Sequential studies of lymphocytes, neutrophils and serum proteins during prednisone treatment. Seven patients (6 with connective tissue diseases, 1 with bronchial asthma) have been studied before, during, and after prednisone therapy. Maximum dose was 15 mg daily, which was tapered off to zero within three months. All patients showed striking subjective improvement during therapy. The ESR reflected this improvement but the acute phase proteins did not. The serum concentration of prealbumin rose significantly during the period of most intensive steroid treatment. IgE decreased in the patient with bronchial asthma, but otherwise the immunoglobulins did not change, and positive serological tests remained unchanged. Contact sensitization to haptens was induced without impairment during therapy. Prednisone induced rises in blood lymphocyte and neutrophil concentrations. Lymphocyte transformation, both mitogen- and antigen-induced, was not influenced by therapy, but PPD-induced inhibition of leucocyte migration decreased. Neutrophil phagocytosis was unimparied, but bactericidal capacity, stimulated nitroblue tetrazolium reduction, and neutrophil and plasma lysozyme concentrations were all depressed during treatment with prednisone.


Diagnosis and treatment of acute gastrointestinal haemorrhage in a small district hospital. Ninety-eight consecutive patients admitted to a small district hospital because of acute gastrointestinal haemorrhage have been studied. Patients with haematemesis and/or melaena were treated with antacids and tranexamic acid from the very beginning and were examined with early panendscopy. All patients were closely observed in an ordinary medical ward by a staff especially trained to handle acute gastrointestinal bleeding. Seven patients required acute surgery. The overall mortality was 4.1%. It is concluded that acute gastrointestinal haemorrhage can be successfully handled with modern diagnosis and treatment in a small hospital.


Hemorrhagic diathesis in a carrier of hemophilia B. A carrier of hemophilia B was found to have an unusually low factor IX level of 13 per cent. Her history of previous bleeding and the hospital course following elective dental extractions were consistent with a mild hemorrhagic diathesis. The patient is a member of a rare kindred of hemophiliacs. The mean level of factor IX in 12 carriers in this kindred was 42 per cent, with a range of 13 to 100 per cent. This patient represents the sixth reported case in which a female carrier of factor IX deficiency was symptomatic.


Association of a chromosomal abnormality with lymphocytes having both T and B markers in a patient with lymphoproliferative disease. The lymphocytes of a patient with leukemic lymphosarcoma were found to have an unusual surface phenotype in that they bound both sheep erythrocytes (a T cell marker) and complement-coated erythrocytes (a B cell marker) but lacked other B cell surface characteristics. Marker chromosomes were present in these cells, but not in other, phenotypically normal cells from the same patient. This case may provide a clue to the chromosomal origin of some lymphocyte surface markers in man.


Further observations on the diagnosis cause, and treatment of endophthalmitis. In our study of 54 suspected cases of endophthalmitis, vitreous aspiration was more sensitive in making a culture-proven diagnosis than anterior chamber paracentesis; Staphylococcus epidermidis was a more common cause of endophthalmitis than previously appreciated; and intraocular antibiotics in the recommended dosage are reasonably safe clinically and add a new dimension to the treatment of endophthalmitis.


Simultaneous bacterial endophthalmitis and sympathetic uveitis after retinal detachment surgery. In a 66-year-old white woman suppurative endophthalmitis and sympathetic uveitis developed simultaneously about eight months after conventional repair of a rhegmatogenous retinal detachment. Histopathologic findings included vitreous abscess with probable staphylococcus organisms, total retinal detechment and diffuse chronic choroiditis with granulomatous foci, typical of sympathetic uveitis.


Binocular enhancement of color discrimination in a deutan. A 31-year-old white male deutan produced reliably different profiles when examined binocularly and monocularly with a Farnsworth-Munsell 100-hue test. Discrimination in the long wavelengths improved under the binocular conditions. Intensive testing yielded no information to account for the phenomenon.


Necrotic myelopathy (myelomalacia) in rats with allergic encephalomyelitis treated with tilorone. Necrosis of the spinal cord was produced by administering tilorone to rats before or during the incubation period of experimental allergic encephalomyelitis (EAE). Under slected conditions of dose and timing, the drug delayed onset of clinical signs but did not prevent progression to paralysis. The lymphocytic component of the inflammatory lesions was reduced, but this was accompanied by a dramatic increase of monocytes in the spinal cord, followed by softening (myelomalacia). This new variant of EAE simulates necrotic myelopathy in man. The similarity provides support for an autoimmune etiology of the latter. Furthermore, the inverse relation between lymphocytic cuffs around vessels and massive monocytic infiltration of the cord adds to the growing evidence that lymphocytic cuffs protect the neural parenchyma by "vascular blockade."


Elastic modulus and stress relationships in stretched and shortened frog sartorii. The longitudinal dynamic elastic modulus (delta stress/delta strain) of 11 sartorius muscles (Rana pipiens; 3 degrees C) was measured at static strains, 0.57 less than L/Lo less than 1.53. Pseudorandom white-noise displacements less than +/-0.031% Lo (mean, peak to peak) were imposed on tetanically stimulated and resting muscles to obtain the isometric moduli. The active elastic modulus at each length was determined as the difference between the low-frequency (15-80 Hz) asymptotes of the tetanic and resting modulus functions. Resting moduli were found to increase with stretch at a declining rate, suggesting that some resting elasticity is attributable to active crossbridges. For isometric, tetanically stimulated muscles above L/Lo = 1.0, the ratio dynamic elastic modulus/active stress was nearly constant (65.4); the data predict zero modulus at a stretched length corresponding to zero active stress. Hence, the modulus per crossbridge exhibits sarcomere length invariance. On the other hand, active muscles below L/Lo = 0.77 manifest a significant (P less than or equal to 0.05) additional modulus beyond that found at the same active stress in the stretched muscle. Sarcomeric structural rearrangements are suggested as a possible source of this additional modulus.


The family and schizophrenia.

The family and schizophrenia. The author discusses the role of the family in the etiology of schizophrenia and suggests how this research might be integrated with our growing knowledge of the biology of schizophrenia. Abnormalities of family interaction-particularly communication deviances-are frequently associated with schizophrenia and may play a causal, rather than epiphenomenal, role in its pathogenesis. Communication processes in family life affect the child's development of attentional and perceptual capacities, which also have strong biologic roots. The author suggests that the study of normal and abnormal perceptual development might be a meeting ground for researchers in the areas of the biological and familial theories of schizophrenia.


Investigations on the influence of different corticosteroids on the development of galactose cataracts in rats. The influence of daily subcutaneous injections of 5 different corticosteroids (15 mg/kg body weight) on the development of galactose opacities in young rats of approximately 60g body weight was investigated. Progress of cataracts was evaluated by planimetry of lens photos. The three glucocorticosteroids used (cortisol, prednisolone, fluocortolone) induced a slight acceleration of cataract development, while a mineralocorticoid (desoxy-corticosterone) caused a marked retardation. A temporary retardation was also observed with fluocortinbutyl, a rapidly metabolized steroid for topical use.


[ERG in Behçet's disease (author's transl)]. Rod- and cone-system electroretinograms from 16 patients suffering of recurrent posterior uveitis and one or more symptoms of Behçet's disease were studied. On the basis of an evaluation of the clinical picture and of the progression three stages of the disease were distinguished. These stages were compared to the changes in amplitude of the b-waves of the ERGs (Fig 1). The findings in this group of patients were also compared to those from 11 patients with "simple" posterior uveitis (Fig. 2). The electroretinographic results in both these groups were highly similar: in all patients progression of the ocular disease was accompanied by parallel reduction in amplitude of the b-wave of the ERG. All ERG responses were affected in a similar way: the rod-system was in general more severly affected than the cone-system in both groups of patients. On the basis of these data it appears that the ERG indicates the stage of retinal damage in posterior uveitis. However, we could not detect ERG changes characteristic for the Behçet type of uveitis.


Ring-shaped alkali burns of the rabbit cornea. II. Early changes of the corneal stroma. Corneas of 32 rabbits were coagulated in a circular zone of 1 mm width and 10 mm diameter. The results of the experiment showed sharply limited injury throughout the entire depth of the cornea without lateral diffusion. The reactions of the corneal stroma during the first three days are described and discussed.


Experiments concerning the human C-wave. The dependence of the human c-wave from the step amplitude was studied qualitatively. The maximum of the c-wave is achieved with light stimuli longer than 10 sec. After a dark period of 10 sec a fully developed c-wave appears. Also, in response to a brilliant photoflash a c-wave could be recorded. The influence of a mobile pupil on the response in the DC-ERG is demonstrated. Responses of the retinal potential to square wave and sinusoidal stimuli of different period times have been registered.


[The Mackay-Marg-tonometer. VII. The continuous registration of the intraocular pressure (author's transl)]. The Mackay-Marg-Tonometer registers continuously the intraocular pressure (Pt) as exactly as an electromanometer connected with the eye provided that the corneal rigidity is eliminitated by a smooth indentation of the cornea by the tip of the probe, the determined deviation of the registered values from linearity is considered and the temperature of the probe is not influenced from outside.


A theoretical model for the eye of new-born infants. A Gullstrand model for the eye of new-born infants is proposed, based on intra-ocular distances obtained by ultrasonography and lens radii measured on sections of deep-frozen preparations (v. Pflugk, 1909). Refractive indices of the media are assumed to be equal or nearly so to those of the adult eye, since no experimental data are available. The focal length of the model is 15.74 mm, the power 84.8 dptr, that of the lens alone 43.4 dptr, and the refractive error +2.8 dptr. A simplified model where the inner surface of the cornea is omitted, has a focal length of 15.63 mm, a power of 85.3 dptr and a refractive error of +2.4 dptr. When the data of v. Pflugk are analyzed statistically it is found that the spread of the lens power is considerably smaller than that which would be expected from the spread of the radii.


[Changes of the phosphatides and their fatty acids in the retina and in the fasciculus opticus after retinal detachment: investigations of human and animal retinae (author's transl)]. In this study the effect of an experimentally provoked retinal detachment on the pattern of the phosphatides and fatty acids of the retina and the optic nerve of adult rabbits was investigated. The analysis was performed one month, and 4 months after the operation, and the values were related to the findings in control animals of the same age, and of the age of one day and 30 days respectively. In this way changes in the total lipide, in the phosphatides and in their fatty acids could be revealed, with a tendency towards the developmental stage of the 20th up to the 30th day of life. Between retina and optic nerve no difference was found neither temporally nor regarding the quantitative reaction. In the detached human retinae the same reactions can be proved as in the animal experiment. The relationship of these findings to the recovery of the operatively reatached human retina is discussed.


[Fructose levels of the aqueous humour after abrasio of the corneal epithelium (author's transl)]. Fructose and glucose levels of cornea stroma and aqueous humour were determined after abrasio of the corneal epithelium within five days. As the glucose levels remained, fructose levels were diminished significantly, when the epithelium was scraped off. The role of the corneal epithelium as a source of fructose in rabbit aqueous humour is discussed.


Testicular reaction to prolonged exposure to nitrous oxide. Male LEW/f Mai rats were exposed to an atmosphere of 20 per cent N2O, 20 per cent O2, and 60 per cent N2 for a maximum of 35 days. Evidence of injury to the seminiferous tubules was found in some animals by the second day. By 14 days, such damage was found in all animals. The toxic effect was confined to the spermatogenic cells, with consequent reduction in mature spermatozoa and appearance of multinucleated forms. Other cells within the testes were resistant to damage. Recovery of spermatogenesis occurred after return to room air for more than three days. Serum testosterone levels were not significantly affected during the prolonged exposure.


Family distribution of lymphocytotoxins in Hodgkin's disease. The prevalence of lymphocytotoxic antibody was studied in 131 relatives of 10 patients with Hodgkin's disease. The study group contained nine families, five of which had two subjects with Hodgkin's disease. One hundred twenty-eight control family members were studied in parallel. Lymphocytotoxic antibody was present in 35.5% of all family members of patients with Hodgkin's disease, and in 8.6% of controls (P less than 0.01). Lymphocytotoxic antibody appeared primarily in consanguineous relatives irrespective of close personal household contact with the probands. The prevalence of the antibody was equal in both first- and second-degree relatives. These findings suggest at least a genetic and possibly an environmental influence in the genesis of lymphocytotoxic antibody among relatives of patients with Hodgkin's disease.


Collateral circulation before and after coronary artery reconstruction. The changes in collateral circulation after coronary artery reconstruction were analyzed in 75 patients with 177 bypass grafts and 18 complementary gas endarterectomies. The quantity of collateral circulation was directly proportional to the degree of coronary obstruction. The changes in collateral circulation depended on the success of coronary surgery or on the progression of the disease in coronary vessels. So, when the grafts remained patent, the collaterals disappeared and when the grafts became occluded, the collateral circulation returned to the preoperative level. Progressive obstruction of the coronaries caused increased collateral circulation.


[Stenoses caused by Murphy's button in the treatment of esophageal varices]. Treatment of oesophageal varices by insertion of Murphy's button arrests haemorrhage but in 2/3 of the cases of secondary stenosis occurs between the 4th and 8th week. The use of Blakemore's probe contributes to this. It is a very severe stenosis in 15 p. 100 of the cases and may require insertion of a wire loop. Dilatation should be started as soon as the first symptoms appear.


Coronary ostial stenosis complicating coronary arteriography. Coronary ostial stenosis is a cause of angina pectoris and sudden death. It is due mainly to atherosclerosis, syphilis, and iatrogenic disease. The last is of growing importance because of the frequency of coronary arteriography and surgical procedures on the aortic valve. Since both may cause stenosis of the coronary ostia, these procedures raise the topic from an obscure morphologic entity to an important consideration in the treatment of cardiac disease. We describe a case of ostial stenosis that was complicated by coronary arteriography.


Systemic and local complications following low-friction arthroplasty of the hip joint. A study of 800 consecutive operations. At the New York Orthopaedic Hospital, a study was made of postoperative complications in 800 consecutive total hip replacements of the Charnley low-friction arthroplasty type. Specially designed records made it possible to document and include all systemic and local complications of this procedure. While the rate of postoperative infection was low (less than 1%), thromboembolism and deep-vein thrombosis incidence was high despite the introduction of a prophylactic anticoagulation regimen. There were no deaths during or immediately after surgery, but six occurred within the first six weeks postoperatively. Two were due to a massive pulmonary embolus (proved at autopsy), two to myocardial infarction (clinical diagnosis), and one to a perforated cecum (proved at autopsy). The incidence of mechanical and technical failures in our series was relatively low and quite comparable with results reported by others.


[The development OF THE vestibular apparatus under conditions of weightlessness]. The spawn of the aquarium fish Brachydanio rerio was developing during 5--6 days under conditions of weightlessness (first on board the spaceship "Sojuz-16", then in the space station "Salut-4") in special aquariums "EMKON", in thermostable installations. Electron microscopically the embryos were found to have a well developed labyrinth in early developmental histologically and cytologically differentiated receptory structures of the macula utriculi and macula saccili. In contrast to controls, the experimental animals showed certain alterations in the otolite organization. In similar experiments the embryos of clawed frog Xenopus laevis in the stage of the tail bud were also placed in special containers "EMKON" and thermostable apparatus "Biotherm-4" and by the spaceship "Sojuz-17" were brought to the space station "Salut-4", where it stayed for 16 days. The initial embryos had already had a well developed acoustic vesicle with macula communis. Inspite of the preliminary load by start acceleration and staying under conditions of weightlessness, they reached the general development fairly similar to controls. As it was shown electron microscopically their labyrinth had highly histologically and cytologically differentiated structures. However, a disturbance of the development of the otolithic membrane and otoconia should be noted. The alterations observed in the otolithic membrane organization in experimental fishes and frogs may be explained by general disorders in calcium metabolism.


Catecholamine-containing cells of the taste buds in the tongue of the frog (Rana temporaria). In a study of the epithelial layer and taste buds of the tongue of the frog using fluorescence, peculiar dumb-bell shaped cells were found in the taste buds of fungiform papillae and these showed a highly-positive reaction to catecholamines. Adrenergic nerve fibres were detected in the vessels of the taste bud and in the epithelium of the tongue. Under conditions of catecholamine deficiency produced by preliminary reserpinization of frogs a decrease in specific fluorescence of the cells and the nerves was observed.


[Changes in the dimensions of motor neurons and their components with different forms of nerve center activation]. Experiments in frogs have shown that a prolonged orthodromic rhythmical activation of motoneurons induce changes in their size and staining. Under these conditions the size of all components of motoneurons (cytoplasm, nucleus, nucleolus) is changed. The cytoplasm size changes are more pronounced than those of the nucleus. Under prolongation of the low frequency stimulation (1 per sec.) of the dorsal roots the changes are of phasic character: an initial enlargement (10 minute-long stimulation) and a subsequent decrease of all the above spinal cord motoneuron components (25 minute stimulation). After the 10 minute high frequency stimulation (50 impulses per second) of nerve centers there occur a sharp decrease of the size of the cytoplasm and the nucleus.


[Reactions of human neck muscle-fibers to vestibular stimulation (author's transl)]. In healthy human subjects activity from single fibers of the splenius-capitis muscle was recorded by means of a microelectrode. Two types of muscle fibers could be distinguished according to their reaction on vestibular stimulation. The first type reacted only to stimuli (angular acceleration) exceeding 10 degrees per sec2. These units showed no resting activity. The second type had a resting activity between 20 to 40 impulses per second. Their reactions under vestibular stimulation resembled that of primary afferent neurones of the vestibular nerve of other vertebrates. The functional meaning of these findings is discussed.


[The facial nerve. Points of topographic anatomy]. The intracranial and basicranial pathways of the facial nerve present certain morphological peculiarities which are too often overlooked. These are considered to be unimportant details or simple abnormalities but are useful for the otologist to know when using a microscope for increasingly complicated surgical techniques.


Mechanical explanation of the on-off effect (diphasic impedance change) in otospongiosis. Impedancemetry gives important information in otospongiosis, both for relative compliance and impedance audiometry. The detection of the stapedius reflex is facilitated by recruitment in some audiometric types of otospongiosis and enables us to solve many of the masking problems which are particularly difficult in this disease due to the very important cross-hearing (or cross-over). Diphasic impedance changes (on-off effect) once detected must be systematically investigated since they allow us to detect otospongiosis early on. This sign is absolutely characteristic of the onset of a stapediovestibular involvement and is of primary interest in this disease because of its early appearance - before any classical audiometric change and any air-bone gap, i.e. before deafness. Diphasic impedance changes must thus be systematically investigated in case of so-called unilateral otospongiosis, in the audiometrically normal ear, and for the detection of otospongiosis in otospongiotic families. It is also helpful in confirming the otospongiotic origin of sensorineural losses before an air-bone gap appears. Our experience with routine stapedectomies and impedance audiometry measurements have led us to a purely mechanical explanation of the on-off effect, i.e. the response of an elastic system to a deformation with a different mechanism of the two inverse peaks, with a different mass and thus a different inertia. This mechanical explanation fits perfectly with anatomical findings. Everything occurs as if the evolutive stages of the onset of the stapediovestibular involvement were defined in impedancemetry, starting from the normal stapedius reflex, first by mixed forms, then by a pure on-off effect, finally by the disappearance of the stapedius reflex.


Perception of static orientation in a constant gravitoinertial environment. The illusions associated with the perception of static tilt in various specific force environments have been reviewed and then classified in such a way that a simple perceptual model could be developed to account for the experimental data. The fundamental conclusion to be drawn from this model is that these illusions can be accounted for by a simple non-linear transformation of the information primarily from the saccule.


Electron microscopic observations of immunoreactive cells in the rheumatoid synovial membrane. The perivascular infiltrates of the rheumatoid synovium were examined in the electron microscope. Lymphocyte-rich, plasma cell-rich, and transitional areas were observed. The transitional areas contained lymphocytes, plasma cells, blast cells, macrophages, and fribroblasts. Although lymphoblasts were frequent, the blast cells were predominantly plasmablasts. Marked degeneration of fibroblasts in the vicinity of lymphoblasts suggested the liberation of a lymphotoxin by the lymphoblasts. There was close contact between blast cells and macrophages and between macrophages and lymphocytes. The close association of lymphoblasts, plasmablasts, and macrophages in the transitional areas suggests that these are sites of T- and B-cell interaction in the rheumatoid synovial immune response.


Cryoimmunoglobulinemia in Felty's syndrome. Seven of 9 patients with Felty's syndrome exhibited cryoglobulins in greater amounts than found in uncomplicated RA but similar to amounts found in RA with vasculitis. Antinuclear antibodies were found in high titer in the sera and cryoglobulins of Felty's patients; when compared to SLE patients, whose sera and cryoglobulins also contained antinuclear factors, an antinuclear antibody reacting with nuclei of polymorphonuclear granulocytes appeared to be selectively concentrated in the cryoglobulins of some Felty's patients.


Cutaneous vessel immune deposits in rheumatoid arthritis. A study to determine the presence of immune deposits in the cutaneous vessels of normal-appearing skin was made in 39 patients with rheumatoid arthritis. Immune deposits in skin vessels were found in 20 of the 32 patients with seropositive rheumatoid arthritis. The frequency of such immune deposits was only slightly higher in patients with clinical vasculitis than in those without such vasculitis. There was an association among the presence of immune deposits in skin vessels, presence of antinuclear antibodies, and elevated serum levels of IgM and IgA. The major immunoreactants detected were IgM and C3. The presence of immune deposits in skin vessels does not differentiate seropositive rheumatoid aptients who have clinical vasculitis from those who do not have clinical vasculitis.


Stimulating factors in abnormal haematologic conditions. Part of the present knowledge, due to the in vitro assays of human normal and leukaemic granulocytopoiesis, is briefly reviewed, with special attention to the meaning of the leukaemic CFU-C, and to the possible pathogenetic role of the relationship of CFU-C with CSF, in normal vs. leukaemic conditions. It is suggested that the role of CSF level during aplasia following cytotoxic therapy could be worthwhile of further investigation. Data are reported on the CSF activity of peripheral blood leukocytes in smouldering leukaemia (low), and in marrow aplasia (high), and of chronic myeloid leukaemia spleen cells (low CSF). Preliminary observations on the CFU-C content of spleen and liver in chronic myeloid leukaemia indicate that the role of these organs should receive adequate consideration.


B-lymphocytosis factor in human plasma.

B-lymphocytosis factor in human plasma. Patients with acute thermal burns experience an increase of serum immunoglobulins associated with marked B-lymphocytosis during the recovery phase from the burn injury. This study was performed to delineate humoral factors which may induce the B-lymphocytosis in such patients. Plasma samples were obtained serially from 14 adult patients and 14 adult controls. One-half ml of plasma was injected intraperitoneally into C3H/He male mice, and absolute numbers of surface immunoglobulin-bearing cells in the mouse peripheral blood were counted. Fractionation of plasma samples was performed. The biologically active plasma fraction, tentatively termed B-lymphocytosis factor (BLF), was cultured with normal human peripheral blood lymphocytes to determine in vitro lymphocyte transformation. The solubility of 125I-labelled BLF in various organic solvents was examined. Plasma obtained from burned patients induced a marked increase of IgG, IgA, and IgM-bearing cells in the peripheral blood of mice within 3 hours after injection. The B-lymphocytosis activity of normal plasma was not significant. The molecular weight of BLF was estimated to be close to that of ribonuclease A (M.W. 13,400). Transformation of normal human peripheral blood lymphocytes was observed when cultured with BLF. 125I-labelled BLF was not soluble in organic solvents. These data suggest that BLF is not a lipopolysaccharide, and plays a role in regulation of B-lymphocyte levels in burned patients.


Lymphocyte responsiveness in systemic lupus erythematosus. Lymphocyte transformation to various mitogens and antogens was studied in selected patients with systemic lupus erythematosus. These patients were selected because they had taken no drug other than low-dose aspirin for 2 months prior to presentation. An impaired transformation response to the mitogens phytohemagglutinin and pokeweed was found. There was no impairment in the response to PPD and Candida. The impaired mitogen response, which could not be corrected using purified, warm-washed, and warm-cultured T lymphocytes, seemed to be a corollary of disease activity.


Left ventricular angiography on exercise. A new method of assessing left ventricular function in ischaemic heart disease. Left ventricular function was studied in 17 patients with ischaemic heart disease and compared with 4 patients with normal left ventricular function. The patients in the homogeneous group of ischaemic heart disease were further subdivided into those 'without angina' (n=5) and those 'with angina' (n=12), depending upon the presence of angina during supine leg exercise at the time of definitive study. At rest there was no significant difference in the heart rate, cardiac output, stroke volume, and left ventricular end-diastolic pressure (LVEDP) in the three groups. During exercise the cardiac output and stroke volume were significantly depressed and LVEDP was significantly raised in the ischaemic heart disease group as a whole but within this group failed to show any significant difference in patients with and without angina. The left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV) measurements showed clear separation of these three groups only on exercise. On exercise, there was decrease in LVEDV and LVESV (P less than 0.05; P less than 0.02) in the group with normal left ventricular function, no change in the group with ischaemic heart disease without angina, and striking increase in LVEDV and LVESV in the group with ischaemic heart disease and angina (P less than 0.01 and P less than 0.02, respectively). This angiographic method of assessing left ventricular function shows clear separation of the three groups and also highlights the significance of angina. Ejection fraction (EF), a commonly measured parameter of left ventricular function, failed to reflect consistent changes on exercise as compared to values at rest which emphasizes the limitations of the measurement of ejection fraction at rest.


Immunological responses of patients with psoriasis and the effect of treatment with methotrexate. A group of thirty-six patients of whom fourteen were being treated with methotrexate, were studied in order to assess T-lymphocyte function by in vitro techniques. Circulating T-lymphocytes in aliqots of blood were assessed by the rosetting technique. No differences were found in psoriatics, whether on methotrexate or not, compared with fifteen control subjects. Lymphocyte counts and lymphocyte transformation to phytohaemagglutinin (PHA) tended to be lower in the psoriatic group as a whole than in the controls, but the differences were not statistically significant, However, a significant inverse relationship was found between the extent of the skin lesions and lymphocyte transformation to PHA, i.e. the smaller the area of skin affected the higher the lymphocyte transformation. Psoriatics treated with methotrexate had fewer skin lesions and higher lymphocyte transformation to PHA than psoriatics not so treated, probably reflecting this inverse relationship. The reason why the presence of extensive psoriasis is associated with depressed lymphocyte transformation is not understood. No evidence was found that methotrexate depressed cell-mediated immunity as judged by these in vitro tests.


Langerhans cells in the epidermis of athymic mice. Langerhans cells were identified with the electron microscope in the epidermis of six athymic nu/nu mice. Their origin in the thymus is ruled out and their functional dependence on either the thymus or T lymphocytes seems improbable.


Lymphocyte abnormalities in mycosis fungoides. Fourteen patients with clinical and histological evidence of mycosis fungoides have undergone a series of immunological tests. Significant findings include the presence of low numbers of E and EAC rosette-forming cells in the peripheral circulation of the mycosis fungoides patients. Elevated levels of IgE were seen in five of the mycosis fungoides patients, and the mean IgE level was significantly higher than in the control series. Possible explanations of these findings are considered.


The scanning electron microscopy of normal human peripheral blood lymphocytes. A study of the effects of various sample preparation techniques for scanning electron microscopy has been undertaken in an attempt to resolve conflicting descriptions of the surface topography of human peripheral blood lymphocytes. By fixing cells in suspension--a technique thought most likely to avoid the production of artefacts--no clearly defined morphological classification of lymphocytes could be made, and when T- and B-lymphocyte enriched preparations were studied their surfaces appeared similar. Both T- and B-rosetted cells showed identical morphological changes as a result of their interaction with red blood cells. The smooth cells described in other reports were found only under certain conditions of preparation. It is therefore not possible to distinguish between T- and B-cell populations, using the S.E.M., on the basis of surface morphology alone.


Effects of inhibitors of protein and RNA synthesis on aldosterone-stimulated changes in phospholipid fatty acid metabolism in the toad urinary bladder. The effects of an inhibitor of RNA synthesis, cordycepin, and an inhibitor of protein synthesis, cycloheximide, on aldosterone-induced changes in lipid metabolism and phospholipid fatty acid composition have been studied in the toad urinary bladder. At the concentrations employed, the inhibitors abolish the hormone-induced increases in total lipid synthesis, phospholipid fatty acid specific activities, and weight percentage of phospholipid long-chain polyunsaturated fatty acids as well as blocking the aldosterone-mediated increase in sodium transport.


Ultra-slow inactivation of the ionic currents through the membrane of myelinated nerve. (1) Voltage-clamp experiments were performed with myelinated fibres isolated from the sciatic nerve of the frog to study slow changes of the specific sodium and potassium currents as a function of membrane (holding) potential and time. (2) The level of the peak sodium current depends on holding potential VH. This dependence can be described by a sigmoidal function uinfinity(VH). The underlying process is called "ultra-slow sodium inactivation" and is different and separable from the short time steady-state inactivation, hinfinity(V), and from the slow inactivation depending on the extracellular potassium concentration (Adelman, Jr., W. J. and Palti, Y. (1969), J Gen. Physiol. 54, 589-606; Peganov, E. M., Khodorov, B.I. and Shishkova, L. D. (1973), Bull. Exp. Biol. Med. 25, 15-19; Khodorov, B. I. Shishkova, L. D. and Peganov, E. M. (1974), Bull. Exp. Biol. Med. 3, 10-14). (3) After a sudden change of the holding potential the sodium current reaches a new steady-state level (due to the transition of uinfinity(VH) to the corresponding value) within approx. 4 min. The kinetics of the transition cannot be described by a single exponential function. (4) A corresponding voltage- and time-dependent process of ultra-slow inactivation exists for the potassium current in the node of Ranvier. The kinetics are faster than those of the sodium system.


Effect of conditioning potential on potassium current kinetics in the frog node. The kinetics of potassium conductance changes were determined in the voltage clamped frog node (Rana esculenta), as a function of conditioning prepotential. The conditioning potential duration varied from 1 to 50 ms and the amplitude between -60 and +130 mV (relative to rest). The conductance kinetics were determined at a single test potential of +20 mV (depolarization) by means of the slope of log [ninfinity - nt] vs. time relationship which defines the time constant of the process (tau). The values of tau, after conditioning hyperpolarizations, were around 5 ms, up to 10 times greater than values obtained following a strong depolarization. The tau vs. pre-potential curve was sigmoid in shape. These differences were only slightly dependent on [K+]0 or conditioning pulse duration. The steady-state current values were also found to be a function of conditioning potential. After conditioning hyperpolarizations, the log [ninfinity - nt] vs. time curve could not be fitted by a single exponent regardless of the power of n chosen. The prepotential dependency of potassium current kinetics is inconsistent with the Hodgkin-Huxley axon model where the conductance parameters are assumed to be in either one of two possible states, and where the rate of transfer from one state to the other follows first order kinetics. In contrast the described kinetics may be consistent with complex multistate potassium "channel" models or membranes consisting of a number of types of channels.


[Determination of choleragen activity in tadpoles]. A method of titration of the V. cholerae toxin obtained from the broth culture filtrates is presented. In difference from the earlier methods, the larvae of Rana temporaria were used as a test object. The tadpoles were placed in the vessels with water containing graded concentrations of the toxin. The titer of the toxin activity was evaluated by the percentage of dead tadpoles. The concentration causing the death of 50 per cent of the tadpoles in the course of the 24 hours was taken as a unit of toxin activity. The method is simple, easily reproducible and economical.


Improved techniques for liquid culture of human and mouse bone marrow. Previous studies using the in vitro diffusion chamber (Marbrook) have shown that bone marrow grown in this system will undergo limited stem cell replication and differentiation to mature granulocytes and mononuclear phagocytes. A series of studies with modified culture systems was initiated to improve cell production and committed stem cell (CFU-C) proliferation in vitro. Introduction of a continuous-flow system and a migration technique providing means of egress for mature neutrophils resulted in substantially improved performance. CFU-C were found to be capable of migration through a 3-mu pore membrane. These studies indicated that membrane surface area, culture medium circulation, and mature cell egress were among the conditions that could be optimized for maximum hematopoietic cell proliferation in suspension culture. The present observations also suggested that large-scale in vitro growth of mammalian bone marrow may be feasible.


[Model of the effect of the vestibular system on blood pressure during sleep]. A structural model of the effect of vestibular system on blood pressure during sleep is proposed. This model reflects joint action of the otolyth system and semicircular canal system, vestibular nuclei, vasomotor centre, vagus nuclei and of the central control mechanism of the state awakeness -- sleep. Anatomic and physiological prerequisites involved in the model are expressed by chains with transmission functions, signal generators, summators etc.


Production of colony-stimulating factor by leukemic leukocytes. The production of colony-stimulating factor (CSF) by the peripheral blood cells of untreated patients with acute myeloid leukemia (AML) was measured in the agar culture system using normal human bone marrow as the source of colony-forming units (CFUc). CSF production was found to be variable and was related to the morphologic subtype of AML--cells from patients with monocytic leukemia produced normal or large quantities of CSF, while (with one exception) those from patients with myeloblastic leukemia produced little or no CSF. There was a general relationship between CSF production and serum lysozyme levels. Attempts to demonstrate a consistent inhibitory effect exerted by leukemic peripheral blood cells on normal leukopoiesis in vitro were negative. Results instead suggested that the addition to the feeder layer of cells from patients with monocytic leukemia could raise CSF levels above those obtained with normal peripheral blood leukocytes alone, possibly by recruiting additional CFUc from normal marrow.


In vitro regulation of granulopoiesis in human leukemia: application of an assay for colony-inhibiting cells. We describe two assays to detect the action of colony-inhibiting cells. In the first assay, we used a simple density separation technique to remove dense neutrophils (PMN) from suspensions of blood and of bone marrow cells prior to culture in semisolid agar. Conditions were arranged to ensure that control suspensions of unseparated cells and test suspensions of buoyant mononuclear cells differed only in their content of neutrophils. The control and test suspensions contained equal numbers of mononuclear cells (and granulocyte precursors). Colony (and cluster) formation was invariably enhanced in neutrophil-depleted cultures of normal cells. In the second assay, dense PMN, treated by an adherence separation procedure, were recovered, and the non-adherent dense PMN were added back to PMN-depleted cultures. A reproducible dose-related decrease in colony (and cluster) formation to basal levels resulted. The inhibitory effect was identical when the PMN were added directly to the culture (overlayer) or to the underlayer. In PMN-depleted cultures obtained from patients with leukemia and other hemopoietic disorders, neither colony nor cluster formation was enhanced, and sometimes it was reduced. When we compared the effect of adding patient and normal non-adherent PMN to target cultures of normal and patient PMN-depleted cells, some leukemic PMN were noninhibitory. Our results suggest that abnormalities of cellular interactions in vitro detected in the first assay may have more than one explanation, as shown when they are subjected to the closer scrutiny possible with the second assay.


Relationship of colony-stimulating activity to apparent kill of human colony-forming cells by irradiation and hydroxyurea. Suspensions of human bone marrow cells were subjected to 137Cs irradiation in vitro and then cultured in semisolid agar medium. Cultures of irradiated cells were stimulated with colony-stimulating activity (CSA) of different potencies, and it was found that the amount of stimulation applied to cultures influenced the apparent kill of colony-forming cells (CFC). It was also found that the effects of irradiation on colony formation were not confined to CFC kill since medium conditioned by cells during irradiation exhibited stimulatory and inhibitory properties after treatment by 600 and 1000 rads, respectively. Studies in which irradiated cells were pretreated with hydroxyurea indicated that CFC in the DNA synthetic phase of the cell cycle were particularly sensitive to low doses of irradiation. The proliferative capacity of CFC surviving 1000 rads was undiminished as judged by their ability to form large colonies. Estimates of CFC kill by hydroxyurea were also affected by the level of CSA.


Human bone marrow lymphocytes: B and T cell precursors and subpopulations. Characterization of the different lymphocyte populations in normal human bone marrow (BM) was attempted and compared to that in the peripheral blood (PB). B cells comprised 34% +/- 11% of lymphocytes in BM and 23% +/- 9% in PB. The majority of B cells carried IgM in BM and IgG in the PB. In the BM, cells carrying complement or Fc receptors were fewer than cells carrying Ig, but in the PB they were equal. T cells comprised 6% +/- 4% of lymphocytes in the BM and 62% +/- 7% in the PB. The majority of BM lymphocytes did not have B or T cell markers; these probably included B and T cell precursors. BM lymphocytes carrying surface Ig increased in a 7-day culture, whereas those of the PB decreased. Pokeweed mitogen induced Ig synthesis in B cells of PB but not those of BM. BM-T cells were more efficient than PB-T cells in inhibiting Ig synthesis of PB-B cells. These results indicate that the BM compartment contains immature B cells that are capable of partial differentiation and maturation in vitro. BM-B lymphocytes are probably not involved in the effector phase of the immune response since they are unable to synthesize Ig and because they carry few receptors for complement of Fc, BM-T lymphocytes are very few and have suppressor capability and therefore may play an essential role in regulation of Ig synthesis by B cells.


Effect of atropine on the decay of miniature end-plate currents at the frog neuromuscular junction. 1 The effect of atropine on the time constant of decay (tau) of miniature end-plate currents was investigated. 2. The atropine-induced shortening of tau was accompanied by a reduction in the voltage-sensitivity of tau. 3. This effect of atropine was reversible and dose-dependent, the voltage sensitivity being abolished with high concentrations of atropine (2.5 X 10(-5)M).


Early experience with the Boerema button for bleeding oesophageal varices. Early experience with the use of the Boerema button for bleeding oesophageal varices is reported. A simplified technique for its insertion is described, and of the 6 patients so treated, only 1 died. No patient has re-bled in the short follow-up period available, and oesophageal appearances suggest that prolonged relief from bleeding can be anticipated. Further exploration of the button ligation transection technique is suggested not only for control of acute bleeding, but also for patients unsuitable for shunt surgery.


The morphology of motoneurons and dorsal root fibers in the frog's spinal cord. Ventral and dorsal roots of the frog's spinal cord were filled with cobaltous chloride, and the resulting cobaltous sulfide precipitate, following treatment with H2S-buffer solutions, was intensified with physical developers. A ventromedial and a dorsolateral motoneuron group could be discerned in the ventral horn. The ventromedial, motoneurons gave origin to a strong dendrite crossing to the contralateral side. In the dendritic arborization pattern of the dorsolateral motoneurons a dorsomedial, a dorsal and a lateral dendritic array were distinguished. They were regarded as representing three different input channels to the motoneurons. Intramedullary branching of motor axons and recurrent axon collaterals were never observed. The dorsal root could be divided into a medial and lateral division carrying small and large caliber fibers, respectively. The end-branches of the small caliber fibers were seen to terminate in the substantia gelatinosa. Fine collaterals of the large caliber fibers also terminated in the substantia gelatinosa; coarser collaterals penetrated deeper and terminated in a triangular-shaped area in the base of the dorsal horn and in the intermediate gray matter. From this area a tail was followed into the ventral horn and several synapses were seen on the proximal dendrites and on the somata of motoneurons. A few dorsal root fibers could be seen crossing to the contralateral side.


Five years' experience with aortocoronary bypass grafting. During a 5-year period (Apr. 14, 1970 to Apr. 14, 1975) 930 patients underwent aortocoronary bypass grafting; the procedure was done as an emergency in 141. Of the entire group 3.3% died at operation, 1.6% died in hospital and 5.8% died later; of the patients undergoing emergency grafting 12.1% died at operation and 5.7% died later. From a detailed analysis of the first 600 patients it was found that both operative and late mortality were clearly related to two factors: severe left ventricular dysfunction at the time of operation and inadequate surgical treatment because of insertion of insufficient numbers of grafts or because of poor blood flow through the grafts.


An approach to immunotherapy using antibody to IgE in mast cell leukemia. Passive immunotherapy was attempted in a patient with mast cell leukemia using antibody against IgE. The results of both in vitro and in vivo studies indicate that although receptor sites for IgE were retained by the malignant mast cell, a secretory defect was present characterized by the spontaneous release of histamine and an impaired secretory response to anti-IgE antibody. Anti-IgE antibody selectively and reproducibly reduced the number of circulating mast cells probably by facilitating their permanent uptake by the reticuloendothelial system. Tolerance was not achieved with high dose deaggregated sheep IgG, nor were we able to confirm the effectivity of immunochemotherapy based on linking chlorambucil to antibody directed against the tumor-associated "antigen" IgE.


Lymphocyte abnormalities in untreated patients with Hodgkin's disease. The study comprises 38 unselected and untreated patients with Hodgkin's disease (HD) and 23 healthy persons. Highly purified blood lymphocytes were analyzed for cells forming rosettes with sheep red blood cells (T lymphocytes), and lymphocytes bearing surface immunoglobulin (B lymphocytes) and/or carrying receptors for complement. Their DNA synthesis, spontaneously, or after activation with mitogens (phytohemagglutinin, concanavallin A, poke weed mitogen) and purified protein derivative (PPD) was measured. Delayed skin hypersensitivity to PPD and mumps antigen was studied. Most HD patients had low numbers of T lymphocytes (50% of the cases below normal range) while the mean B-lymphocyte level was normal but with a greater variation than in the control group. Lymphocytes from most patients were poorly stimulated by T-cell mitogens. Two-thirds of the patients and one healthy control had negative skin reaction to 2 TU PPD and the DNA synthesis of their lymphocytes after activation with PPD was low. Large lymphoid cells (greater than 9-mm diameter) were commonly present in HD blood and the spontaneous DNA synthesis was high, particularly in lymphocytes from stage B patients. The percentage of T lymphocytes and the stimulation of lymphocytes by T-cell mitogens or by PPD, a T-lymphocyte function, did not correlate and each test only detected defects in about half the cases. Simultaneous application of all tests revealed abnormalities of blood T lymphocytes in 33 out of 38 patients. Although the defects were usually more pronounced in patients with advanced disease, the impairment of T lymphocytes and their functions is present in all stages of Hodgkin's disease.


Treatment of spontaneous leukemia in AKR mice with chemotherapy, immunotherapy, or interferon. AKR mice are genetically destined to develop Gross (RNA) virus-induced lymphatic leukemia. Leukemic AKR mice treated with combination vincristine, cyclophosphamide (Cytoxan), and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea sustained a 180% increase of life-span. Combination chemotherapy plus immunization with neuraminidase-treated allogeneic (Gross virus-induced) G2G leukemic cells intradermally resulted in 35% of animals surviving beyond 150 days without evidence of the disease. It is significant that allogeneic E2G leukemic cells as immunogen were as effective in prolonging the life-span of the immunized leukemic AKR mice as were syngeneic leukemic thymocytes. Virazole (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), an antiviral compound, alone showed no apparent antitumor effect. However, in experiments in which the clinically diagnosed leukemic AKR mice received a combination of cytoreductive therapy [vincristine plus prednisone or, more effectively, vincristine, Cytoxan plus 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea, followed by Virazole], there was a noticeable reduction of the viral titer, a delay in the reappearance of viable clonogenic cells, and an increase in the survival time for the leukemic AKR mice as compared to those receiving cytoreductive therapy alone. The effectiveness of purified mouse interferon in AKR mice was also examined. The decrease in the viral titer of animals that received interferon treatment was markedly greater than of those receiving a combination of cytoreductive therapy with Virazole or immunotherapy. The administration of mouse interferon had a direct effect on the appearance of the spontaneous leukemia in AKR mice. The median life-span of the control animals was 36 weeks, whereas 45% of the AKR mice treated with five doses of 5 X 10(4) units of interferon are still alive at 54 weeks of age. Thus, interferon not only reduces the Gross murine leukemia virus titer in the chronically infected AKR mice but also significantly delays the appearance of the primary lymphoma.


The differentiation of cytotoxic T lymphocytes in vitro: an ultrastructural study. T killer cells were identified morphologically in two different culture systems. The first system allowed identification by comparing under identical culture conditions two types of stimulation, one leading to cytotoxic activity levels that were very high (H-2 stimulation) and the other to levels which were practically nil (M-locus stimulation). A second system allowed identification by the use of a collaborative system in which relatively pure precursors of T killer cells were mixed with precursors of T amplifier cells from which they were distinguishable by their Thy-l antigen. In this latter case, surface labelling techniques had to be used. As in the in vivo situation, T killer cells were medium-sized pale cells with evidence of a well-developed secretory and motile apparatus. No evidence of highly active protein synthesis was found. Other T cells were dark and mainly derived from the T amplifier population, again consistent with in vivo findings. There was considerable background proliferation, even in the absence of any added antigen, and this included the formation of some well-developed plasma cells.


Correlation of platelet survival time with occlusion of saphenous vein aorto-coronary bypass grafts. Platelet survival time is frequently shortened in patients with coronary artery disease, and it is one of several factors that might contribute to graft occlusion after saphenous vein coronary artery bypass (CAB). In 35 patients with CAB, average platelet survival (autologous labeling with 51Chromium) was shortened in 20 with one or more saphenous vein grafts occluded and normal in 15 with all grafts open. Of 15 with all grafts open, individual levels of platelet survival were normal in 10 while in 20 with one or more grafts occluded platelet survival was normal in only one. Platelet survival was not altered by coronary surgery and nine of ten with shortened platelet survival pre-operatively had graft occlusion. Platelet survival did not correlate with either parent artery occlusion or serum lipoproteins. These findings suggest a relationship between shortened platelet survival and saphenous vein graft occlusion and suggest that platelet suppressant therapy might be useful in preventing graft occlusion.


Synthesis of folate polyglutamates in human cells. 1. Synthesis of polyglutamate derivatives from radioactively labelled folic acid, folinic acid and methotrexate has been studied in human phytohaemagglutinin-transformed lymphocytes. 2. With labelled folic acid as the precursor, approximately 20% of the labelled cell folate was found in each of the mono-, tetra-, penta- and hexaglutamate peaks after 72 h of incubation. At earlier times, the amounts of labelled folate polyglutamates were proportionately greater and the amount of labelled higher folate polyglutamates was lower. After only 4 h incubation over 80% of the intracellular labelled folate was still in the monoglutamate form. 3. With labelled folinic acid used as precursor, approximately 30% of labelled cell folate after 72 h incubation was in the form of folate pentaglutamate, with tri- and tetra-glutamate forming the other major peaks. The speed of formation of polyglutamate derivatives was substantially more rapid than from folic acid. 4. Methotrexate was found to decrease considerably the amount of folate polyglutamate formation from labelled folic acid in lymphocytes byt nevertheless some di-, tri- and traces of tetra-glutamate were formed. On the other hand, methotrexate had no effect on folate polyglutamate formation with labelled folinic acid used as the precusor. 5. Polyglutamate derivatives of labelled methotrexate were formed by human lymphocytes with mean amounts of 4-5% of di-, 1-5% of tri-, 1-0% of tetra- and 0-7% of penta-glutamate derivatives being formed over the period 48-72h of culture. 6. Pentaglutamate derivatives probably constitute the largest group of intracellular folates in human cells but a complex mixture exists. 7. The enzyme synthesizing polyglutamate derivatives of folate in human cells prefers a reduced folate as substrate but the requirement for a reduced form is not absolute. The nature of the reduced folate is uncertain but it is suggested on the basis of previous work that tetrahydrofolate rather than methylhydropfolate or any other reduced folate monoglutamate is the preferred substrate.


[Early diagnosis of leukaemic transformation of malignant non-hodgkin lymphoma in childhood (author's transl)]. Fresh tumour cells from four children, aged 3-11 years, with malignant non-Hodgkin lymphoma were examined with four different immunological cell markers (E-rosettes, membrane-immunoglobulins, receptors for complement, and receptors for Fc fragment). In three patients a T-cell marker (E-rosettes) was found in most of their tumour cells, the marker differing from that of T-lymphcoytes by different temperature kinetics. This difference may be used to recognise earlier than previously possible the frequently observed diffuse infiltration of bone marrow (leukaemic transformation) and of the nervous system in the course of the disease.


[Pain suppression in the trigeminal region by means of transcutaneous nerve stimulation]. On the basis of the gate control theory, an attempt was made to influence acute pain by transcutaneous nerve stimulation (TNS) in the region of the trigeminal nerve. After favorable first results in clinical application, we determined sensation and pain treshold values of teeth in two groups of patients by exactly defined electric stimuli of different degrees. After transcutaneous electro-stimulation of the pertinent ramus of the trigeminal nerve with rectangular stimulating currents, the threshold measurements were repeated. The thresholds were raised by an average 79% as far as sensation was concerned, and by an average 69% as far as pain was concerned.


[Hypothetical concept: the physiopathological entity of monoaminergic psychoses]. The importance of amino acid transport across the blood-brain barrier as the limiting factor in the metabolism of monoamines has been emphasized by many recent publications. Particularly critical is the transport of tryptophan, since tryptophan hydroxylase is not saturated. This transport is regulated by complex mechanisms, both at the periphery (total and free plasmatic levels and levels of the other essential amino acids) and centraly (by feedback mechanism initiated at the pre- and post-synaptic levels). The hydroxylated derivatives of tryptophan and tyrosine, i.e. 5-HTP and L-DOPA, most probably share the same transport mechanism as these amino acids themselves. In manic-depressive patients, the uptake of L-5-HTP is increased during the depressive phase, while the uptake of L-DOPA, is increased during the manic phase. We suggest that an increase in the uptake of tryptophan may set off oscillations in all the monoaminergic systems, thus providing a biochemical model of manic-depressive psychosis. In terms of this model, melancholy would be due to a hyperserotoninergic syndrome together with a relative hypocatecholaminergic syndrome. Mania would be due to a homogeneous hypercatecholaminergic syndrome together with a relative hyposerotoninergic syndrome. Such a model is compatible with present knowledge of the physiology of monoamines, of the semeiology and biological disturbances of manic-depressive psychosis, and of the treatment of this disease. It reconciles the monoaminergic and ionic theories of the disease better than other existing hypotheses. A reduced transport of tryptophan with a secondary increase in the transport ot tyrosine provides a conceivable model for schizophrenia. Indeed, a serotoninergic hypoactivity coupled with a dopaminergic hyperactivity, with or without a noradrenergic deficiency, would account for the semeiology quite adequately. This model too would be compatible with present knowledge of monoamine physiology, of the biochemical disturbances underlying schizophrenia and of the mode of action of anti-psychotic drugs. This unitarian heuristic concept of the monoaminergic psychoses would be in better agreement with the classic clinical data concerning this disease (typology intermediate syndromes and crossed heredity).


Deoxyribosyl transfer catalysis with trans-N-deoxyribosylase. Kinetic study of purine(pyrimidine) to pyrimidine(purine) trans-N-deoxyribosylase. Kinetic studies were carried out in order to investigate the enzymic mechanism of a 215-fold-purified purine(pyrimidine) nucleoside: purine(pyrimidine) deoxyribosyl transferase fraction from Lactobacillus helveticus. A variety of natural deoxyribonucleosides and bases were used as substrates. Initial velocity, product inhibition and isotopic exchange studies are consistent with a ping-pong bi-bi mechanism. The kinetic parameters are used to show that this fraction is free from any contamination by a specific purine nucleoside: purine deoxyribosyl transferase also found in the same strain of L. helveticus.


Control mechanisms of endotoxin and particulate material stimulation of hemopoietic colony forming cell differentiation. Through injection of particulate materials and endotoxins (ET), possible control mechanisms of murine hemopoietic colony forming cells (CFC) were investigated. The experimental system employed two inbred strains of mice that responded with a similar increase in splenic CFC after injection of particulate materials, sheep red blood cells (SRBC) and colloidal carbon (cc), but differed in their response to ET. The strains similarly phagocytosed radiolabelled SRBC and ET, suggesting that the CFC changes were not dependent solely on phagocytosis of ET. The CFC from low ET responder strain responded in vitro to colony stimulating factor (CSF) elicited by ET in serum of the high responder strain, demonstrating that lack of response to ET is due, at least in part, to failure to produce CSF. Subjection of serum from either strain to chloroform extraction did not significantly increase its stimulating capacity, suggesting that the increased stimulatory ability in response to ET was due to increase in the CSF level rather than to a decrease in the level of inhibition.


Assessment of bone marrow function: microscopy versus the agar colony assay. Changes in bone marrow status followig cytotoxic chemotherapy were measured by means of peripheral blood counts, bone marrow cytology and colony-formation in agar culture. A correlation is described between colony-forming ability and marrow differential count.


Anaemia and the induction of myeloid leukaemia in RFM mice. The results from short term experiments provide little support for the idea that the anaemic stress produced by phlebotomy acts as a trigger for myeloid leukaemia in mice genetically prone to the development of the disease. Longer term investigation has also failed to reveal any difference between bled and control mice and at this time (16 months after bleeding) no animals have died from myeloid leukaemia. These observations are in contrast to the recently reported effect of phlebotomy as a trigger for myeloid leukaemia in unirradiated RFM mice and in irradiated rats. The results given in this paper are discussed in relation to the haemopoietic stem cell compartment in leukaemogenesis and the relationship between these cells and the mature cells in the peripheral blood.


Behavior of horizontal semicircular canal afferents in alert monkey during vestibular and optokinetic stimulation. The behavior of single vestibular nerve fibers from the lateral semicircular canal was recorded during sinusoidal oscillations of the head, during optokinetic stimulation with the head stationary, and during spontaneous oculomotor behavior in the alert monkey. The response of similar fibers to adequate vestibular stimulation was also studied in some of the animals under deeply anesthetized conditions. In the alert animals all units were spontaneously active and their discharge was modulated only by adequate vestibular stimulation. Ipsilateral horizontal rotations of the head were excitatory for all units. No modification of this basic vestibular response by visual stimulation including full-field striped drum rotation was observed. Furthermore no correlation of unit activity with oculomotor function including voluntary saccadic and pursuit eye movements was found in any of the units. The regularity of spontaneous discharge was the most consistent characteristic that differentiated the unit response into types. Most units were very regular in discharge, but a few were very irregular. The averaging of unit discharge over several cycles of oscillatory head rotation showed that the irregular type units were also consistently modulated by adequate vestibular stimulation. Both regular and irregular type units were found in the anesthetized animals. Unimodal distributions of the quantitative values for unit resting discharge rate, sensitivity, and phase relationship were found. The distributions for these three parameters were similar in the units recorded in the anesthetized animals. Thus at least these characteristics of semicircular canal response seem not to be affected by the vestibular efferent system which should be altered or eliminated in the case of the anesthetized animals.


Genetic control of LDH isozymes in the Rana esculenta complex. Studies of LDH isozymes in the European green frogs showed that the synthesis of the B subunits is controlled by 3 alleles at a single genetic locus. The genetic evidence supports the hypothesis that Rana esculenta is the hybrid of R. lessonae X R. ridibunda.


Effect of orotic acid on liver glycogen of different animal species. The effect of orotic acid on the liver glycogen content in the mice, frogs and catfish was studied. It was observed that the orotic acid significantly increases the glycogen content in the liver of mice and catfish as it does in rats. On the other hand it causes a fall of the glycogen level in frogs in experiments made both in autumn and spring. This effect was modified by amino acids administered together with orotic acid.


A population of human lymphocytes staining for esterases. A population of lymphocytes is found to stain positively for esterases. The positively staining lymphocytes are more predominant among T than B lymphocytes and are significantly increased on stimulation with PHA. Treatment with cholinestrase inhibitors reduces their number significantly.


Peripheral T-lymphocytes in juvenile-onset diabetics (JOD) and in maternity-onset diabetics (MOD). The percentage and absolute number per mm.3 of peripheral T-lymphocytes were determined in 11 juvenile-onset diabetics (JOD), in 21 maturity-onset diabetics (MOD), and in 18 normal subjects (NS). The percentage was significantly lower in JOD (38.1) than in MOD (57.2) and NS (56.5). The absolute T-lymphocytes number per mm.3 was significantly lower in JOD (833) than in NS (1,260); this was also true for JOD as against MOD (1,026), even if the difference was not statistically significant. No difference was found between MOD and NS, or between MOD on oral therapy and on insulin treatment. The decrease of peripheral T-lymphocytes in JOD was not related to associated illness or drugs. The data presented suggest the possibility of an altered cell-mediated immunity in juvenile-onset diabetics.


[Clinical coronarographic characteristics and pathogenetic mechanism of angina pectoris with s-t elevation (author's transl)]. The study of 46 patients with frequent anginal episodes characterized by S-T elevation (so called "variant angina pectoris") demonstrated that this type of electrocardiographic pattern does not characterize a homogeneous group of patients. In fact, while in some patients angina occurred only at rest, in others it occurred also on exercise. Sometimes ecgraphic alterations characterized by S-T depression were observed on the same leads which on other occasions had shown S-T elevation. The angiographic picture revealed: absence of significant coronary alterations in 10% of cases, stenosis greater than 75% in one main branch in 29%, in two branches in 39% and in three branches in 22% of cases. The hemodynamic monitoring carried out on 14 of these patients demonstrated that the ecgraphic modifications occur before the onset of the hemodynamic parameters which control myocardial O2 consumption. This suggests a primitive reduction of regional myocardial blood supply as a cause of the ischaemic episodes. The study of the regional myocardial perfusion with 201Tl technique in 6 patients confirmed this hypothesis. Coronary angiography carried out during an ischemic episode showed that the reduction of myocardial blood supply was caused by a spasm of a large coronary artery involving a long segment of the vessel, reversible by nitroglycerin administration. Aorto-coronary by-pass operation performed on 6 patients was followed by the disappearance of pain in two patients, even though the "by-pass" patency was angiographically proved in two patients.


Co-operation between macrophages and a factor from lymphocytes in tumor lysis in vitro. Peritoneal cells from C3H/He mice immunized against syngeneic MM46 ascites tumor cells specifically lysed these tumor cells in vitro, while spleen cells or lymph node cells from immunized hosts were completely ineffective. The effector cells differed from lymphocytes in their morphological characteristics, property of adherence, phagocytic activity, and sensitivity to anti-theta serum. The cytolytic action of the peritoneal cells was not due to cytotoxic lymphocytes, but to macrophages. These macrophages lysed tumor cells in co-operation with a factor derived from immunoglobulin-bearing lymphocytes. Neither macrophages from immunized hosts nor the factor from lymphocytes alone had a cytolytic action on the target cells. Normal macrophages showed some cytolytic activity in the presence of the factor from lymphocytes.


[Influence of substances that change the serotonin level of the brain on the analgesic effect of promedol in rats]. In tests with determination of pain reaction in rats registered by their squeak and arising in reponse to a single electric irritation of the tail evidence was obtained to the effect that substances both lowering the serotonin content in the brain (p-chlorphenylalanine, reserpine) and raising it (5-oxytryptophan, pargilin) cause a fall of the threshold, viz. 5-oxytryptophan and pargilin display antagonism to the analgetic effect of trimeperidine hydrochloride, whereas p-chlorphenylalanine, and inhibitor of trypophan-hydroxylase and tipindol, an antagonist of serotonin, do not exert any noticeable influence on the extent of the analgesic effect of trimeperidine hydrochloride.


Upper gastrointestinal endoscopy in the pediatric patient. The value of upper gastrointestinal endoscopy in adults is well established. This study of 50 children demonstrates that upper gastrointestinal endoscopy can be performed safely and effectively in this age group without general anesthesia. Endoscopy appears more sensitive than radiology in the detection not only of superficial mucosal lesions, but of gastric and duodenal ulcers as well.


Acute hemorrhagic incarceration of prolapsed gastric mucosa. In some patients with hiatus hernia, vomiting may propel a plug of redundant gastric mucosa into the distal esophagus, where it becomes incarcerated and engorged. Significant bleeding may result. Reduction of the hernia controls the hemorrhage. Endoscopy after the acute episode may demonstrate a gastric mucosal lesion considered to be characteristic of the syndrome.


[Anti-inflammatory, analgesic and antipyretic actions of 1-(m-chlorophenyl)-3-N, N-dimethylcarbamoyl-5-methoxypyrazole (PZ-177)]. We have reported that PZ-177 was found to have potent inhibitory activity on acute inflammatory edema. In this paper, the anti-inflammatory, analgesic and antipyretic properties of PZ-177 were assessed by a battery of standard tests. PZ-177 inhibited the increased vascular permeability induced by histamine, xylene and acetic acid. The activity was the same as the anti-edematous one and was more potent than that of mepirizole. PZ-177 did not inhibit ultraviolet erythema in guinea pigs, proliferation of granulation tissue in cotton pellet and granuloma pouch tests of rats and adjuvant arthritis in rats. Wound healing was not prolonged and the agent was weak in ulcerogenic action. PZ-177 did not affect heat denaturation of bovine serum albumin at pH 5.3, but inhibited hyperthermic hemolysis at pH 7.4 and exerted a stabilizing effect on biological membranes. This is considered to be one of the mechanisms of action. When analgesic action was tested by the writhing and Haffner's methods in mice, the compound revealed a more potent activity than did mepirizole and aminopyrine. Utilizing the Randall-Selitto's analgesic method in rats, a significant rise in pain threshold was obtained only at the inflamed foot. The antipyretic action was less than aminopyrine in febrile rabbits. From the above results, PZ-177 may be classified as a potent analgesic and anti-inflammatory agent but has no effect on proliferation of granulation tissue and chronic inflammatory disease.


[Pharmacological studies of 2-(5H-(1)benzopyrano(2,3-b)pyridin-7-yl)propionic acid (Y-8004). (I) Anti-inflammatory, analgesic and antipyretic actions]. A newly synthesized anti-inflammatory agent, Y-8004 demonstrated a greater inhibition than did indomethacin (IM). on inflammatory response such as ultraviolet erythema in guinea pigs, carrageenin edema, evans blue and carrageenin-induced pleuritis and acetic acid-induced peritonitis in rats. On the other hand, the inhibition of Y-8004 was to the same extent as IM regarding granuloma formation around cotton pellet and the development of adjuvant arthritis in rats, however, Y-8004 was only half as effective as IM regarding exudation in granuloma pouch. In addition, the agent was effective in alleviating established adjuvant arthritis, the anti-inflammatory activity was not mediated by stimulation of the adrenals, and glucocorticoid-like activity could not be demonstrated. Furthermore, analgesic and antipyretic activities were to the degree as seen with IM, and the analgesic property of Y-8004 was considered to be peripheral as is the case with IM. The ulcerogenic activity of Y-8004 was observed to be mainly in the jejunum and ileum of the rat, but compared to IM, there were considerable differences between the ulcerogenic and the effective doses. As Y-8004 has a wider therapeutic margin than IM, this non-steroidal anti-inflammatory agent should be quite applicable for clinical purposes.


[Possible role of immune-phenomena in the pathogenesis of rheumatoid arthritis (author's transl)]. The R.A. is accompanied by a variety of different immune-phenomena. These are not restricted to the well known and diagnostically exploited IgM-rheumatoid factors in serum, but involve also rheumatoid factors of the Ig-classes G and A, which, at least partially are produced by lymphoid cells, which infiltrate the synovial membranes. These cellular infiltrations consist of macrophages, B and T lymphocytes, the latter being in excess. There is now good evidence that locally deposited, complement activating immune-complexes participate in the inflammatory lesions of the R.A.-joints by inducing the release of hydrolases from phagocytic cells. This event is also mediated by lymphokines and complement factors. Is is suggested that the pathogenicity of the immunoreactions occuring within the synovial tissue and fluid is a quantitative rather than a qualitative problem. In contrast to other tissues, the anatomy of the joint may favour the local accumulation of the immune-complexes. Moreover abundant immuno-reactions may be provided by a defective T-cell mediated control. Thus there is strong indication that immune-phenomena play an important role in the pathogenesis of R.A. This does not exclude the significance of metaboltic disturbances of the connective tissues for this disease.


Enumeration of polyclonal mitogen-responsive cells in different lymphoid tissues of the mouse. The relative number of cells capable of responding to Con A, PHA and LPS in the spleen, blood, lymph node and Peyer's patches of CBA mice has been quantified by means of a cytological analysis technique. No difference has been found between Con A- and PHA-responsive cells in spleen and lymph node. The lymphoid tissues of T cell-deprived mice have a reduced content of PHA responsive cells, but LPS responsiveness is within normal limits. Pretreatment of peripheral lymphocyte populations with high concentrations of anti-O antiserum and complement abolishes the response of the treated cells to PHA, but not to LPS, whereas similar treatment with a cytotoxic anti-immunoglobulin serum, which has no effect on PHA-responsive cells, only partially reduces the response to LPS. The results for mitogen responsiveness are discussed with reference to other methods of quantifying T and B cells using cell-surface markers.


Dextran-triggered T cells heighten T- and B-cell reactions to mitogens. Dextran administered to mice of six strains has been found to cause enhanced responses of spleen cells to the mitogens Con A and LPS. When added to cultures of spleen cells in vitro in a wide range of concentrations dextran, alone, was neither mitogenic nor toxic. The enhancement is mediated through T cells since it was absent in spleen cells from dextrantreated athymic mice. Furthermore, for the enhanced response to LPS, T cells from dextran-treated mice apparently must be in close association with B cells for longer than 2 h. The enhancement is accomplished through a humoral factor(s) produced by splenic T cells. The T cell-derived enhancing factor(s) has been shown to affect allogeneic as well as isogeneic T and B cells.


Characterization of dextran-activated T-cell factors. Dextran given to mice caused splenic T cells to elaborate factors in vitro which heightened normal splenic B- and T-cell responses to the mitogens LPS and Con A, respectively. Chromatographic separation of dextran-triggered spleen cell supernatants revealed two T cell-derived enhancing factors which affect T cells (TDEF-TI and TDEF-TII) and two that alter B cells (TDEF-BI and TDEF-BII). All appear to be proteinaceous because exposure to trypsin destroyed their activities. Furthermore, their presence was found to be dependent upon protein synthesis since cycloheximide treatment of the cells inhibited synthesis whereas mitomycin C treatment did not. Based on absorption studies, receptors for TDEF-TI and TII were detected on thymic cells as well as on O-deficient bone marrow cells, whereas receptors for TDEF-BI and BII were on bone marrow cells but not thymic cells.


Immunochemical characterization of the anti-RNA antibodies found in scleroderma and systemic lupus erythematosus. II. Reactivity with hsa-coupled, uridine-containing, monophosphoric ribodinucleotides. Sera from patients with scleroderma have been found to have anti-RNA antibodies which react with human serum albumin (HSA)-coupled uridine and uridine monophosphate (UMP) and are inhibited by uracil, uridine and UMP. Scleroderma sera react uniformly with 5'-polyuridylic acid (poly(U)) and fail to react with polyadenylic, polyuridylic acid poly(A) - poly(U)) which is also indicative of their uracil specificity. Anti-RNA antibodies found in systemic lupus erythematosus (SLE) are immunochemically different from those found in scleroderma in that, instead of being uniformly specific to uracil, they are markedly heterogeneous and may react with uracil, uridine and/or UMP. SLE sera frequently react with poly(A) - poly(U), indicating also their ability to recognize the double helical structure of double-stranded RNA. Thirty-seven scleroderma and thirty-four SLE sera from as many patients with either of these conditions were tested against HSA-coupled, uridine-containing monophosphoric dinucleotides in an attempt to characterize further their anti-RNA antibodies. Scleroderma sera were found to react primarily with dinucleotides in which uridine was the base proximal to the carrier protein and, except for sera that also contained antibodies to adenosine which reacted with UpA, they failed to react with dinucleotides in which uridine was in a terminal position only. Reaction with dinucleotides in which uridine was proximal to the carrier protein could be inhibited by uracil but not by the corresponding terminal base. Some lupus sera were found to react with both dinucleotides that contain the same bases in opposite sequence, e.g. ApU and UpA, while others were found to react with only one of the sequences. They were also found to react more frequently with dinucleotides in which HSA was coupled to a base other than uridine, suggesting that the reaction is primarily due to anti-DNA antibodies. Because immunization with dinucleotides coupled to protein prepared by the same method we have used, yields higher specificity to the base attached to the carrier protein, our findings suggest that, in scleroderma, a single event, akin to that of immunization with a purified antigen, gives rise to the anti-RNA antibodies, whereas in systemic lupus erythematosus there is a considerably wider immunological aberration.


Lymphoblastic lymphoma of convoluted or acid phosphatase type-a tumor of T precursor cells. Five lymphatic neoplasms with strong focal acid phosphatase reactivity were selected from a group of acute lymphocytic leukemias and lymphoblastic lymphomas. All five cases showed an anterior mediastinal mass and exhibited identical morphology. This type of lymphoma has been described by Lukes under the term "malignant lymphoma of convoluted lymphocytes". Analysis of surface membrane receptors revealed that the tumor cells lacked surface immunoglobulin and receptors for Fc-fragment, but possessed receptors for complement (C3), untreated SRBC (ES) and SRBC treated with neuraminidase (ESN). By applying a mixed rosette assay using nucleated chicken erythrocytes coated with antibodies and C3, and denucleated ESN, it was found that a considerable number of tumor cells in all five cases formed mixed rosettes, i.e. that they bore the C3 receptor characteristic of B cells and simultaneously the E receptor characteristic of T cells. Thus the tumor cells resembled immature thymocytes of 10-15 weeks' gestation, which also show focal acid phosphatase reactivity and simultaneous expression of C3 and E receptors.


Electron transfer oxidation of DNA radicals by paranitroacetophenone. The reaction of a typical electron-affinic sensitizer, paranitroacetophenone (PNAP) with the model compounds thymine, thymidine, thymidylic acid, deoxyribose and single and double-stranded DNA has been investigated by pulse radiolysis. Radicals formed by one-electron reduction of the bases and of DNA react rapidly and efficiently with PNAP by electron transfer. A small yield of transfer (less than 10 per cent) is also observed arising from oxidation of the radicals formed by the small proportion of OH which react at the sugar moieties in DNA. In contrast, electron transfer oxidation by PNAP of radicals formed by the addition of OH to the base moieties, e.g. thymine, is not an efficient process. Further, addition of the sensitizer to the thymine OH-adduct proceeds at a rate that is too low to measure by pulse radiolysis. We conclude that, since the major sites of OH reaction with DNA are the heterocyclic bases (greater than 80 per cent), oxidation of the resultant radicals is unlikely to be a major step in the mechanism of sensitization by this typical hypoxic-cell sensitizer.


Determination of the number of photoreactivating enzyme molecules per haploid Saccharomyces cells. Two haploid radiation-sensitive mutants of Saccharomyces were studied to investigate the formation of complex between photoreactivating-enzyme and substrate after ultra-violet irradiation. Using photo-flashes, the time necessary for maximum complex formation has been determined. Within 1 min, 70 per cent of the complexes have been formed. To determine the number of photoreactivating enzyme molecules per cell, the maximum dose decrement obtained after one photo-flash was determined and corrected for the effects of non-photoreactivable lesions. The corrected maximum dose decrement was found to be identical for both strains (8-5 erg mm-2). The number of photoreactivating-enzyme molecules involved in the photorepair of nuclear DNA damage was calculated as 272 +/- 27.


An elusive factor affecting mutation frequency in Tradescantia stamen hairs: its influence on r.b.e. A comparison of data from several experiments designed to determine either relative biological effectiveness (r.b.e.) or oxygen-enhancement ratios (o.e.r.) as a function of neutron energy revealed a puzzling variability in mutational response for pink mutations in Tradescantia stamen hairs. For some reason that we cannot determine, when the exposure fixtures and accompanying experimental procedures were changed as necessitated by the two studies, the expected mutation frequencies changed for X-rays and for four neutron energies. The other four neutron energies gave the expected results. As a consequence of these changes in mutation frequencies, the magnitude of r.b.e. values changed as well as the relationship of r.b.e. to neutron energy. Consequently, when r.b.e. values were determined using a closed but aerated exposure fixture instead of exposures made in free air, the resulting r.b.e. versus neutron-energy curve more closely paralleled that found by others for the inhibiton of root growth in Vicia faba.


Immunologic aspects of leprosy as related to leucocytic isoantibodies and platelet aggregating factors. The incidences of various iso- and autoantibodies in a random population of 112 unselected leprosy patients is presented. Low titers of leucocytic isoantibodies and platelet aggregating factor were detected in the sera of a variable number of such patients. The leucoisoagglutinins were found in 8% of the sera of tuberculoid as well as lepromatous leprosy patients, whereas the leucoisocytotoxins were detected in a larger percentage of the lepromatous (40%) as well as tuberculoid (28%) cases. The platelet aggregating factors (PAF) were positive in 51.2% and 45% of lepromatous and tuberculoid cases respectively. Of the 21 positive sera for PAF, the antiplatelet factor by antihuman globulin consumption test could be demonstrated only in 66.6% and 50% of lepromatous and tuberculoid sera respectively. To study the frequencies of these newly detected antibodies or antibody-like factor and to compare their occurrences with other well-documented autoantibodies present in the sera of leprosy patients: cryoglobulins, antinucleoprotein antibody and thyroglobulin autoprecipitin were also studied in the sera of the same population of leprosy patients. It has been observed that the simultaneous occurrence of all these auto- and isoantibodies in the serum of one patient is a rare phenomenon. Leucocytic and platelet counts of these patients having antibodies against leucocytes and platelets were found to be within normal limits. Accordingly, it is suggested that the low levels of antileucocyte antibody and antiplatelet factor are probably harmless to the hosts. On the other hand, it is postulated that these antibodies may act as enhancing factors by being specifically adsorbed on the lymphoid cells, thus rendering them unresponsive to mitogenic stimulus in vitro. From these studies it seems that leprosy, especially the lepromatous type, is associated with some of the serological features suggestive of an autoimmune aberration.


The repair, protection and sensitization of papain with respect to inactivation by H2O2 and OH: effects of dithiothreitol, penicillamine, cystine and penicillamine disulphide. While dithiothreitol repairs the peroxide-produced sulphenic acid derivative of papain in a fast reaction involving only one dithiothreitol molecule, penicillamine reacts with it to form papainCys25SSPen. Disulphide is also formed in the absence of peroxide (see article) by reactions of papainCys25S- AND PenS- radicals derived from -OH reactions in penicillamine-papain mixtures. A similar formation of papainCys25SSCys occurs in mixtures of cysteine and papain. However, unlike papainCys25SSCys, papainCys25SSPen cannot easily be restored to the active form of papain by the exchange reaction with CysSH, and this may have significance for an understanding of the sensitizing action of penicillamine observed in some in vivo systems. Under the action of OH radicals dithiothreitol has less of a tendency to form mixed disulphides and is more effective in repairing papain-OH intermediates than either cysteine or penicillamine. Due to secondary reactions of RSOH and other oxidized species the disulphides of cysteine and penicillamine are less effective than the sulphydryls in protecting papain against inactivation by -OH.


Structural damage of gamma-irradiated ribonuclease revealed by thin-layer isoelectric focusing. Ribonuclease, irradiated with 60Co gamma-rays in dilute aqueous solution or in the dry state, has been investigated with respect to its charge and size properties. Thin-layer isoelectric focusing revealed extensive change in irradiated RNase; new enzymatically-active components, mainly with isoelectric points lower than in unirradiated RNase were observed. Thin-layer gel chromatography indicated the formation of aggregates which are partially active enzymatically. Aggreation depended on enzyme concentration and was less in more dilute solutions-- at equal degrees of inactivation. Structural damage in the so-called 'native' monomers was revealed by thin-layer isoelectric focusing, their charge properties being distinctly modified.


Extrachromosomal deoxyribonucleic acid in wild-type and photosynthetically incompetent strains of Rhodopseudomonas spheroides. Three covalently closed circular species of extrachromosomal deoxyribonucleic acid have been identified by electron microscopic analysis in strains of Rhodopseudomonas spheroides. The weights of these plasmids, as determined from contour length, are about 75 X 10(6), 66 X 10(6), and 28 X 10(6) daltons for both aerobically grown and photosynthetically grown R. spheroides strain 2.4.1 (NRS) and for the photosynthetically incompetent strain V-2 (obtained by N-methyl-N-nitro-N'nitrosoguanidine mutagenesis) and 74 X 10(6), 66 X 10(6) and 34 X 10(6) daltons for a second photosynthetically incompetent strain, SLS I (obtained by incubating strain 2.4.1 [NRS] in medium containing sodium lauryl sulfate). Buoyant densities uere found to be 1.717 g/cm3 (58% guanine plus cytosine) for the plasmids of 66 X 10(6), 28 X 10(6), and 34 X 10(6) daltons in weight and 1.724 g/cm3 (65% guanine plus cytosine) for those weighing about 75 X 10(6) daltons. Possible functions of these plasmids are discussed.


Exodus of 42K+ and 86Rb+ from rat thymic and human blood lymphocytes exposed to phytohemagglutinin. We have found that PHA produces an alteration in the lymphocyte membrane which allows 86Rb+ or 42K+ in prelabeled lymphocytes to exchange for cations present in washing solutions. These observations suggested that PHA might induce an increase in the exodus of intracellular potassium during incubation in physiologic media. We, therefore, examined 86Rb+ and 42K+ efflux from rat and human lymphocytes during incubation in tissue culture medium. The rate constant for efflux, Ke, was significantly increased by PHA. 86Rb+ efflux was increased by 27% in rat thymic lymphocytes and by 78% in human blood lymphocytes following PHA treatment.


Suppressor thymus-derived lymphocytes in fungal infection. Thymus-derived lymphocyte (T-cell) function, as determined in vivo by cutaneous reactivity to several antigens and in vitro by responsiveness to mitogens and antigens, was assessed in 14 patients infected with a variety of fungal organisms. While all patients manifested a normal frequency of peripheral blood T cells, only seven patients reacted to at least one of the antigens used for cutaneous testing and demonstrated normal in vitro T proliferative responses. Three patients exhibited cutaneous anergy but normal in vitro T-cell reactivity while four patients demonstrated persistent anergy and marked in vitro T-cell hyporeactivity which was independent of activity of infection, concurrent medication, or any associated disorders. The marked diminution of in vitro T-cell reactivity noted for these later four patients was not due to a deletion of antigen- or mitogen-reactive cells. Thus, patients' cells which had been initially cultured for 7 days without any mitogenic or antigenic stimulus and which were subsequently washed and recultured with phytohemagglutinin, concanavalin A, or histoplasmin demonstrated a marked increase in their responsiveness. Moreover, this reactivity noted for recultured cells could be suppressed by a nonphagocytic, nonadherent, nonimmunoglobulin-bearing, sheep red blood cell rosette-forming population of cells isolated from the fresh peripheral blood mononuclear cells of the same patient. While these "regulator" T cells were capable of suppressing T-proliferative responses to antigens and mitogens, they did not diminish pokeweed mitogen-induced immunoglobulin synthesis by normal bone marrow-derived lymphocytes. Patients in whom suppressor "T" cells were found were at risk for relapsing, disseminated fungal infection.


Role of mercaptoethanol and endotoxin in stimulating B lymphocyte colony formation in vitro. Mercaptoethanol is necessary to permit B lymphocyte colony formation in semi-solid agar cultures of cells from normal mouse lymphoid organs. Transfer studies on developing colonies showed that, in part, this was a direct action on B lymphocyte colony cells but evidence was produced that in the presence of mercaptoethanol lymphoid organ cells release a factor promoting colony growth. Endotoxin strongly potentiated B lymphocyte colony formation in vitro by a direct action on colony cells but in the absence of mercaptoethanol did not allow cell survival or proliferation.


Separation of lymphocyte mitogen from lymphotoxin and experiments on the production of lymphotoxin by lymphoid cells stimulated with the partially purified mitogen: a possible amplification mechanism of cellular immunity and allergy. A mitogenic factor (MF) from guinea pig lymph node cells (LNC), which was produced by stimulating immune LNC with the specific antigen, ovalbumin, was partially purified by the sequential use of Sephadex G-200 gel filtration. CM-cellulose ion exchange chromatography, DEAE-cellulose ion exchange chromatography, and polyacrylamide disc gel electrophoresis. The product was purified at least 100-fold with regard to protein content. In addition, the purified MF was functionally pure with respect to the absence fo lymphotoxin (LT), another guinea pig lymphokine.


Thymus-derived peripheral lymphocytes from human newborns inhibit division of their mothers' lymphocytes. Lymphocytes from human newborns inhibit division of their mothers' lymphocytes. Three days after we cultured equal numbers of cells from a mother and her baby in the presence of PHA, mitosis of the mother's lymphocytes was suppressed 13-fold compared to that of the baby's lymphocytes. At the end of 3 days the number of baby's lymphocytes were doubled those of the mother's. The survival rates and mean mitotic indexes of both pairs of cell were roughly equivalent (mean +/- S.E: baby 2.4 +/- 0.8; mother 2.6 +/- 0.7), indicating that the lack of dividing lymphocytes from the mother was caused by inhibited division of the mother's lymphocytes, no enhanced growth of the newborn's cells. The cell population in newborns that is responsible for the inhibition effect resides in the T cell-enriched population. Lymphocytes from one newborn were not able to inhibit division of lymphocytes from another newborn, suggesting that lymphocytes from newborns could continue to divide despite their inhibitory effect. Other experiments showed that actively dividing fetal fibroblasts, amnion cells from the newborn, and continuous T lymphoblastoid cell lines were unable to inhibit mitosis of lymphocytes of the mother.


Adjuvant regulation of T cell function.

Adjuvant regulation of T cell function. The effect of complete Freund's adjuvant (CFA) on distinct T cell functions was investigated. Adjuvant was found to suppress the generation of cytolytic T cells in vivo when mixed with allogeneic P815 cells before immunization of C57BL/6 mice. Inoculation of the mice with either adjuvant or adjuvant emulsified with allogeneic cells resulted in whole splenic populations or immunoabsorbent-purified T cells that did not generate cytolytic activity in vitro against allogeneic cells. Mixing T cells from normal and adjuvant-treated mice before in vitro sensitization resulted in suppression of lytic activity. However, memory T cells were not subject to the same suppressive regulation as were precytotoxic T cells since adjuvant had no effect on subsequent boosting of memory.