune fluorescence tests.

The immunosuppressive effect of extracorporeal irradiation of the blood was investigated by in vitro blast transformation tests on circulating lymphocytes and on lymphocytes isolated from lymph nodes and by B-lymphocyte counts before, during, and after the treatment. Two consecutive patient series, from a controlled clinical trial of the effect of extracorporeal irradiation of the blood on the course of kidney transplantation, were studied. B-cell depeltion was found to be relatively larger than the total lymphocyte depletion. In vitro transformation tests on both circulating and lymph node lymphocytes showed large individual variations. There were no characteristic correlations between the results of these tests or with the number of circulating lymphocytes. Nor were there any characteristic changes in these tests during treatment. These results, together with previous experience, seem to contraindicate the value of irradiation of  the blood as an immunosuppressive treatment.


The interaction of nonmitogenic and mitogenic lectins with T lymphocytes: association of cellular receptor sites.

The relationship between the surface receptors on neuraminidase-treated human blood lymphocytes for the mitogenic lectins Phaseolus vulgaris leukoagglutinin (La), concanavalin A (Con A) and soy bean agglutinin (SBA) and the non-mitogenic lectin Helix pomatia A hemagglutinin (HP) was investigated. Two different techniques, co-capping with different fluorochrome-labeled lectins and cell binding-inhibition experiments with 125I-labeled lectins, were used. The results demonstrated that the nonmitogenic lectin HP and the mitogenic lectins SBA, La and Con A bind either to the same macromolecule (s) or to different but physically linked macromolecules on the surface of human T lymphocytes. In contrast, only part of beta2-microglobulin (beta2-m) or beta2-m-bearing complexes, appear to be physically linked to the lectin receptor complex(es). On the lectin-binding substance(s) at least two saccharide structures were recognized, one of which binds both HP and SBA and another which binds SBA and La (and probably also Con A) but not HP.


Intraventricular treatment of Serratia marcescens meningitis with gentamicin. Pharmacokinetic studies of gentamicin concentration in one case.

A neurosurgical patient with postoperative meningitis caused by Serratia marcescens was treated with intraventricular as well as intramuscular gentamicin. Gentamicin concentration in serum and CSF was determined at different times after the administration. Serratia marcescens could not be isolated from CSF after 3 days of therapy. Determination of gentamicin concentrations in CSF showed that gentamicin should not be given intraventricularly more than once a day to avoid accumulation of the drug. No adverse effect was noticed although the CSF concentration reached 450 mug/ml.


Antibodies of surface antigens of lymphocytes and lymphoblastoid cells in cold-agglutinin-positive sera from patients with Mycoplasma pneumoniae infection.

IgM antibodies reacting in the cold with surface antigens of normal human blood lymphocytes were demonstrated by indirect immunofluorescence (IFL) in cold-agglutinin-positive sera from 21 patients with Mycoplasma pneumoniae (MP) infection. Twenty to fifty per cent of the lymphocytes were stained. MP sera reacted also with 75%-100% of cells from two lymphoblastoid cell lines and one Burkitt lymphoma line and with about 80% of peripheral blood lymphocytes from one patient with chronic lymphatic leukaemia. The IFL reaction was negative with cells from leukaemic lymphoid T-cell line (Molt-4). Lymphocyte fractionation experiments gave no evidence of a selective reactivity of MP sera and B or T lymphocytes of peripheral blood. Removal of cold agglutinins from the MP sera by absorption with human O erythrocytes significantly reduced the IFL reactivity with lymphocytes and lymphoblastoid cells, indicating the presence of I antigen on these cells. Furthermore, lymphoblastoid cells but not Molt lymphoid cells absorbed out most of the cold erythroagglutinins.


Multiple lymphonodular cryptococcosis, cured by 5-fluorocytosine.

A 5-year-old boy was admitted with an acute febrile illness and painful and enlarged cervical lymph nodes. A chest X-ray showed right tracheobronchial lymph nodes. A lymph node biopsy demonstrated a tuberculoid appearance, with epitheloid cells, giant cells, and also necrotic zones. Cryptococcus neoformans was isolated both in culture and after animal inoculation. While amphotericin B was not tolerated by the patient, the oral administration of 5-fluorocytosine resulted in a rapid recovery.


Morphogenesis and pathogenesis of chronic lung diseases. VIII. Cellularization of lung interlobular areas as a preliminary phase of peribronchovascular fibrosis.

An experimental investigation of the lung interlobular areas was performed by elicitation of rabbits with antigens (aspergillar and human-serum proteins) administered in aerosols or intramuscularly in Freund's adjuvant. The cell accumulations in the interlobular areas developed irrespective of the antigen, duration of exposure and route of administration. The cells accumulated (reticulo-lymphoid, plasma cells, eosinocytes) were counted and the areal surface measured. The total cell count and the proportion of plasma cells appeared to be related to time, dose and antigenicity of the proteins administered. Fibrillogenesis was also observed between cells in the interlobular areas during prolonged administration of antigens, pointing out the importance of the interlobular lesions in chronic lung processes.


[The application of relaxation in hospital geriatrics].

On a three years base experience in the geriatric department of Geneva's university psychiatric clinic, the paper studies among practical problems encountered in the application in institutional geriatry of relaxation, those related to therapists' training and to the nature of therapy control established for them and their patients. Problems pertaining to the management of the cure according to the method of J. de Ajuriaguerra amd M. Cahen are viewed, and the position of relaxation in the post-graduate psychiatric training defined. The study also mentions the influence of relaxation applied to the aged patient on his human environment in and out of the hospital. These notes are complementary to those already presented on the indications of relaxation in geriatry, the way body is preceived by the aged patient through relaxation, and it's consequences on the adjustment of an aging person.