Glucocorticoid action on rat thymic lymphocytes. Experiments utilizing adenosine to support cellular metabolism lead to a reassessment of catabolic hormone actions. Inhibition of glucose uptake has been proposed as a primary cause of many of the subsequent inhibitory effects of glucocorticoids. This hypothesis has been tested in experiments where adenosine is substituted for glucose. Like glucose, adenosine maximally supports glycolytic and oxidative ATP generation, and by its use the hormonal inhibition of glucose uptake is circumvented. With adenosine, inhibition by cortisol is seen at at least one other metabolic site, respiratory ATP synthesis. This action can be observed by hormone-induced increases in levels of lactate, pyruvate, and AMP that accompany a lowering of ATP. Evidence for this metabolic action is also seen when cells are provided with a limiting amount of glucose; despite inhibition of glucose uptake, a cortisol-induced increase in lactate accompanies the reduction in levels of ATP. Decreased respiratory ATP synthesis is also suggested by a hormonal reduction in the metabolism of labeled exogenous pyruvate to 14CO2. Several experimental approaches suggest that inhibition of oxidative ATP production, rather than of glucose uptake, is the event most responsible for glucocorticoid-induced changes in the balance of adenine nucleotides, which in turn contribute to effects on protein synthesis and uridine uptake. First, the characteristic inhibitory cortisol effects on adenine nucleotides and protein synthesis are undiminished when adenosine is substituted for glucose. Second, in adenosine-supported cells the onset of the hormone-induced increase in levels of lactate corresponds closely to the appearance of measurable reductions in ATP. In contrast, when cells are supported by glucose, the hormonal inhibition of glucose uptake is maximal by 30 to 35 min, nearly an hour before effects on levels of ATP are detectable. Third, when cells are made strongly dependent upon glucose for ATP production by deprivation of exogenous substrate and cortisol is added at 90 min, a characteristic inhibition of the uptake of glucose added 40 min later is seen; nevertheless, this is insufficient to prevent added glucose from immediately and fully restoring ATP, rates of protein synthesis, and uridine uptake. Inhibitory effects on ATP, protein synthesis, and uridine do appear after an additional hour or so, a time commensurate with the development of an inhibition of oxidative metabolism. Fourth, limiting added glucose can reduce uptake more than cortisol, without reducing levels of ATP.


Morphological changes in frog pronephric cell surfaces after transformation by herpes virus. A scanning electron-microscope study has established that there are major modifications in the surface membranes of malignant cells transformed from the pronephric kidney of the frog. Tumours were induced in vivo after exposure of embryos Lucké Herpes virus. A pronephric cell line from normal embryos and 3 tumour cell lines derived from experimentally induced adenocarcinomas of the pronephros were observed. The normal embryonic kidney cells have their surfaces covered with long fingerlike microvilli throughout the cell cycle. In contrast, the surface of the pronephric tumour cells are mainly covered by multiple, ruffled or parallel straight microridges and short, stubby microvilli. These comparisons were made on cells subject to similar culture conditions. The topographic changes in the tumour cells are considered significant since the characteristic microridges and stubby villi were consistently found in all 3 pronephric tumour lines.


A human T-independent B lymphocyte mitogen extracted from Nocardia opaca. Nocardia water soluble mitogen (NWSM), a mitogen specific for mouse and rabbit B cells, activates blood, spleen, and tonsil lymphocytes from all the humans tested. Evidence is presented that it acts selectively on human B lymphocytes. B-enriched cells were recovered from anti-Ig-coated Sephadex columns or after elimination of E rosette-forming cells: they were able to incorporate tritiated thymidine when they were cultivated in the presence of NWSM whereas they were not activated by PWM. Conversely T-enriched suspensions did not respond to NWSM although they were able to be stimulated by PHA and PWM. Moreover, the response to NWSM remained unchanged after T cells had been killed by anti-HTLA serum and complement and disappeared after B cells had been killed by anti-HBLMA serum. After stimulation by NWSM, the number of direct plaque-forming cells to HRBC, LPS, and TNP was significantly increased, showing a polyclonal activation of human B lymphocytes. Since no evidence of T cell help for B cell activation has been found, NWSM thus appears to be a T-independent human B lymphocyte mitogen.


The effector cells in human peripheral blood mediating mitogen-induced cellular cytotoxicity and antibody-dependent cellular cytotoxicity. The identity of the effector cells in human peripheral blood capable of mediating mitogen-induced cellular cytotoxicity (MICC) and antibody-dependent cellular cytotoxicity (ADCC) was investigated utilizing effector cell populations consisting of purified polymorphonuclear leukocytes, macrophages, lymphocytes, and cell surface immunoglobulin (sIg)-negative and sIg-positive lymphocyte subpopulations obtained by Sephadex anti-Fab immunoabsorbent column fractionation techniques. Chicken erythrocytes (CRBC) and Chang liver cells were used as target cells in both cytotoxicity assays. With CRBC targets MICC was mediated by polymorphonuclear leukocytes, macrophages, sIg-positive lymphocytes (B cells), and sIg-negative lymphocytes. On the contrary, with Chang liver cells as targets, MICC was mediated only by lymphocytes, and effector cells occurred exclusively in sIg-negative lymphocyte subpopulations containing thymus-derived lymphocytes (T cells). Further purification of sIg-negative lymphocyte subpopulations on antigen-antibody coated plastic surfaces yielded a nonadherent T lymphocyte population depleted of Fc receptor-bearing lymphocytes that was capable of mediating MICC against both CRBC and Chang cell targets. With use of CRBC targets, ADCC was mediated by polymorphonuclear leukocytes, macrophages, and sIg-negative lymphocyte subpopulations. However, with Chang cell targets, ADCC was mediated only by lymphocytes, and effector cells were present only in sIg-negative lymphocyte subpopulations. SIg-positive lymphocytes (B cells) and T lymphocytes were not effective in mediating ADCC against either CRBC or Chang cell targets. These studies demonstrate that the nature of the target cell employed in MICC and ADCC reactions is of critical imporatnce in defining the effector cell(s) capable of mediating cytotoxicity.


Identification of multiple cytolytic components associated with the beta-LT class of lymphotoxins released by mitogen-activity human lymphocytes in vitro. Cytotoxic activity (lymphotoxin (LT) associated with the 50,000 dalton beta-LT class of human lymphotoxins has been resolved into multiple components by chromatography on DEAE-cellulose or electrophoresis on polyacrylamide gels. The two components, termed beta-LT, and beta-LT2, are separable from the 90,000 m.w. alpha-LT, since neither component is neutralized by incubation with heterologous rabbit anti-alpha-LT antisera. However, the two components differ in their overall charge and relative heat stability with the betaLT1 component being more positively charged than the beat-LT2 molecule and extremely heat labile.


The induction of hapten-specific T cell tolerance by using hapten-modified lymphoid cells. I. Characteristics of tolerance induction. BALB/c mice were made tolerant to the T cell-dependent phenomenon of contact sensitivity to DNFB by i.v. injection of syngeneic lymphoid cells which had been previously modified with DNFB in vitro. The highly efficient unresponsiveness, as measured by ear challenge and in vitro antigen-induced cell proliferation, was shown to follow dose-response kinetics both in vivo and in vitro and to be exquisitely specific for the DNP moiety. The kinetics of tolerance induction were shown to be very rapid and had been previously shown to be long lasting. Unresponsiveness was more efficient when the hapten-modified cells were introduced by the i.v. route and tolerance could be increased by repeated injection of tolerogen. The tolerance could be transferred to normal syngeneic recipients by spleen and/or lymph node cells from tolerant donors. A wide variety of hapten-modified lymphoid cells, including mixed cell populations and enriched populations of T cells, B cells, and macrophages, were capable of inducing tolerance. The unresponsiveness was dependent  merely on the association of DNP to the lymphoid membrane proteins and not upon the viability of the hapten-modified cells. These experiments support the hypothesis that in hapten-specific T cell sensitivity, as exemplified by contact sensitivity to DNFB, specific T cell tolerance in actively induced by hapten on self-membrane. In other hapten-specific antibody-forming systems, tolerance appears to be most readily induced by hapten on soluble self protein or on a nonimmunogeneic carrier.


Cell surface immunoglobulin. XIX. Susceptibility of IgD and IgM on murine splenocytes to cleavage by papain. The present studies were designed to determine the effect of papain upon IgM and IgD on the surface of murine splenocytes. By using radioiodinated cells, it was shown that IgD is more susceptible to cleavage by papain than IgM. The difference in susceptibility to papain of the two isotypes was not observed when cell lysates were employed, suggesting that attachment to the plasma membrane affects the accessibility of IgM to papain. The major site of attack of the enzyme on IgD appears to be in the hinge region. The possible biologic implications of such a cleavage are discussed.


The induction and regulation of guinea pig B-lymphocyte proliferation in vitro. Conditions for the in vitro induction of proliferation have been examined in a population of guinea pig lymph node lymphocytes enriched for B lymphocytes. Known B cell mitogens such as bacterial lipopolysaccharide and tuberculin-purified protein derivative induced DNA synthetic responses in this B lymphocyte population as did a number of dinitrophenyl hapten-protein conjugates, all in the apparent absence of T cell participation. B cell proliferation occurred most efficiently in serum-free medium with both heterologous and homologous sera inhibiting maximum responses. In vivo immunization with hapten-protein conjugates failed to enhance subsequent in vitro B cell responsiveness to these materials beyond that owing to recruitment by contaminating antigen-primed T cells. Macrophage-associated antigen, which efficiently triggered T cell proliferation was much less effective at initiating B cell DNA synthesis than was soluble antigen not bound to macrophages. Furthermore, although accessory cells were required for the development of T cell DNA synthetic responses, macrophages of factors produced by them inhibited spontaneous or induced B cell 3H-thymidine incorporation.


Ontogeny of the antibody-forming cell line in mice. II. Maturation of B cells during fetal development. This paper maps the developmental stage reached by B cells in mouse fetuses of different ages. The "maturity" of these cells was assessed in a functional way by measuring the time taken for cells to generate antibody-forming progeny when injected into carrier-primed irradiated adult hosts and challenged daily with antigen. A steady uninterrupted progression in development of B cells occurred between 13 days of gestation and birth. There was no evidence for a stage during which B cells could only be paralyzed and not induced by antigen.


Hapten specific IgE antibody responses in mice. V. Differential resistance of IgE and IgG B lymphocytes to X-irradiation. The studies presented in this paper were undertaken to determine whether IgE- and IgG-producing murine B lymphocytes could be distinguished by differential resistance to x-irradiation in vivo. Sensitivity or resistance of B lymphocytes to various doses of x-irradiation was monitored by measuring the production by irradiated cells of hapten-specific IgG and IgE antibody. The results indicate that both primed and unprimed IgG B lymphocytes are less radioresistant than corresponding IgE B lymphocytes. Primed IgG B lymphocytes are more radioresistant than unprimed IgG B cells whereas unprimed IgE B lymphocytes are at least as radioresistant as primed IgE B lymphocytes. The relative radioresistance of primed IgE vs IgG B cells was best demonstrated in an adoptive transfer system. Thus, exposure of ASC-primed mice to 300 R 24 hr after transfer into these mice of syngeneic, DNP-KLH-primed spleen cells led to a sustained failure to produce IgG anti-DNP antibody after challenge with DNP-ASC; under these conditions IgE anti-DNP production was not impaired. This was shown to reflect differential radioresistance of the corresponding B cell populations. In addition, exposure to x-irradiation tended to augment IgE anti-DNP antibody responses when compared to unirradiated controls. This phenomenon is thought to reflect the effects of x-irradiation on regulatory mechanisms controlling the mouse IgE response and is explored in detail in an accompanying manuscript. The results described in this paper are discussed in the light of our evidence suggesting that, in both mouse and man, IgE B lymphocytes have certain unique characteristics by which they may be distinguished from other classes of B lymphocytes.


Hapten-specific IgE antibody responses in mice. VI. Selective enhancement of IgE antibody production by low doses of X-irradiation and by cyclophosphamide. Exposure of BALB/c, A/J, and (BALB/c X A/J)F1 mice, which are IgE high responder animals, to total body x-irradiation ranging from 50 to 200 R resulted in a dose-dependent enhancement of the hapten-specific IgE antibody level as compared to unirradiated control mice. In contrast, anti-hapten antibody responses of the IgG class in these same animals were rarely enhanced, and when so, were of a lesser degree. This relatively selective augmentation of the IgE vs IgG antibody responses was observed in both unprimed and primed mice. By utilizing adoptive transfer systems, it was demonstrated that the enhancing effects of x-irradiation resulted from its action on the carrier-primed cell population and not upon the responding B cells or upon macrophages. The data presented herein suggest that this enhancement phenomenon is the result of the elimination of T cells (or their products) with suppressive functions and that these cells are neither dependent upon nor specific for the carrier antigen employed in the immunization. This hypothesis is given indirect support by the observations that treatment of the same strains of mice with cyclophosphamide, in doses known to abrogate suppressive T cell functions, resulted in a similar enhancing effect to that observed after low doses of x-irradiation. In addition an interesting difference between IgE and IgG precursor B lymphocytes was observed by the ability of IgE B cells to differentiate to the secretory state at a strikingly more rapid rate than IgG B lymphocytes when exposed to comparable T cell helper influences. These observations may provide important clues to the cellular mechanisms of the immune regulation of the IgE response and its relationship to allergic diseases.


Contrasting effects of BCG on spleen and lymph node antibody responses in nude and normal mice. Subcutaneous footpad injection of BCG causes a marked augmentation of popliteal lymph node plaque-forming cell (PFC) responses to DNP-derivatized hemocyanin and to sheep red blood cells, both T-dependent antigens, but not to DNP-derivatized Ficoll, a T-independent antigen. This augmentative effect occurs in normal thymus-bearing heterozygous (nu/+) mice, but not in congenitally athymic nude mice (nu/nu). In contrast, intravenous injection of BCG causes a suppressed splenic PFC response to subsequently administered T-dependent or T-independent antigens in both nude and nu/+ mice. BCG's augmenting effect on the lymph node appears to be mediated by a T-helper cell. BCG's suppressive effect in the spleen is not attributable to T cells. The actual mechanism of the BCG-mediated suppressive splenic effect remains incompletely defined at present.


Abnormalities of cellular immune response in arthritis induced by rubella vaccination. The rubella-specific antibody, activity the levels of immunoglobulins and complement in the serum, the number of T cells, and the nature of cell-mediated immunity as measured by lymphocyte transformation (LTF) of circulating lymphocytes in response to rubella virus and phyto-hemagglutinin (PHA) were studied in 15 children who manifested arthralgia or arthritis after parenteral immunization with HPV-77 DE/5 or RA27/3 live attenuated rubella virus vaccines. Eighteen appropriately matched subjects who developed no post-vaccine complications were included as controls. The immunoglobulins, complement, and rubella antibody levels were similar in all subjects. Although significant rubella specific cell-mediated immunity was detectable in most control subjects, the activity was markedly depressed in subjects with arthritis. The LTF activity in response to PHA was approximately equal in both groups. These findings suggest a selective depression of cell-mediated immunity to rubella virus in subjects with arthritis associated with rubella vaccination.


Anatomical observations on the distal extremity of the vestibular aqueduct. A hitherto unobserved channel was observed, opening from the bony vestibular aqueduct under the dura. The location was in the centre between the contact of the aqueduct with the bulbar wall and the entrance of the aqueduct into the saccus. No connection was found between this formation and the vascular channels leading into the aqueduct or with the 'paravestibular canaliculus'. Albeit some of the examples were taken from Menière cases no interpretation in this direction was attempted. Strategical location claims further consideration as to morphology and function.


Induction and abrogation of unresponsiveness in nude mouse cells. Nude mice were injected with antigen and T cells at different times to induce unresponsiveness to SRBC. Spleen cells derived from these mice were tested in vitro for the capability to produce antibody-forming cells against sheep erythrocytes in the presence of a T-cell-replacing factor. It was found that priming with antigen alone did not result in paralysis but a later injection of thymus-derived lymphocytes together with antigen results in unresponsiveness of these cells in vitro, provided there was an interval of several days between the in vivo administration of thymus lymphocytes and the explantations of cells to in vitro cultures.


Cross-reactive lysis of trinitrophenyl (TNP)-derivatized H-2 incompatible target cells by cytolytic T lymphocytes generated against syngeneic TNP spleen cells. Normal spleen cells, when cultured with irradiated trinitrophenyl (TNP)-derivatized syngeneic spleen cells, develop cytotoxic effectors that lyse most effectiviely a TNP-derivatized target that is H-2 compatible with the effector. However, these effectors also lyse to a lesser extent TNP tumor and TNP spleen targets that are H-2 incompatible. This cross-reactive lysis correlates with the degree of cytolysis seen on the TNP-derivatized syngeneic target; it appears to be medicated by Thy 1.2-bearing cells and is inhibited by antisera to the K and/or D loci of the target cell and not by antisera to non-K or non-D surface antigens. Nonradiolabeled TNP-derivatized lymphoid cells syngeneic to either the stimulator or the target are able to competitively inhibit cross-reactive lysis, while TNP chicken red blood cells are unable to specifically inhibit lysis. These data on cross-reactive lysis of TNP-conjugated targets are most consistent with the altered-self hypothesis.


Spontaneous redistribution of surface immunoglobulin in the motile B lymphocyte. This paper reports that B cells undergoing translatory motion spontaneously segregate their surface Ig to one portion of their plasma membrane. The spontaneous redistribution of surface Ig was found to be: (a) selective, concanavalin A-dependent on translatory motion and energy metabolism. Abundant B cells undergoing motility were found after cultures in lipopolysaccharide or trypsin, or after brief exposure to cholinergic drugs.


Multiple H-2 linked immune response gene control of H-2 D-associated T-cell-mediated lympholysis to trinitrophenyl-modified autologous cells: Ir-like genes mapping to the left of I-A and within the I region. One of the more recent associations of the murine H-2 major histocompatibility complex (MHC) with immune function has been the finding that cytotoxic T-effector cells generated by sensitization with viral-infected (1-6), chemically modified (7-9), or weak transplantation antigen-associated (10,11) syngeneic cells can efficiently lyse target cells which express the same viral, chemical, or weak antigenic agent, and which share the H-2K and/or H-2D regions of the MHC with the responding and/or stimulating cells. Furthermore, an additional contribution of a gene(s) within the H-2 complex has been demonstrated which controls immune response potential (Ir genes) in the generation of cytotoxic effector cells to trinitrophenyl (TNP)-modified self components (12,13). In such studies it was found that certain B10 congenic strains generated good cytotoxic responses to both TNP- modified H-2K and H-2D region products, whereas other B10 congenic strains exhibited preferential or exclusive reactivity against TNP-modified H-2K region products. Some of these recombinant strains differing in response potential to TNP- modified H-2D products expressed the same haplotype at the D end, but differed at the K end of H-2. The low responsiveness observed in the B10.A strain to TNP-modified H-2D(d) when compared to B10.D2 and (B10.A x B10.D2)F(1) for the same specificity, suggested a role of dominant Ir genes which map in K, I-A, I-B, I-J, and/or I-E (12, 14). In the present report an attemnpt was made to further map within the MHC the Ir gene(s) controlling cell-mediated lympholysis (CML) to TNP-modified H-2D(d), by using recombinant mouse strains on the A and B10 backgrounds. Irrespective of the genetic background, the s and k haplotypes at the K end generated high and low cytotoxic responses, respectively, to H-2D(d)-TNP. The intermediate responder and low responder status of the A.TL and A.AL strains, respectively, indicated that a gene mapping in the K region of H-2 influences response potential. Furthermore, the differences in the levels of cytotoxicity detected in the A.TH and A.TL strains suggested an additional I region influence. Taken together these findings raise the possibility that multiple genes mapping within different regions of the MHC control the level of T-cell-mediated cytotoxicity to chemically modified autologous cells.


Cooperation across the histocompatibility barrier: H2d T cells primed to antigen in an H-2d environment can cooperate with H-2k B cells. H-2d spleen cells derived from either tetraparental or semiallogeneic radiation bone marrow chimeras can be primed to antigen within H-2d recipients to generate helper T cells capable of cooperating in a secondary response with equal efficiency with H-2d or H-2k B cells. Thus it would seem that the cooperative act between T and B cells does not require that the T cell interacts with its target B cells by either cell interaction genes or via an altered self mechanism involving both antigen and the target B-cell I-region products. This does not preclude a requirement for associative recognition or altered self in the interaction of helper T cells with accessory cells.


Daily variations in the effects of disturbance on growth, fattening, and metamorphosis in the bullfrog (Rana catesbeiana) tadpole. Bullfrog tadpoles subjected to the daily disturbance of water replacement demonstrated differences in the rates of growth and metamorphosis and in fatbody weights which depended on the time of day when water replacement occurred. Early daily disturbances stimulated larval growth whereas midday disturbances stimulated metamorphosis. The time when the daily disturbances caused fattening changed during metamorphosis so that younger tadpoles fattened when disturbed early in the photoperiod and older tadpoles fattened when disturbed at midday.


Thymus dependence of rabies vaccine.

Thymus dependence of rabies vaccine. Immune responses to rabies vaccine were compared with those to known thymus-dependent and thymus-independent antigens, in nude mice and their normal litter mates. No antibody response to, or protection against, challenge was observed in nude mice inoculated with either 1 or 2 doses of rabies vaccine. A single dose of the same vaccine induced a substantial antibody response and protected normal mice. These data indicate that the antigens in rabies vaccine that induce neutralizing antibody and protect mice are thymus-dependent.


Precision of reinnervation of original postsynaptic sites in frog muscle after a nerve crush. Regenerating neuromuscular junctions in the cutaneous pectoris muscle of the frog were examined by light and electron microscopy up to three months after crushing the motor nerve. The aim was to determine the precision of reinnervation of the original synaptic sites. More than 95% of the original postsynaptic membrane is recovered by nerve terminals and little, if any, synaptic contact is made on other portions of the muscle fibre surface. Even after prolonged denervation when the Schwann cells have retracted from 70-80% of the postsynaptic membrane, regenerating terminals return to and cover a large fraction of it. Although synapses are confined to the original synaptic sites, the pattern of innervation of muscle fibres is altered in several ways: (a) regenerating axon terminals can fail to branch leaving small stretches of postsynaptic membrane uncovered; (b) two terminal branches can lie side by side over a stretch of postsynaptic membrane normally occupied by one terminal; and (c) after growing along a stretch of postsynaptic membrane on one muscle fibre, terminals can leave it to end either in extracellular space or on the postsynaptic membrane of another fibre. Altogether the results demonstrate a strong and specific affinity between the original synaptic sites and regenerating nerve terminals.


Altered patterns of innervation in frog muscle after denervation. The pattern of reinnervation of muscle fibres after a nerve crush was examined in the cutaneous pectoris muscle of the frog by microscopy and electrophysiology. Normally, about 16% of the muscle fibres are innervated by more than one motor neuron. Two months after reinnervation, about 50% of the fibres are polyneuronally innervated and this high incidence persists for at least seven months. The total number of neurons reinnervating the muscle, as well as the number of muscle fibres comprising the muscle, are normal. However, nerve fibres sprout branches at the site of the crush, and, therefore, the number of axons entering the muscle is greater than normal. Regenerating axons contact muscle fibres precisely at the original synaptic sites and the terminal branches from different axons that end on the same muscle fibre often run side by side occupying stretches or original postsynaptic membrane normally covered by one terminal. Our findings indicate that the amount of synaptic contact during regeneration is limited by the amount of original postsynaptic membrane and that any number of axons that reach vacant portions of original postsynaptic membrane can make synaptic contact with it. Surprisingly, control cutaneous pectoris muscles, situated contralaterally to those that were denervated, also exhibited an abnormal pattern of innervation. Although neither nerve nor muscle was disturbed by the operation, there was a higher incidence of polyneuronal innervation (27% vs 16%) than in muscles of normal animals.


Intramembranous particle distribution at the node of Ranvier and adjacent axolemma in myelinated axons of the frog brain. The plasma membrane of myelinated axons in the frog brain has been examined by the freeze-fracture technique. The cytoplasmic leaflet of the axolemma contains numerous randomly distributed particles in nodal and internodal regions but relatively fewer particles in the axoglial junctional portion of the paranodal region. Particle distribution is even less uniform in the outer leaflet of the axolemma, which contains a low concentration of particles in the internodal region and a relatively high concentration at the node of Ranvier (approximately 1200 particles mum-2). The nodal particles tend to be larger than most intramembranous particles, approaching 200 A diameter. The paranodal region of the leaflet is virtually devoid of such particles except in the narrow helical 'groove' which faces extracellular clefts between terminating glial processes. In places this pathway widens to form 'lakes' up to approximately 0.3 mum2 area which contain large numbers of large particles resembling those at the node. The concentration of particles at the node is in the same range as the concentration of sodium channels estimated to be in this region and it is suggested on the basis of their location and concentration that these particles represent ionophores. The distribution of particles in the paranodal region suggests that the large intramembranous particles do not have free access to the axoglial junctional portion of the membrane and therefore the movement of such particles along the paranodal region of the membrane may occur primarily in the membrane of the 'groove' spiraling through this portion of the axolemma. Such a restriction in surface area for particle movements on either side of the node of Ranvier could result in trapping of particles at the node and thus contribute to their concentration in the nodal axolemma.


Nucleosides. 1. 9-(3'-Alkyl-3'-deoxy-beta-D-ribofuranosyl)adenines as lipophilic analogues of cordycepin. Synthesis and preliminary biological studies. A series of lipophilic 9-(3'-alkyl-3'-deoxy-beta-D-ribofuranosyl)adenines of increasing chain length was synthesized from the corresponding branched sugars via titanium chloride catalyzed ribosylation of chloromercuri-6-benzamidopurine. Enhanced growth inhibitory activity was observed against (CCRF-CEM human lymphoblastic leukemia cells in culture as the length of the alkyl side chain in the sugar and the resultant lipophilic character of the nucleoside were increased. Experiments involving incorporation of radiolabeled uridine, thymidine, and leucine revealed that in contrast to cordycepin (1) the 3'-n-butyl and 3'-n-hexyl analogues 5 and 6 markedly inhibit not only RNA synthesis but DNA and protein synthesis as well.


Influence of regenerative capacity and innervation on oncogenesis in the adult frog (Rana pipiens). Twenty-two sarcomas were induced in 19 adult frogs (Rana pipiens) treated with 3-methylcholanthrene pellets. Thirteen of these tumors arose first in a denervated forelimb, and only 2 arose first in normal or nerve-supplemented control forelimbs (P = 0.004). The remaining tumors developed either as a second tumor in a tumor-bearing frog or in hindlimbs. The critical role of innervation in regenerative capacity suggests that the predilection to tumor formation in the denervated limbs may have resulted from their lessened regenerative capacity.


Effects of thymectomy and antithymocyte serum on spontaneous regression of Friend virus-induced erythroleukemia. To evaluate the role of immune response in regression of leukemia, we studied the effect of immunosuppression on the spontaneous regression of a leukemia induced by a specific strain of Friend murine leukemia virus complex (RFV). Thymectomy of newborn but not adult outbred Swiss mice markedly inhibited regression. The effect of antithymocyte serum (ATS) on regression depended on the timing of ATS treatment. Regression was markedly inhibited in leukemic mice given ATS just before the start of regression. During leukemia development, ATS treatment but not thymectomy potentiated splenomegaly and delayed the start of regression. Both ATS treatment and neonatal thymectomy increased mortality as a function of the decrease in disease regression. Treatment with normal rabbit serum also inhibited regression but, when given during leukemia development, affected neither the splenomegalic response to RFV nor the number of deaths. The data demonstrated that an intact immune system was required for leukemia regression and suggested that some thymus-dependent parameter of immune response was a major factor in regression.


Suppressor factor secreted by T-lymphocytes from tumor-bearing mice. Spleen cells from C57BL mice bearing the syngeneic carcinoma 3LL enhanced tumor growth. Tumor growth was also enhanced by a soluble factor found in the media of cultured spleen cells from tumor-bearing animals. This factor suppressed a protective immune response of the host and was found to be a product of T-lymphocytes. Removal of B-lymphocytes and macrophages did not prevent its appearance in the culture media, whereas removal of T-lymphocytes inhibited its appearance. Similar suppressor factors were obtained from C3H mice bearing the 3LL tumor and from mice with other tumors. The suppressing factor produced after the growth of 3LL tumor also enhanced the growth of other tumors. It could act on strains incompatible with the donor of the factor-producing cells. Hence tumor growth was possibly facilitated by soluble products of T-lymphocytes that were found in spleens of tumor-bearing mice and that nonspecifically suppressed immune defense mechanisms.


Cytotoxicity responses to melanoma cells by human lymphoid cell subpopulations. Lymphoid cell subpopulations from normal donors and patients with malignant melanoma were assessed for cytotoxicity. Unfractionated mononuclear cells and T-cells from melanoma patients gave cell-mediated cytotoxic (CMC) responses to melanoma target cells but not to human fibroblasts. These specific CMC responses to melanoma cells were partially inhibited by autologous serum. Non-T-cells and nonrosetting cells from melanoma patients were not directly cytolytic for melanoma target cells; however these same subpopulations were cytotoxic in the presence of autologous serum, which indicated antibody-dependent cell cytotoxic responses. Non-T-cell subpopulations from normal donors were not cytotoxic when incubated with autologous serum. A third cytotoxic mechanism was demonstrated with complement (C3) receptor-activated lymphocytes. From both melanoma patients and normal donors, cells forming rosettes with erythrocyte-antibody-complement were nonspecifically cytotoxic for lung fibroblasts and melanoma target cells, These responses were independent of antibody, since melanoma serum presumably containing antibody to melanoma target cells neither enhanced nor blocked cytotoxicity mediated by C3 receptor-bearing lymphocytes. The results indicated that lymphoid cell subpopulations from the same melanoma patient could express at least three different lymphocyte-mediated cytotoxicity mechanisms against melanoma target cells.


The Fv-2r resistance gene in mice: its effect on spleen colony formation by Friend virus-transformed cells. To determine the mechanism by which the recessive Fv-2r gene confers complete resistance to spleen focus formation and to the induction of early splenomegaly characteristic of the Friend virus (FV) disease syndrome, we compared the parameters of FV infection in susceptible DBA/2 (D2) (Fv-1n, Fv-2s) and partially congenic D2.Fv-2r (Fv-1n, Fv-2r) mice. After infecting these mice with N-tropic FV complex, we followed the replication of spleen focus-forming virus (SFFV) and the generation of SFFV-transformed tumor colony-forming cells (CFC) in their spleens. By both parameters D2.Fv-2r mice were 20- to 100-fold less susceptible than DBA/2 controls, but the inhibition was only partial. Transplantation of washed spleen cells from SFFV-infected DBA/2 mice resulted in equal growth and recovery of tumor CFC from both D2.Fv-2r and Fv-2s mice. However, these tumor cells grew as colonies in Fv-2s mice, whereas they grew diffusely in the spleens of D2.Fv-2r hosts and did not develop into macroscopically or microscopically visible colonies. Thus the completeness of the resistance to spleen focus formation that defines the Fv-2r gene was reflected only in the complete suppression of the colonial growth of tumor cells, whereas the other parameters of infection showed no or only partial inhibition.


Evidence for rhythms of mitotic activity in normal and adenocarcinoma cells of the renal tubules of Rana pipiens. Kidneys were studied from 1,111 leopard frogs (Rana pipiens) after exposures to a 12-hour light-12-hour dark environment. Circadian mitotic rhythms were observed in cells of normal and spontaneous adenocarcinomatous proximal convoluted tubules from these animals. Student's t-tests verified the existence of two distinct cell populations, normal and adenocarcinomatous, in the proximal tubules. Both the mitotic variations and the t-test values were significant with P values of 0.05 or less. Mean mitotic values for the normal and spontaneous adenocarcinomatous proximal tubule epithelia were generally lower during the light-phase and higher during the dark-phase periods of the control day. The mitotic rhythm of the cancerous epithelium was almost always superimposable in outline over that of the normal epithelium during the same experimental period; i.e., the correspondence of phases of the normal and cancerous mitoses was almost identical in a single graph, although the amplitude of the cancerous mitoses was always higher. In addition to the reproducible circadian rhythms, the data demonstrated evidence for the existence of ultradian, as well as circannual rhythms.


An assessment of intratumor phagocytic and surface marker-bearing cells in a series of autochthonous and early passaged chemically induced murine sarcomas. Single cell suspensions from five different 3-methylcholanthrene-induced tumors in CBA mice were examined in the autochthonous host and sequentially for 5-11 passages. They were also examined for Fc receptor-bearing, phagocytic, theta antigen-positive, and surface immunoglobulin-bearing cells. The preparations contained a high proportion of phagocytic and marker-bearing cells both in the original host and during early passage. This proportion was consistent for any particular tumor and passage. Between different tumors, however, the proportions were sufficiently different to allow the tumor to be identified on this basis; this suggested that various chemically induced tumors may be unique in their tumor-host relationship as measured by the type of cells which infiltrate them. With on-going early passage of the tumors, the proportion of marker-bearing cells decreased to a constant level in most instances, mainly because of a reduction in the percentage of phagocytic cells. The tumor with the least macrophages (MBQA, less than 5%) consistently appeared more rapidly and killed the host more rapidly than did the tumor with the most macrophages (MBQD, 15-30%), but was not significantly different in its growth rate. The theta antigen- and Fc receptor-positive cells within these tumors were derived from the animal receiving the tumor inoculum, and thus represented host cell infiltration of the tumor. The results were discussed with reference to fundamental concepts of the immunology of chemically induced tumors and the importance of host cell infiltration within these tumors.


Dependency of sister chromatid exchange in T- and B-cells on the incorporation of deoxyribonucleosides into chromosomal DNA. Human T-cells (CCRF-HSB2) did not incorporate tritiated thymidine ([3H]TDR)--1.0-5.0 muCi/ml--into the nuclei, where.as they readily incorporated tritiated deoxycytidine (E13H]CDR). When contamination with pleuropneumonia-like organisms was ruled out, these findings strongly suggested a deficiency of the enzyme thymidine kinase in the cells. Human B-cells (CCRF-SB) and normal T-lymphocytes (NTL) readily incorporated [3H]CDR, [3H]TDR, and tritiated 5-bromodeoxyuridine, and they clearly exhibited differential staining of the sister chromatids (SCD). When nonisotopic bromodeoxyuridine (BUDR), 10(-6)-10(-4) M, was used with the B-cells and NTL, SCD were clearly evident and sister chromatid exchange (SCE) was relatively infrequent; when the concentration was 10(-7) M, SCD staining was poor but the frequency of SCE was high. SCE frequencies in NTL, measured by autoradiography after incorporation of [3H]CDR, were the same as SCE frequencies measured by staining with BUDR at 10(-4) M. In the case of CCRF-HSB2, 10(-4) M BUDR produced relatively high frequencies of SCE as did 10(-7) M BUDR with the former two cells. However, [3H]CDR with CCRF-HSB2 gave relatively low frequencies of SCE, of the magnitude observed after 10(-4) M BUDR was used with NTL and the B-cells. Thus the high frequency of SCE in CCRF-HSB2 cells may have been due to the staining property of chromosomes that had incorporated low levels of BUDR.


Evidence for splenic suppressor cells in C3H/He, T-cell-deprived C3H/He, and nude mice bearing a 3-methylcholanthrene-induced fibrosarcoma. Suppressor cells were demonstrated in the spleens of C3H/He mice carrying 3-methylcholantrene-induced fibrosarcomas. These cells inhibited the in vitro reactivity of normal lymphocytes to T- and B-cell mitogens. They disappeared within a few days after the tumor was surgically removed. Pretreatment of spleen cells (ScC) from tumor-bearing (TB) mice with either iron and a nagnet, antiserum against Thy 1.2 antigen plus complement, or antiserum against immunoglobulin plus complement demonstrated that the suppressor cells were adherent, non-T-cells bearing immunoglobulin at their surfaces. The suppressive effect could still be demonstrated by addition of SpC from TB mice 24 or 48 hours after phytohemagglutinin stimulation of normal SpC, SpC from TB C3H/He mice inhibited mitogen-induced stimulation of both C3H/He and DBA/2 lymphocytes. In T-cell-deprived TB C3H/He mice, suppressor cells were also observed and had the same characteristics as those in non-T-cell-deprived mice. In nude mice, however, although suppressor cells were active, they were not adherent and did not bear immunoglobulin at their surfaces. The existence of these suppressor cells may be one reason why the immune system of TB animals is unable to reject the tumor.


The effect of adrenaline on the K+ -activated hyperpolarization of the sympathetic ganglion cell membrane in bullfrogs. Effects of adrenaline on K+ -activated hyperpolarization of bullfrog sympathetic ganglion cells, preganglionic nerve axons and splanchnic nerve axons were studied. The K+ -activated hyperpolarization recorded from ganglion-postgangaline (0.3 mM). On the other hand, the K+ -activated hyperpolarization of postganglionic, preganglionic nerve axons and splanchnic nerve axons was not affected under the same experimental conditions. The facil-tatory effect of adrenaline on the K+ -activated hyperpolization was gradually intensified when the application of adrenaline was sustained for up to 60 min. The effect was reversible. The K+ -activated hyperpolarization recorded from ganglion cell-bodies by intracellular microelectrodes was similarly augmented by adrenaline (0.1 mM). Adrenaline in this concentration, however, caused no significant changes of the membrane potential and conductance in the presence of ouabain (0.002 mM) which completely and reversibly inhibited K+-activated hyperpolarization. Noradrenaline showed similar but less effected and isoproterenol showed no significant effect on the K+ -activated hyperpolarization. The facilitatory effect of adrenaline was inhibited in the presence of phentolamine but not of DCI. These results suggested that the intraganglionic membrane of ganglion cells possessed some kind of adrenergic alpha-receptors and the electrogenic Na+ pump of ganglion cells was accelerated by some unknown mechanism when adrenaline reacted to these receptors.


Effect of 1-(m-chlorophenyl)-3-N,N-dimethyl-carbamoyl-5-methoxypyrazole (PZ-177) on drug-metabolizing enzyme on rat liver. Effect of 1-(m-chlorphenyl)-3-N,N-dimethylcarbamoyl-5-methoxypyrazole (PZ-177) (62.5 and 250 mg/kg) on rat liver was investigated by measuring liver weight and drug-metabolizing enzyme activity. The effects of PZ-177 were compared with those of phenobarbital, phenylbutazone, and tiaramide hydrochloride. Increase of liver weight and liver/body weight ratio was observed in the rats treated with PZ-177 or phenobarbital, however, normal values were reverted to 1--2 weeks after treatment. PZ-177 similar to phenobarbital, significantly enhanced the activity of aminopyrine demethylase and aniline hydroxylase after 1,2, and 4 weeks of treatment. In contrast, tiaramide hydrochloride decreased the activity of aminopyrine demethylase and aniline hydroxylase after 1 week of treatment, and significantly enhanced the activity of these enzymes after 4 weeks. The content of cytochrome P-450 and the activity of NADPH cytochrome C reductase were also increased by treatment with PZ-177. The sleeping time by hexobarbital was shortened significantly by the administration of PZ-177. Vmax for both aminopyrine demethylase and aniline hydroxylase increased by treatment with PZ-177. However, only the Km for aniline hydroxylase was increased by treatment with PZ-177. From the results of these experiments, PZ-177 may be classified as a phenobarbital-type inducer.


[Pathology of exogenous mycotic endophthalmitis (author's transl)]. The histological examination of five bulbi with exogenous mycotic endophthalmitis reveals invasion of fungi confined to the anterior segment including the anterior vitreous body. Hyphae are found within abscesses, and granulomas respectively. The posterior eye remains relatively free, however a posterior vitreous detachment always exists together with a massive retraction of the vitreous gel. These findings should be kept in mind if intravitreal injections of amphotericin-B, or a vitrectomy are considered. After intravitreal injections of amphotericin-B no retinal lesions could be revealed.


[Observations on the pathogenesis of essential progressive iris atrophy with corneal dystrophy and secondary glaucoma (author's transl)]. A report is given of a case of a unilateral condition of this type in a 30-year-old woman, who was observed and repeatedly photographed for more as 7 years.


[Indications and limits of local tri-methacycline therapy in pyogenic infections of the eye (author's transl)]. In addition to the preoperative treatment of acute dacryocystitis local administration of tri-methacycline proved to be of benefit in cases of endophthalmitis consequent to injury. Its subconjunctival administration is the therapy of choice for serpentic ulcers of the cornea.


Immunospecific labeling of mouse lymphocytes in the scanning electron microscope. Bone marrow-derived (B) and thymus-derived (T) Balb/c mouse lymphocytes were identified in the scanning electron microscope (SEM) by the immunospecific attachment of one of several kinds of large-molecular-weight markers distinguishable in SEM. These markers (tobacco mosaic virus, keyhole limpet hemocyanin, bushy stunt virus, and bacteriophage T4) could be modified with hapten groups and linked with anti-hapten antibody, in an indirect (sandwich) scheme, to hapten-modified anti-cell-surface antibody bound to the cell surface. Hapten-modified antibodies to B cell antigens (goat anti-mouse-immunoglobulin) or to T cell antigens (rabbit anti-mouse brain) were employed to identify these two lymphoid cell types in unfractionated spleen, mesenteric lymph node, bone marrow, and thymus cell populations. The topography of B cells was always indistinguishable from that of T cells. No surface features were found to be unique to either cell type. In suspension, the majority of B and T cells had one or no microvilli regardless of the tissue source of the labeled cells. Cells in suspension that had microvilli (usually 10% of the total cell population) were always unlabeled. However, after cell contact with a glass surface, approximately half of both the B and T cell population had a villous topography.


Effect of p-nitrophenyl diazonium fluoroborate on cholinergic mechanisms. Electrophysiological experiments were done to investigate the effect o p-nitrophenyl diazonium fluoroborate (p-NPD) on motor endplates of the frog's m. cutaneus pectoris. The compound has no direct depolarizing effect on the postsynaptic membrane and stabilizes it irreversibly when added to the bath. Longtime iontophoretical applications of p-NPD produce a biphasic effect: initially a potentiation of the depolarizations due to acetylcholine (ACh) (both iontophoretically applied and presynaptically liberated), and subsequently an inhibition of the response to ACh. When the acetylcholinesterase (AChE) is inactivated previously, only the inhibiting effect of the compound is demonstrable. The association constant of p-NPD to purified AChE and to membrane fragments of electroplax was determined by biochemical methods. The compound's affinity to the AChE was found to be about 20 times greater than to the acetylcholine receptor (AChR). Iontophoretical application of p-NPD to cholinergic neurons in the hippocampal cortex of the cat also produced the characteristic biphasic effect on ACh-induced activity of these investigated neurons. The results suggest that the biphasic effect depends on the capacity of p-NPD to combine with both the AChE and the AChR. The AChE is first inhibited with low concentrations thereby potentiating the ACh response. At higher concentrations the AChR's are progressively inhibited too, thereby diminishing the excitability of the postsynaptic membrane up to a complete block.


Effect of atropine and oxotremorine on the release of acetylcholine from the frog spinal cord. The in vitro frog spinal cord has been used to study acetylcholine (ACh) release and spinal root potentials. The preparation bathed in an eserine-containing medium spontaneously released ACh into the bathing fluid. This release was enhanced by atropine in a dose-related and long-lasting manner and transiently by oxotremorine. The release rate of ACh was increased by low frequency ventral root stimulation; this increase was found to be proportionally the same after application of atropine. Oxotremorine did not modify the elctrically-evoked ACh release but blocked or reduced the effect of atropine. It is concluded that the stimulatory action of atropine on ACh output cannot be entirely explained by an interaction of atropine with presynaptic cholinergic receptors and that other indirect mechanisms (via interneurones) may play a role in this effect.


Changes in human  lymphocyte subpopulation in Hodgkin's lymphoma. An investigation of 33 patients with Hodgkin's lymphoma--both treated and untreated--has revealed lymphocytopenia and a significant decline in the absolute number of T lymphocytes labeled with rosettes with sheep erythrocytes to be due in these patients not to the tumorous disease itself, but probably to the intensive nature of the therapy. A marked decline in the absolute number of B lymphocyte subpopulation, determined by the formation of rosettes with mouse erythrocytes, occurs during a fresh relapse of patients with an active Hodgkin's lymphoma. This decline is probably independent of the preceding treatment, of the clinical stage of the disease and of its histological type.


T and B lymphocytes in malignant melanoma patients. The method of formation of spontaneous (E) and immune (EAC) rosettes and the test of lymphocyte survival in short-term cultures with phytohemagglutinin (PHA) have been used as parameters of cellular immunocompetence in 64 patients with malignant melanoma and 33 control donors. Significant changes have been found in the number of T lymphocytes whose values corresponded to the clinical stage as well as to the clinical postoperational course in the patients. A decreased number of T lymphocytes was a sign of progression of the disease, while a normal value indicated remission. Lowered ratios of T lymphocytes were followed by an increased proportion of both the B lymphocytes and the null, nonrosetting cell elements. The results in patients with malignant melanoma permit the relevant parameters to be considered as an effective in vitro correlate of cellular immunity of these patients.


[Dimer-X ventriculography (author's transl)]. After the first report on ventriculography with a water-soluble contrast medium, Conray, by Campbell et al., many authors reported complications such as convulsion which are attributable to the irritating effect of this agent. On the other hand its value has been appriciated. Recently Gonsette recommended a new water-soluble contrast medium, meglumine iocarnate (Dimer-X), for ventriculography and reported that this new agent is less epileptogenic and less harmful. Because of these advantages, they have been performing ventriculography routinely with Dimer-X and recognized its usefulness. The only noticeable complication has been the transient elevation of body temperature in almost a half of the series. As far as our experience goes there is no case of convulsive seizure as complication. As compared to gas ventriculography, the fine details of dimension and configuration of the ventricles are far more beautifully delineated with the water-soluble contrast media.


The excessively small ventricle on computed axial tomography of the brain. Computed axial tomography has made it possible to observe excessively small ventricles in a variety of disorders of the CNS. This finding is presumably due to non-specific and diffuse swelling of brain parenchyma, and is illustrated in cases of trauma, neoplasm, encephalitis, pseudotumor cerebri, metabolic disorder, and probable dilantin effect. It is likely that other causes will be encountered in the future.


The effect of L-5-hydroxytryptophan on self-mutilatin in Lesch-Nyhan disease: a negative report. Four patients with Lesch-Nyhan disease were treated with L-5-hydroxytryptophan, alone, or in combination with carbidopa, and their effect on self-mutilatory behavior was compared to that observed during periods in which placebo was administered. Observation periods were carefully standardized because of the ease with which patient-observer interactions can influence the behavior of the Lesch-Nyhan patient. The dosage level was sufficient to produce undesirable side-effects (diarrhea and vomiting). No effect on self-mutilation was observed under test conditions in the hospital or in the natural environment of the home. These results contrast with previous beneficial effects reported by others.


[Indications and contraindications for surgery in coronary insufficiency]. The indications to aortocoronary by-pass technique have during the last two years developed thanks to surgical, emodinamic and clinical exsperiences. The mortality of patients in whom surgery is limited electively to the intervention of aorto-coronary by-pass is at present around 4%. The principal indications to surgery are: a) existence of more than one coronary artery disease; b) a good diameter of the by-passing artery (more than 1 mm) corresponding to the site of the by-pass graft; c) a left ventricular telediastolic pressure lower than 20 mm of Hg; d) left ventricular function with ejection fraction not lesser than 0,40; e) absence of any associated severe and irreversible damages. The comparative data obtained recently from coronary patients medically and surgically treated would show at 4 years a survival rate higher than in those who underwent aorto-coronary by-pass.


Electrical stimulation in the relief of pain: a pilot study. A group of 26 patients who suffered from chronic pain resistant to other therapeutic measures, were given electrical stimulation in two forms. The first utilised penetrating acupuncture needles connected to a standard Chinese electrical impulse generator and the second method employed American transcutaneous stimulators with conducting skin electrodes. At long term follow-up 50 percent of patients treated exhibited sustained relief--20 percent when the device was used alone and a further 30 percent when it was combined with other forms of specific pain therapy. There was no difference in the response to needle acupuncture or transcutaneous stimulation. The best response was seen in patients with neuralgic disorders and painful musculo skeletal syndromes affecting the cervico thoracic region.


Hepatic cirrhosis, alcohol and haemorrhage. Fifty consecutive patients with cirrhosis of the liver were investigated, including 29 with gastrointestinal haemorrhage. Over two-thirds of these patients gave a history of heavy alcohol intake. The necessity for fibre-endoscopy is stressed in that barium studies alone showed oesophageal varices in only 40 percent of patients and erosive lesions were often present. Gastric varices, demonstrated by gastrophotography in 25 percent of patients with portal hypertension, were not readily detectable by standard barium meal or endoscopy. Radio-isotope scanning of the liver and spleen was invaluable in supporting not only the diagnosis of cirrhosis, but also the presence of portal hypertension, since the spleen was palpable in only 50 percent of such patients.


Histocompatibility antigens and immune responsiveness; their relevance to rheumatic diseases. Associations between histocompatibility antigens and human diseases have been found. Some of the highest correlations are with the so-called "rheumatoid variant" disorders. Data gained from ummunogenetic studies in laboratory animals has been invoked in speculation on the significance of the high antigen associations in disease pathogenesis. While much of this data better supports theories on the aetiology of other conditions with less significant antigen associations, it is discussed here with reference to the rheumatic diseases.


The etiology and drug therapy of kinesia: investigations by means of the coriolis effect under cyclizine. The typical symptoms of kinesia were produced in 30 healthy test subjects by means of the Coriolis effect and the effect of cyclizine upon them was investigated in a single blind trial. The drug showed a clear effect on the autonomic symptoms (nausea) while there was no evidence of inhibition of the peripheral vestibular function.


Galvanic vesitbular test.

Galvanic vesitbular test. Galvanic stimulation of the vestibular system provokes a nystagmus as well as a tendency to fall. The direction of these phenomena depends on the localization of the anode. In this study the value of the minimal current strength (threshold), which is able to provoke nystagmus with a constant frequency during at least 30 sec was determined. Also the effects of the lesions in the vestibular system on these threshold values were measured. The method of bipolar-biaruricular stimulation showed to be the most sensitive one. A striking difference was found in the thresholds in rabbits with a vestibular organ with a lesion on that side. In that case the threshold for a nystagmus directed to the side with the intact ear was at its lowest. The conclusion is drawn that the galvanic vestibular test is suitable for the detection of the localization of a vestibular lesion in patients, especially when this lesion is located in the peripheral vestibular organ.


[Cochleovestibular disorders after diving accidents]. Cochleo-vestibular lesions may result from decompression accidents and barotrauma. The etiology of both clinical syndromes as well as their therapy is discussed on the basis of seven personal observations.


[Pendular and rotatory vestibular habituation]. The present investigations demonstrate in animals (rabbits) the existence of a habituation to the vestibular pendular stimulation comparable to the rotatory habituation by constant angular acceleration. There is no mutual transfer, however, between the two habituations. This confirms that the two modes of stimulation are not equivalent. All the tests have been made by ENG recording in total darkness.


[Optokinetic nystagmus studied through otoneurologic methods]. The horizontal optokinetic nystagmus (NOC) has been studied during 5,000 otoneurological investigations. In 16.25% of all our cases, the NOC was found to be either weakened in both directions, or only in one direction. There has been no constant relationship between intensity of the spontaneous nystagmus and NOC asymmetry in case of peripheral vestibular lesion. NOC asymmetry seems to be a reliable sign of the evolution of a lesion. Cases without peripheral hypofunction have been divided into three groups: ocular disturbances, brain stem lesions and hemispherical lesions. In these cases the value of the localization of the asymmetry in NOC and nystagmus induced by vestibular tests has been studied. In hemisperical lesions, when asymmetry affected exclusively the NOC, the direction of the weakened NOC was always towards  the healthy side. When asymmetry affected not only NOC but even nystagmus induced by vestibular stimulations, this weakened side of the nystagmus was less significant.


Upper gastrointestinal hemorrhage clinical, radiological and endoscopic correlation of 100 consecutive cases. One hundred consecutive cases of upper gastrointestinal hemorrhage were studied clinically, radiologically and endoscopically. Erosive gastritis, duodenal and gastric ulcer, and bleeding esophageal varices accounted for 85% of the cases. The presenting sign of hematamesis or melena was of no value in localizing the bleeding site relative to the pyloric sphincter. Erosive lesions of the esophagus and stomach were suspected clinically in less than 50% of the cases and were the lesions least amenable to radiologic diagnosis and where early endoscopy was most useful. Our observations demonstrate again the frequent association between ethanol or aspirin ingestion and erosive gastritis.


Nystagmic modulation of neuronal activity in rabbit cerebellar flocculus. 1. The responses of neuronal elements in the flocculus of the awake, restrained rabbit were recorded during horizontal vestibular nystagmus in the dark. 2. Purkinje cells showed both vestibular (Types I and II) and eye movement modulation of simple spike activity. Type I Purkinje cells most commonly were inhibited in association with the ipsilaterally directed fast phase of nystagmus and excited during contralaterally directed fast phases. Type II Purkinje cells had a similar modulation but in the opposite direction. Variations on this pattern included an increase in firing during fast phases in both directions. 3. Presumed mossy fibers and granule cells also exhibited both vestibular and nystagmic modulation in various combinations. The nystagmic modulation often began during the fast phase and continued into the early part of the slow phase. Mossy fibers showing both vestibular and nystagmic modulation probably arise from the vestibular nuclei and/or the perihypoglossal nuclei. 4. Floccular control of brain stem nuclei utilizes not only vestibular but also eye movement signals and probably all sensory and internal signals involved in the regulation of gaze.


Block of potassium channels of the nodal membrane by 4-aminopyridine and its partial removal on depolarization. 1. Voltage clamp experiments were done on single myelinated nerve fibres of the frog, Rana esculenta. 2. 53 muM 4-aminopyridine (4-AP) reduced IK to about one-fifth if tested with infrequent (1/min) and short (10 ms) depolarizing pulses; the onset time constant under these circumstances was ca. 160 s (14-15 degrees C). After prolonged treatment the effect was virtually irreversible. 3. At equilibrium with 4-AP, increasing the frequency of short pulses removed part of the block, the block removal accelerating with increasing pulse duration and frequency. 4. In 53 muM 4-AP unblocking of K channels during long (0.8 s) depolarizing pulses proceeded with a time constant, taur, of ca. 0.2 s. Restoration of block at the resting potential proceeded with a much larger time constant, tau'r, of ca. 1 min. 5. The stationary fraction, rinfinity, of K channels conducting in 53 muM 4-AP was 0.66, 0.41, and 0.24 at V = 120, 50, and 0 mV, respectively. 6. In a series of experiments with [4-AP] varying between 13.3 and 848 muM, taur decreased from 0.25 to 0.10 s (V = 130 mV, ca. 17 degrees C) while rinfinity followed the empirical relation 1/rinfinity = 1 + ct + cv exp(-0.77 EF/RT) with E = V - 70 mV. ct and cv are dimensionless quantities that increase with [4-AP] and reflect the voltage-independent and voltage-dependent component, respectively, of block. 7. Block of K channels and partial removal are also observed with inward IK at raised [K+]O. Removal proceeds on depolarization even if IK is additionally but temporarily suppressed by tetraethylammonium. Hence neither direction nor amplitude of IK but only the pulse potential seems to determine the extent of block for a given [4-AP].


In vitro colony growth of acute myelogenous leukemia. Colony formation in vitro by marrow cells from patients with untreated acute myelogenous leukemia (AML) and from patients in AML relapse is infrequent using the standard Robinson assay. A newly developed culture system has been described in which marrow from AML patients in these disease stages form leukemic cell colonies. In this in vitro system, phytohaemagglutinin is the essential stimulator for colony formation. The leukemic origin of the colonies has been proven by ultrastructural morphology and cytogenetics. It appears that colony formation by leukemic cells in this system is predominantly independent from the leukocyte factor which is the main stimulator in the Robinson assay for growing colonies of marrow cells from haematologically normal individuals.


Oncogenesis in human acute leukemia.

Oncogenesis in human acute leukemia. By selecting, for discussion, some aspects of oncogenesis in human acute leukemia, we hope to focus attention on areas of current interest which promise to provide important advances in our knowledge and understanding of human neoplasia, and, in time, may lead us nearer to the goal of disease control and eventual eradication.


Iodination as a probe for small regions of disrupted secondary structure in double-stranded DNAs. Conditions were established where the thallium-catalyzed iodination of random coil DNA proceeded 100-200 times faster than for native DNA. This reaction was explored as a probe for localized regions of disrupted base pairs in duplex DNA. A heteroduplex was constructed between DNA fragments produced by Hind II + III cleavage of phi80 plac DNA and phi80 plac DNA containing the Ll deletion (73 nucleotides in length). This heteroduplex incorporated twelve times as much iodine as the parent homoduplex fragments. Hence the technique could reveal the presence of a few (two or more) nonpaired cytosines, if they existed within an otherwise helical DNA fragment 789 base pairs long. Iodination studies were performed on superhelical SV40 DNA and on linear lambdaplac DNA. Analysis of the relative amount of iodine in restriction endonuclease fragments of these DNA's revealed the absence of localized single-stranded regions.


[Hemorrhages of the digestive tract. Diagnosis and treatment using selective arteriography and perfusion of intra-arterial vasopressin]. Diagnosis of GI bleeding can safely be done by selective angiography of abdominal vessels. Patients are studied during acute bleeding phase with the Seldinger-Odman technique. In our experience we have a success rate of 89.4% in cases of arterial bleeding. Once diagnosis has been made, the selective catheter can be used to perform an infusion of a vasoconstrictive drug or selective embolization to treat the bleeding. This technique gives good results in case of arterial bleeding and is only a paliative method in case of esophageal varices.


Regulation of the induction of colonies in vitro by normal human lymphocytes. Lymphocytes isolated from normal human peripheral blood can be induced to form colonies in vitro by incubation with the appropriate inducer. Phytohemagglutinin can induce colonies with T (thymus-derived) lymphocytes. Optimun colony formation with about two colonies per 10(2) peripheral blood lymphocytes was obtained by adding, in addition to phytohemagglutinin, autologous plasma, autoologous red blood cells, and fresh L-glutamine or L-cystine. In the absence of these fresh amino acids, no colonies were formed at seeding levels below 10(5) cells per 35 mm petri dish. The addition of either of these amino acids gave a 10-fold decrease in the minimum number of cells that had to be seeded for colony formation. Lipopolysaccharide did not induce the formation of colonies, but enhanced the formation of T cell colonies by phytohemagglutinin. The mixing of lymphocytes from persons with and deficient in glucose-6-phosphate-dehydrogenase (EC 1-1-1-49) has shown that phytohemagglutinin-induced colonies can be derived from single cells and are, therefore, clones. No colonies were formed by lethally irradiated cells. Incubation with pokeweed mitogen also induced the formation of colonies. With autologous plasma and autologous red blood cells, pokeweek mitogen induced about one colony per 5 X 10(3) cells seeded and no colonies at seeding levels below 10(5) cells per petri dish. The minimum number of cells needed for colony formation by pokeweed mitogen was not decreased by fresh L-glutamine or L-cystine. The results indicate that normal human lymphocytes can be cloned in vitro and that induction of these lymphocyte colonies can be regulated by lectins and other specific factors.


[Immunoblastic lymphadenopathy and toxacariasis. Report of a case]. This is a report of a case a larval granulomatosis associated with immunoblastic lymphadenopathy, corroborated by laboratory and histologic studies compatible with that. The etiopathogenesis, clinical picture and diagnosis of both diseases are commented, and the possible relationship between them is stressed.


The concept of prevalence applied to psychiatric disorders and symptoms. Statements about prevalence, of the type 'x% of the general population are mentally ill', imply a concept of prevalence that is difficult to define operationally. It requires the specification of a cut-off point, a level of severity from which the presence of an illness can be inferred, and this is largely arbitrary. A more generally useful type of statement compares the frequency distribution of severity for declared cases with that for the rest of the population. This avoids the need for a defined cut-off point. We are still left with the problem of defining a dimension of severity and a declared case, but these should follow easily from a clear statement of the purpose of any specific inquiry. The argument is illustrated from the results of a study of self-referrals to general practitioners.


A study of the factors influencing mortality rates from gastrointestinal haemorrhage. A prospective study is reported of 300 consecutive patients admitted to the General Hospital, Birmingham, because of acute gastrointestinal haemorrhage. The characteristics of the group have been outlined and the causes of death examined. It is shown that in patients diagnosed as having peptic ulcer or erosions, the major causes of death were thrombotic vascular disease and surgical complications. Current policies in the management of gastrointestinal bleeding are examined in this light, and it is concluded that gastric resection should be avoided wherever possible, and that procedures should be considered which might reduce intravascular clotting. The advisability of immediate surgery is also questioned and a case made for consideration of a policy of more prolonged resuscitation. A detailed analysis of mortality rates is included from reported European series, with particular reference to the increasing proportion of older patients. Taking this into consideration, it is argued that mortality rates are continuing to improve, and that early diagnosis must be an important contributory factor. It is also pointed out that not only are nearly half the patients in present studies over the age of sixty, but also the risk of developing such a haemorrhage is much greater in the older sections of the community. Gastrointestinal bleeding is more of a geriatric than an adolescent problem.


Hodgkin's disease: a war between T-lymphocytes and transformed macrophages? The interaction between Reed-Sternberg (RS) cells and autogeneic T T cells was investigated. It was found that T cells cytolyse RS cells in the following sequential manner: Stage 1, T cells affix the tips of their microvilli onto target cells, Stage 2, T cells subject cell membranes to tearing, and shearing forces which produce gaps and holes; Stage 3, target cells lyse and T cells "crawl" away. The relationship between the events occurring at the cellular level and those observed clinically are discussed. Hodgkin's disease holds a fascination for clinicians and "bench" scientists alike, perhaps because of the enigma and challenge it represents. It is not surprising, therefore, that many questions go unanswered. For example, we are still addressing ourselves to the following questions: What is the origin of the Reed-Sternberg (RS) cell? If a macrophage, then why do T cells attach to it and what is the nature of the T cell-RS interaction? Why is cellular immunity so often impaired even in patients in the early stages of the disease? Why do patients with Hodgkin's disease sometimes develop autoimmune hemolytic anemia when they are, in fact, immunologically hyporesponsive? In this paper, I shall present evidence which answers a few of these questions and provides hypothetical answers to the others.


The significance of the macrophage content of human tumours. The effective localization of an immunogenic rat sarcoma (HSBPA) is related to its macrophage content. In order to infiltrate this tumous with macrophages, T-cell function is important. In a tumour of low immunogenicity, MC3, with a low macrophage content, thymectomy has little effect on the ease with which such a tumour metastasizes. The monocytes in the peripheral blood of a rat myeloid leukaemia are of host origin and are significantly raised during the growth of the leukaemia. Similar monocytoid cells are found in human acute myelogenous leukaemias and appear to be important in the prognostic features of this type of leukaemia. The origin of these monocytoid cells has not been elucidated. In 56 solid human tumours the macrophage content of metastatic tumours is low (less than 10%) whereas the range in primary or locally recurrent tumours is 0-30%. It is too early to say whether the low macrophage infiltrated primary will readily metastasize compared to the high macrophage containing tumour.


Increase in "Null" cells in acute lymphocytic leukemia in remission on long-term immunotherapy. In an attempt to elucidate a possible mode of action of immunotherapy in ALL, we studied the mononuclear subpopulation in a group of patients with all in remission on long-term immunotherapy, a similar group on chemotherapy, and a group of normal individuals. Comparison of the three groups demonstrated a significant increase in the number and percentage of "null" cells in the immunotherapy group relative to the two others. Although the nature of these cells is unknown, circulating stem cells, "K" cells, or modified T, B, or monocytic cells are raised.


Revised seminology of the different mononuclear cells under scanning electron microscopy. Scanning electron microscopy shows that the thymus cell surface is not smooth but slightly undulated; this type of surface characteristic is found on the cells of several types of T-lymphocyte tumors such as T-cell lymphosarcoma, mycosis fungoides, and T-immunoblastic lymphosarcoma. The cell surface of Frabricius' bursa is covered with numerous short villi. They are found on the cells of several kinds of B-lymphocyte tumors, including B-cell chronic lymphoid leukemia, B-prolymphocytic lymphosarcoma, and B-immunoblastic lymphosarcoma. Mycosis fungoides cells frequently have a characteristic shape. Normal and myeloma plasma cells are similar in shape but their surface is covered with numberous characteristic tiny balls. Immunoblasts are twice the size of so-called small lymphocytes. In the blood and in the lymphocyte population transformed by mitogens, cell surfaces vary from completely smooth (with no undulations as in thymic cells) to villous, with short to very long villi. These variations are visible even when a constant technique and the critical-point drying method are used. Their significance, however, is not known.


Integrated EMG feedback in the management of spasmodic torticollis and focal dystonia: a prospective study of 80 patients. In summary, then, without consideration of specific circuits or transmitter agents, one can conceive of a hypothetical model that involves both learning and the functional nature of the defect in torticollis and focal dystonia to describe the results obtained. The model must be further elaborated upon and tested, preferably in a quantitative manner. Naturally, the specific finding of a defective transmitter agent (e.g., GABA) such as described in parkinsonian syndrome (dopamine) or the interruption of a specific pathway that causes and improves a dyskinesia is desirable. In this chapter we have described the use of integrated EMG feedback for the treatment of focal dystonia or spasmodic torticollis. Although we have achieved significant results, it remains clear that further research in the treatment of these disorders is required. However, since this treatment does not require medication or surgery and the possibility for significant improvement is greater than 40%, it should be attempted in patients with focal dystonia or torticollis prior to other forms of therapy. SFT should be considered as a standard mode in the medical armamentarium used for the treatment of these disorders, either primarily or in conjunction with other forms of medical, surgical, and physical therapy.


Simultaneous determination of arsenic, copper, manganese, selenium, and zinc in biological materials by neutron activation analysis. A method for the simultaneous determination of arsenic, copper, manganese, selenium, and zinc in biological material was developed by the incorporation of separation procedures for copper and zinc into an existing procedure. Investigation of the performance characteristics of the method was carried out with reference to copper and zinc. For certain materials characterized by a high Cu/Zn ratio, or a high zinc content, or both, such as liver, copper interferes in the determination of zinc thus requiring a small correction by an iterative procedure. Blank values for copper depend on the rinsing of the irradiation container, and a single rinsing with redistilled water was found superior to other rinsing procedures. Nuclear interference was negligible. The accuracy of the method was checked by analysis of Standard Reference Materials and the precision verified by analysis of Intercomparison Samples. Results are presented for 5 male foetuses of 3-5 months' gestational age. The distribution of arsenic, manganese and selenium is similar to that previously reported for adults. With the exception of liver, concentrations of copper in foetal organs were lower than values in the literature indicate.


Biologic and analytic components of variation of concentration values of selected serum proteins. The magnitude and statistical significance of the various biologic and analytic sources of variation of the serum concentration values of seven proteins: albumin, alpha1-antitrypsin, transferrin, orosomucoid, IgG, IgM, and IgA, were evaluated in 12 healthy subjects. Blood specimens were obtained at 0800 h, 1100 h, and 1400 h on one particular day. The analytic error was partitioned into pre-instrumental and instrumental components; the biologic variation was separated into inter-subject variation of mean levels and intra-individual within-day variation. The mean levels of the subjects differed significantly for all seven proteins studied. For the group as a whole there were no consistent diurnal variations of significance. However, for all the proteins, except for IgM, significant individual within-day biologic fluctuations were noted. The within-day biologic variation was smaller than the total analytic variation for transferrin, IgG, orosomucoid, and IgM. When the total analytic variation was separated into pre-instrumental and instrumental components, it was found that the pre-instrumental sources of variation were of a relatively greater magnitude for albumin, IgG, IgA, alpha1-antitrypsin, and IgM.


Interaction between normal and leukaemic human cells in agar culture. The influence of leukaemic cells from 12 patients with acute leukaemia on normal granulopoiesis in agar culture was investigated using leukeamic cell feeder layers. Leukaemic feeder cells from 7 of the 12 patients elicited no colony growth, while cells from the remaining 5 stimulated normal colony growth. In 3 of the 7 non-stimulatory patients release of inhibitory factors from the leukaemic cells seemed responsible for the effect on normal granulopoiesis, while inappropriate colony stimulating factor (CSF) production by the feeder cells could not be ruled out in the remaining 4 patients. When the leukaemic cells were cultured with, as well as without, conditioned medium, cells from 5 of the patients formed clusters. Growth in these cultures did not correlate to the effect found in the feeder layer experiments.


The effect of syngeneic peripheral blood cells on the formation of colonies by normal human bone marrow cells in diffusion chambers in mice. This paper describes the influence of cells capable of releasing colony stimulating activity (CSA) in vitro on the formation of granulocytic colonies by normal human bone marrow in diffusion chambers in mice. A carbonyl iron method was used to remove phagocytic cells from normal human bone marrow. This treatment prevented spontaneous colony and cluster formation when the cells were cultured in agar in vitro at initial concentrations of 2-5 x 105 cells per ml. However, non-phagocytic bone marrow cells formed granulocytic colonies when inoculated into diffusion chambers at 105 cells per chamber and cultured in 450 R-irradiated or non-irradiated mice. The formation of granulocytic colonies by carbonyl iron treated marrow in diffusion chamber cultures was not consistently enhanced by the admixture of 1.4 x 105 1500 R-irradiated syngeneic light density blood cells (less than 1.077 g/ml) to the chamber inoculum. In contrast, these cells induced cluster or colony formation when added in the same proportion to the marrow cells in agar cultures in vitro. Addition of 1.4 x 105 1500 R-irradiated high density blood cells(greater than 1.077 g/ml) to the inoculum resulted in a slight, non-significant decrease in the number of colonies in diffusion chambers. The stimulating effect of host irradiation on neutrophilic colony formation was independent of the presence of CSA releasing cells in the chamber inoculum.


Changes in the surface of virus-infected cells recognized by cytotoxic T cells. II. A requirement for glycoprotein synthesis in virus-infected target cells. Infection of cells with either ectromelia or lymphocytic choriomeningitis (LCM) virus in the presence of 2-deoxy-D-glucose (2-DOG) inhibited by up to 70% the extent to which the infected cells become susceptible to virus-specific cell-mediated lysis. The concentration of 2-DOG used had little effect on the extent of total protein synthesis (incorporation of [35S] methionine) but inhibited (up to 25%) glycoprotein synthesis, as measured by incorporation of [3H] fucose. This suggested that glycoprotein synthesis was a necessary event for infected cells to become susceptible to T-cell mediated lysis. The profiles (polyacrylamide gel electrophoresis) of newly synthesized, cellular glycoproteins from unifected and ectromelia-infected cells in the presence and absence of 2-DOG were compared and found to be very complex, with only minor changes. However, when convalescent serum from infected mice was used to isolate newly synthesized components from the cell surface shortly after infection, it showed four main species ranging in size from 25,000 to 70,000 daltons. 2-DOG inhibited production of these by 70%, thus corresponding to the biological data. The nature of the new glycoproteins seen in infected cells and whether they are in fact the structures recognized by effector T cells remain to be determined.


[Demonstration and analysis of immune complexes in rheumatic diseases]. By means of an immunofluorescence technique, immune complexes have been demonstrated in circulating blood leukocytes, in serum and in joint effusions of patients with various rheumatic diseases. Such complexes are present within cell inclusions in about 30% of patients with rheumatoid arthritis (RA). RA patients has immune complexes in serum in 75% of cases and in joint effusions in over 80% of cases. Soluble immune complexes were demonstrated in the serum of about 30% of age-matched patients with degenerative joint disease, while such complexes are present in the serum of only 1.5% of a younger, normal control group. The immune complexes chiefly contain IgG, frequently IgM and only rarely IgA. CO complement component can frequently be demonstrated within such complexes. In RA patients a statistically significant correlation (p less than 0.001) could be established between the presence of soluble immune complexes and erythrocyte sedimentation rate, but no correlation was observed between the presence of such complexes and the Lansbury joint index. The possible pathogenetic role of immune complex clearance by circulating leukocytes in rheumatoid arthritis is discussed.


[Therapy of inflammatory-rheumatic diseases with levamisol, an immunity modulating substance]. Since cellular and humoral immune mechanisms were shown to be involved in the pathogenesis of rheumatic diseases, efforts have been made to influence these systems therapeutically. Aside from suppression of the immune response, studies have been conducted to evaluate to what extent immunostimulation might be of value in the treatment of rheumatic diseases. Levamisole, chemically a simple synthetic agent recently shown to have immunorestorative capacities in anergic cancer patients, has been administered in several rheumatic diseases. The drug was administered either continuously or intermittently in a daily dose of 150 mg over several months. In about half of the rheumatoid arthritis patients a significant improvement was noted. Beneficial effects and sometimes even dramatic improvement lere observed in some patients with systemic lupus erythematosus, ankylosing spondylitis and Reiter's syndrome. Levamisole did not alter the course of psoriatic arthritis. Significant adverse reactions were leukopenia and allergic skin reactions. Other side effects were mild and did not require interruption of drug intake. The use of levamisole in rheumatic diseases is still experimental, but with accumulating experience it may provide a true improvement in control of rheumatic diseases.


Essential role of macrophages in chronic inflammatory processes. It is clear that the macrophage plays a central role in the mediation of chronic inflammatory processes. The discussion below only alludes to certain of the mediators secreted by macrophages which contribute to chronic inflammation, and the reader is referred to other sources for further discussion of these and others. The combined activities of these products may account in large part for the effects of macrophages on its pericellular environment and neighboring cells during chronic inflammation.


In vitro stimulation of lymphocytes by neutral proteinases from human polymorphonuclear leukocyte granules. Two neutral proteinases, polymorphonuclear leukocyte (PMN) elastase and cathepsin G, were purified from azurophil granules of human PMN. Both enzymes were found to stimulate both human and mouse lymphocytes in vitro. Experiments with mouse cells showed that the PMN proteinases are B-cell stimulants. Stimulation appears to depend on direct proteolytic action on the lymphocyte surface and not to require the mediation of serum factors of the help of T-cells.


Anti--DNA antibodies in patients with leukemia and lymphoma. 217 sera from 33 patients with acute myeloid leukemia (AML), 42 with chronic myeloid leukemia (CML), 12 with acute lymphatic leukemia (ALL), 22 with lymphoma, and 20 with other malignant diseases were examined by a radioimmunological technique for the presence of antibodies against DNA. The levels of single-stranded DNA binding activity was significantly higher in all 3 types of leukemia and lymphoma compared to those of healthy controls. In contrast, none of these sera exhibited a positive reaction with double-stranded DNA. In some cases of leukemia, the level of serum anti-DNA antibodies increased after the decrease of the leukocytes count.


[Spontaneous hemobilia in the differential diagnosis of upper gastrointestinal hemorrhages]. Hemobilia, biliary tree hemorrhage, is characterized by melana and/or haematemesis, biliary colic and clinical jaundice. The rare cause of gastrointestinal bleeding probably accounts for quite a large percentage of gastrointestinal hemorrhages of undetermined source. In the evaluation of gastrointestinal bleeding the hepato-biliary system is seldom examined unless trauma has occurred. However, 10-15% of cases with hemobilia are non-traumatic. Three cases are presented illustrating three different causes of non-traumatic hemobilia observed during the last three years. The diagnostic problems and the therapeutic possibilities are described.


[Psychsomatic aspects of rheumatic, especially soft tissue rheumatic diseases]. Rheumatic diseases may be connected to varying degrees with psychic factors. On the one hand, rheumatic diseases may produce psychic reactions, while on the other hand rheumatic symptoms--especially in extra-articular rheumatism--may be induced by psychosomatic hysteric pararheumatic diseases and depressive mechanisms. Special reference is made to psychosomatically induced extra-articular rheumatic diseases in which not only the complex genesis but also the clinical symptomatology are discussed. During therapy more attention should be directed to psychic factors than in the past, as only an intensive psycho and/or psychopharmacotherapy can influence the disease.


The prevalence of anaemia and iron deficiency in the Indian community in Natal. A prevalence study of iron deficiency and anaemia was done among the Indian population of metropolitan Durban. In all, 2500 subjects were studied. This survey confirms previous impressions of a high incidence of anaemia and iron deficiency. Iron deficiency was observed in 33% of females and 20% of males. Anaemia was observed in 38,1% of females and 44,3% of males. A high incidence of anaemia was also found in children under 10 years of age-28,6% for females and 41,6% for males.


Computed tomography in the diagnosis of colloid cyst. The diagnosis of colloid cyst of the third ventricle is notoriously difficult and contributes significantly to the high mortality. Three cases are presented in which computed tomography has contributed to the diagnosis by showing (1) the dilatation of the lateral ventricles without dilatation of the midline ventricular system, and (2) the lesion as an area of increased density within the third ventricle. Computed tomography may reduce the overall mortality in this condition by reducing the number of patients who succumb undiagnosed during an acute phase of raised intracranial pressure.


Amyloidoma of the gasserian ganglion.

Amyloidoma of the gasserian ganglion. A case report, the third in the literature, is presented of a patient whose progressive numbness in the second and third divisions of the trigeminal nerve led to the discovery of an isolated amyloidoma of the gasserian ganglion. The clinical impression of tumor was confirmed by surgical and pathologic findings.


Simultaneous subdural effusion and hydrocephalus in infancy. Hydrocephalus and subdural hematoma or effusion of infancy rarely present simultaneously, where both are active contributors to acutely increased intracranial pressure. In three cases, clinical findings characteristic of both were present. Decompression of one can facilitate expansion of the other. Rapid progression of unsuspected hydrocephalus could be responsible for some of the poor results reported after treatment of subdural effusion alone. This possibility should be considered whenever progress is unsatisfactory during treatment of subdural effusion.


Endarterectomy of the left anterior descending and mainstem coronary arteries: a technique for reconstruction of inoperable arteries. The proximal left anterior descending coronary artery (PLAD) is an area of predilection for such severe and diffuse calcific arteriosclerosis that reconstruction of these vessels often is impossible. The branches of this segment include the septal perforators, median artery, the left anterior descending coronary artery, and its first and second diagonal branches. Successful endarterectomy, therefore, would revascularize large areas of the left ventricle and interventricular septum. We have performed 45 such operations during the past 13 months. Following endarterectomy there are several methods of reconstructing the endarterectomized vessel, the preferable technique being the addition of a saphenous vein bypass to the endarterectomized segment. Patients selected for this operation were mostly in the fair (58%) and poor risk (42%) categories; there were no good risk patients. Diffuse arterial disease was the rule. The average ejection fraction was 0.48. The operation was successful with respect to graft patency, bypass flow rates, and symptomatic relief. The operative mortality rate in the entire group was 15%, including the 19 poor risk patients in six of whom elective preoperative use of an antra-aortic balloon pump was required. Most of the surviving patients (92%) were either symptom free or greatly improved. Only two patients were clinically unchanged. There was one late sudden death. This operation is indicated when there is extensive involvement of the life main, the proximal left anterior descending coronary artery and its major branches. It is the only possible way to revascularize otherwise inoperable arteries.


Family studies of patients with reduced ristocetin aggregation and abnormalities of factor VIII and/or platelet function. Factor VIII procoagulant activity (VIIIc), antigen (vWa), mobility of the antigen on two dimensional immunoelectrophoresis and platelet function were studied in 9 families with reduced ristocetin induced platelet aggregation rate (RIPA) and/or deficiency of plasma factor(s) required for ristocetin aggregation of washed normal platelets (vWf). the families could be subdivided into 4 groups. Group I showed dominant inheritance and reduced levels of VIIIc and vWa characteristic of typical von Willebrand's disease. All patients had reduced vWf and in 7 of 10 RIPA was reduced. Group II showed normal levels of VIIIc but reduced vWa. All showed reduced vWf but RIPA was reduced in one patient only. There was a good correlation between vWf and vWa and VIIIc in both groups. The bleeding time correlated with vWf in group I but not group II. Group III showed normal or nearly normal VIIIc and vWa but there was an increased mobility of vWa compared to normals and to groups I and II. RIPA was markedly reduced as was the vWf in one patient. Group IV is represented by one child with a strong family history of bleeding, who had reduced RIPA and defective platelet release reaction. The vWf in this child was normal and the ratio between VIIIc and vWa was similar to that seen in carriers of haemophilia. This spectrum of abnormalities of ristocetin aggregation justifies the use of the term 'von Willebrand's syndrome'.


Release, aggregation and lysis of human platelets by antilymphocyte globulin and antiplatelet serum. Human platelets labeled with 51Cr were used to determine the contribution made by platelet lysis to the platelet release reaction and platelet aggregation induced by rabbit antihuman platelet serum (APS) and equine antihuman thymocyte globulin (ATG). Platelets were tested in both plasma (PRP) and non-plasma containing media. Antibodies directed against platelets, either as APS or ATG, induced significant amounts of platelet release and aggregation, as well as some degree of lysis, in the absence of complement. The presence of complement increased platelet lysis and aggregation, but not the release reaction. Non-immune horse gamma globulin produced different responses depending upon whether platelets were investigated in PRP or non-plasma containing media. Aggregation was seen in the latter but not the former. These differences can be explained by the presence of plasma components which prevent non-specific immune complexes from causing platelet aggregation. Since platelets in vivo are always in a plasma medium, one must be wary of utilizing data from platelet studies in synthetic plasma-free media as the basis of explaining clinical events. These observations demonstrate at least two, and possibly three, different mechanisms whereby ATG could activate platelets causing thrombotic complications and thrombocytopenia, i.e., via 1) specific and, 2) non-specific non-lytic pathways and 3) a lytic pathway.


[Bronchoplasty in tumor surgery (author's transl)]. A series of 80 bronchial resections and other broncho-plasties is presented; 60 operations were performed on the right side, while only 20 on the left side. The most frequent variation was the "sleeve lobectomy" (upper lobe with main bronchus). The attention is called to other possibilities so as: the reinplantation of the middle lobe after removal of the lower lobe and the intermede bronchus, the anastomosis between the left main bronchus and the upper lobe bronchus when the dividsion of the main bronchus must be removed together with the lower lobe, the repair of the continuity on the right side by means of a double anastomosis etc. Lethal postoperative complications occurred in 7 cases; 29 patients died in consequence of recidives or metastases and 44 are alive (22 more than 3 years, 8 more than 5 years). These procedures may significantly enlarge the resectability of the cancer in old patients and in those with limited respiratory reserve.