Activity of serum alpha-amylases in cystic fibrosis. A new method which uses a differential inhibitor to measure pancreatic and salivary type alpha-amylases (EC 3.2.1.1) was applied to serum samples from 46 cystic fibrosis (CF) patients (age range 4-14 years) and 50 controls of the same age group. The levels of pancreatic type amylase were lower in the CF patients (median 26.5 I.U./1) than the controls (median 81.5) (P less than 0.001). The results for salivary-type enzyme, however, did not support the previously reported finding of higher than usual levels in CF patients. This discrepancy is probably due to differences in analytical methods. It is felt that this procedure will be of value in the investigation of patients for cystic fibrosis and other pancreatic disorders.


The role of the host immune response in the development of tissue lesions associated with African trypanosomiasis in mice. A variety of tissue lesions occurs in African trypanosomiasis, in the pathogenesis of which direct toxic effects of the parasite as well as immunological mechanisms may be involved. The purpose of the present study was to evaluate the role of the host immune response in inducing tissue damage in this disease and particularly in the production of lesions in striated muscle. The development of muscle lesions in T. brucei infection was studied in several groups of mice with different forms of immunodeficiency, as well as in normal mice. In the normal mice, foci of intense inflammation and necrosis were found in the cardiac and skeletal muscles 2 weeks or more after infection. In these lesions, there was a heavy deposition of IgG and IgM, and of trypanosomal antigens. In irradiated, newborn mice, and athymic nude mice infected with T. brucei, these inflammatory lesions were not found, although large numbers of trypanosomes were present between the muscle fibres. The characteristic lesions could be induced in athymic nude mice by transfer of normal spleen cells or of normal T lymphocytes 1 week after the onset of infection. The lesions were also partly induced by transfer of antibody to T. brucei. No antibodies to tissue components, particularly to cardiac myofibrils, were found in any of the infected mice. The results of this study show that immunodeficiency suppresses the development of the characteristic muscle lesions of African trypanosomiasis. The relative importance of humoral and cellular immune mechanisms in the pathogenesis of these lesions is not year clear.


T- and B-lymphocyte subpopulations following radiotherapy for invasive squamous cell carcinoma of the uterine cervix. Lymphocyte subpopulations in patients with cervical carcinoma were studied before and after radiotherapy. T lymphocytes were recognized by their ability to form spontaneous rosettes with sheep erythrocytes (E rosettes). Two surface marker characteristics were used to detect B lymphocytes: receptors for activated complement responsible for erythrocyte--antibody--complement (EAC) rosette formation, and surface membrane immunoglobulin (SmIg), readily stainable by immunofluorescence. We have demonstrated a significant depression of total lymphocytes after radiotherapy which persists for more than 5 years. This reduction in lymphocytes is due to a loss of E rosette-forming T cells, SmIg-bearing B cells and null cells. Absolute numbers of EAC rosette-forming B cells are not altered by treatment, and there is a rise in this cell type when the results are expressed as percentages of the total lymphocyte count. The possible functional immunological significance of these changes is discussed.


Neurodiagnostic studies and the management of head injury. The rational management of patients with head injury calls for the closest cooperation between the radiologist and neurosurgeon. Until the last three to four years, cerebral angiography had been considered the diagnostic procedure of choice for the management of patients with suspected traumatically induced intracranial mass lesions. Experience with CT scanning now indicates that for a number of reasons this procedure is to be preferred in the diagnosis of head injuries. It is more rapid than angiography, routinely visualizes the entire brain, is noninvasive, resolves lesions that are much smaller than any visualized by angiography and defines the density and thus the nature of traumatic lesions in a manner not possible with previously employed techniques. Using CT scanning in a sequential fashion we have routinely been able to visualize the appearance of new lesions in the post-traumatic period and have as well, been able to develop insights into the temporal appearance and disappearance of white matter edema as measured by Hounsfield numbers. In the late post-traumatic period, it has been valuable in defining hydrocephalus, porencephaly and other post-traumatic lesions that have a significant bearing on both therapy and prognosis.


Third factor and edema formation.

Third factor and edema formation. Urine extracts as well as plasma and urine fractions from normal persons during extracellular volume expansion and from patients with edema of different origin were tested for natriuretic (rat bioassay) and antinatriferetic (frog skin) activity. Whereas the extracts and fractions from normal persons with extracellular volume expansion proved to have a distinct natriuretic and antinatriferetic effect, no such effect was observed with urine and plasma preparations from patients with sodium retention and edema. Whether or not edema formation is mediated by a loss of natriuretic activity remains still to be clarified.


[Positive effects of L-dopa on a "marginal" symptomatology observed in parkinsonians]. In some patients with parkinsonism, we have found and, often, cured by L-DOPA: 1) An unfrequent symptomatology (oculomotor, sensory, syncinesias, "Babinski" sign), not included in the classic rating scales. 2) A symptomatology "attributable to frontal lesion": grasping; inability to reproduce a serie of three gestures; inability to react to an audio-visual stimulus by a definited opposite gesture. In such patients, the improvement is in total contrast with the lack of effect of L-DOPA in several patients with frontal lesions, but without parkinsonism. It is possible that the last constatation may contribute: a) to localize more exactly the topography of dopaminergic pathways, b) to approach the respective parts of the cortical and subcortical structures in the programming of the movement.


Effect of thiocyanate and other univalent anions on the binding of thyroxine to rat liver nuclei and homogenate. The binding of thyroxine (125I-T4) in rat liver homogenate and isolated nuclei was investigated in vitro. In homogenate, the binding of T4 was modified by thiocyanate ion (SCN-) added to the incubation mixture as potassium thiocyanate. The displacing effect of SCN- increased with increasing concentrations of this compound, the lowest effective dose being that which significantly displaced T4 from liver homogenate (105 pmol per one ml medium). Moreover, SCN- significantly increased the displacing effect of unlabelled T4. In contrast, however, no effect of SCN- was found on the binding of T4 in the isolated liver nuclei. In sonicated nuclei no effect of SCN- on T4 binding was found, but specific binding of T4 under these circumstances was impaired. Finally, in a homogenate a displacing effect of other univalent anions (BF4-, ClO4- and MnO4-) was found resembling that of SCN-. It is suggested that, in the liver homogenate, SCN- displaces T4 from non-specific binding sites. This view is also supported by the fact that in liver nuclei, where specific binding sites prevail, no effect of SCN- was observed.


Participation of hypothalamus in the response of interrenal tissue to stress of frog Rana ridibunda. Frogs of species Rana ridibunda were divided into 6 groups: 1. control; 2. sham operated; 3. with transsection (TS) in front of the median eminence; 4. with TS under optic chiasm; 5. with TS in front of the optic chiasm; 6. hypophysectomized. On the experimental day a half of the animals of each group was stressed by restraint and the level of plasma corticosterone was measured. The results show that TS in front of the median eminence, under optic chiasm and in front of the optic chiasm increased the resting levels of corticosterone in plasma. The most intense response to stress was observed in frogs with TS in front of the median eminence and optic chiasm, while that after TS under optic chiasm was less. Hypophysectomized frogs responded to stress by increase of corticosterone level in plasma.


Increased sensitivity of bone to parathyroid hormone in castrated mice. The inhibitory effect of endogenous testosterone on parathormone induced bone changes in mice was studied with the aid of the analysis of calcium and protein content in femur and of plasma calcium and alkaline phosphatase. It was found that the absence of endogenous testosterone for seven days after castration resulted in a decrease in the bone protein and calcium content and in plasma alkaline phosphatase as compared to controls. In parathormone treated castrated mice the protein content of the femur and plasma alkaline phosphatase were raised to control values, but the decrease in the calcium content of the femur was further potentiated. Finally, the administration of parathormone to intact male mice caused only a depletion in calcium content of the femur. It may be concluded that the response of bone to parathormone is enhanced in the absence of endogenous testosterone. In view of this finding one of the possible explanations may be that endogenous testosterone protects the bone by the inhibition of its sensitivity to parathormone.


Induction of B lymphocyte colony growth in vitro by thymus-derived stimulating factor. Murine lymphoid cells which were stimulated in liquid culture containing thymus culture fluid (Thy-CF) and seeded in a soft agar culture system, proliferated and developed into B cell colonies. Two types of colonies were formed: large colonies within the upper layer and small flat colonies on the surface of the upper layer. Thy-CF prepared from cells of normal hydrocortisone-treated mice had a higher cloning potential than Thy-CF prepared from untreated mice. At concentrations of Thy-CF in culture medium greater than 35%, Thy-CF prepared from normal mice had an inhibitory effect on colony formation. Cells of nude mice were also able to form B cell colonies if thymocytes of normal mice were mixed with lymphoid cells in the culture medium. Thymocytes elaborate a B lymphocyte colony-stimulating factor which, with the help of T cells, triggers a B cell population into colony formation and immunoglobulin production.


Influenza virus-specific cytotoxic T cells in man; induction and properties of the cytotoxic cell. Human peripheral blood lymphocytes have been sensitized in vitro to influenza virus antigen. After an induction period of 4--14 days, cytotoxic cells which lyse autologous influenza virus-infected lymphoid cells could be demonstrated. The cytotoxic cell is a T lymphocyte which shows specificity for sensitizing influenza virus type A or B. It cannot distinguish between major subtypes of influenza A virus. The use of virus-infected normal lymphoid cells as target cells overcame the difficulties of nonspecific killing encountered with some transformed cells.


Requirement for matching T cell and B cell subsets in secondary anti-hapten antibody responses. The in vitro secondary anti-hapten response to trinitrophenylated keyhole limpet hemocyanin (TNP-KLH) has been investigated using B and T cells from the same or a pool of identically primed syngeneic individuals. The optimum antibody response obtained from B cells of any given animal was seen when the same individual's T cells were used as a helper cell source. This individual preference was lost if secondary challenge in culture was made with TNP on a heterologous carrier, with the helper cells obtained from suitably primed individuals or a pool thereof. These data are interpreted in terms of a network theory for the regulation of immune responses under physiological conditions.


Stimulation of specific suppressor T cells in newborn responder mice by the terpolymer L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). The effects of immunization with the terpolymer of L-glutamic acid60-L-alanine40-L-tyrosine10 (GAT), the copolymers of L-glutamic acid60-L-alanine40 (GA) and of L-glutamic acid50-L-tyrosine50 (GT), were compared in adult and newborn BALB/c and BALB.B mice. as expected, BALB/c (H-2d) and BALB.B (H-2b) adult mice were responders to GAT and GA and nonresponders to GT, which induced suppressor T cells in BALB/c but not in BALB.B mice. in contrast, newborn mice expressed different phenotypes. Two-week-old mice developed responses to GAT, GA and GT-complexed methylated bovine serum albumin, but immunization at birth with these copolymers induced a cross-reactive tolerance in both strains. Neonatal GAT tolerance could be transferred in adult and involved suppressor T cells in the two inbred strains, whereas the GT-specific immune suppression was not demonstrable in newborn BALB/c mice. The significance of these data to our understanding of the regulation of specific immune response and tolerance is discussed.


Studies on induction and control of cell-mediated autoimmunity. I. Induction of "autoreactive" T lymphocytes in mice by cyclophosphamide. Injection of a single dose of cyclophosphamide (CY) (125 mg/kg) or a combination of a small dose of CY (20 mg/kg) and 2.5 mg/kg lipopolysaccharide induces a transient appearance of autoreactive T lymphocytes (T-ARC) in the spleens of mice. The T-ARC activity reaches a peak 6 days after CY injection and could not be detected 8 days after this treatment. For testing T-ARC activity, spleen cells were injected into the footpads of syngeneic recipients, and the resulting lymph node enlargement at the draining site of cell inoculation and the content of nucleated cells in the lymph node was determined. Possible explanations of this autoimmune phenomenon are discussed. It is postulated that CY-resistant precursors of T-ARC are stimulated by "new" antigenic sites present on the surface of B lymphoblasts repopulating the CY-damaged spleen in a period of transient absence of CY-sensitive suppressor cells.


Studies on induction and control of cell-mediated autoimmunity. II. Prevention of induction and activity of autoreactive T cells by suppressor cells and by a suppressive serum factor. Autoreactive T lymphocytes (T-ARC) can be detected in the spleen of mice treated with a single dose of cyclophosphamide (CY) (125 mg/kg), a peak occurring 6 days after CY injection. Eight days after CY treatment, the mice develop a specific anergic state. This anergic state can be transferred to normal syngeneic animals by either splenic nylon wool-nonadherent lymphocytes (suppressor cells, S-ARC) or by the serum of anergic mice, implying the development of an active suppressive mechanism due to CY treatment. Precursors of both potentially T-ARC as well as S-ARC coexist in the spleen of normal animals. Precursors of S-ARC present in the spleen and in the thymus of normal animals are sensitive to CY. However, committed S-ARC obtained from anergic mice are resistant to CY. Committed S-ARC as well as their precursors prevent induction of T-ARC. Committed S-ARC counteract expression of committed T-ARC activity, whereas precursors of S-ARC fail to do so. The autoimmune phenomenon described here represents an in vivo animal model system for induction of T-ARC and for the control mechanism which normally prevents induction and/or expression of cell-mediated autoreactivity by specific suppressor cells and by suppressive factors.


Loss of reactivity of a BALB/c myeoloma tumor with allogeneic and syngeneic cytotoxic T lymphocytes. It was previously observed that MOPC-315EL, a subline of the BALB/c myeloma tumor MOPC-315, varies in its ability to interact with primary anti-H-2d cytotoxic thymus-derived lymphocytes (CTL) while remaining invariant in its expression of cell surface antigens recognized by anti-H-2d sera. This paper demonstrates (a) that secondary anti-H-2d CTL also fail to recognize the late tumor cells, and (b) that two other CTL systems (anti-minor histocompatibility antigens and anti-2,4,6-trinitrophenyl), which require recognition of both H-2 products and other surface antigens, also fail to react with the late tumor cells. The defect in the late tumor cells was evident when they were used as targets, inhibitors, and stimulators of CTL activity.


Role of membrane receptors in the induction of an in vitro secondary anti-hapten response. I. differentiation of B memory cells to plasma cells is independent of antigen-immunoglobulin receptor interaction. In these experiments, we show that the interaction of antigen and B cell surface immunoglobulin is not essential for the generation of an IgG in vitro response to the hapten p-azophenyl-lactoside (lac). In our experimental system, keyhole limpet hemocyanin (KLH) was first selectively attached either to H-2, Ia or Ig receptors of lac-primed B cells by a hapten sandwich technique or to Fc receptors by complexes of azophenyl arsonate (ars)-coupled KLH and anti-ars. The labeled cells were then cultured with KLH-specific T cells for 5 days in the absence of antigen. Under all conditions of attachment we observed a significant anti-lac IgG response. We have demonstrated an absolute requirement for KLH-specific helper T cells. The results thus indicate that T helper cells are by themselves, regardless of the B cell antigen that serves to effect bridging, sufficient to activate B memory cells. We could find no evidence to support either a matrix theory or a two-signal hypothesis as currently proposed.


Role of membrane receptors in the induction of an in vitro secondary anti-hapten response. II. Antigen-immunoglobulin receptor interaction is not required for B memory cell proliferation. In this study it has been investigated whether the interaction of antigen and B cell surface immunoglobulin (sIg) is required for full clonal expansion of memory B cells specific for the hapten, p-azophenyl-lactoside (lac). Cultures of lac-primed B cells and keyhole limpet hemocyanin (KLH)-specific T cells were activated in three ways: (a) by the antigen lac-KLH, (b) in the absence of lac epitopes by attaching KLH to the H-2 antigens of the B cells, and (c) in similar conditions where lac epitopes were supplied on carriers unrecognized by helper T cells. Dilution analyses showed that the yield of IgG anti-lac plaques per activated precursor was identical in all situations, and that the increased responses observed in the presence of lac epitopes were due to an increase in the frequency of activated precursors. Our results thus indicate that specific interacting T cells convey both the differentiative and proliferative signals to B memory cells, and are at variance with proposals advocating that an antigen-induced proliferative phase is succeeded by a T-cell-dependent differentiative event. We suggest that the effect of sIg-antigen interaction may be to cycle some precursors into a more easily activated state.


Canine granulopoiesis: alterations induced by suppression of gram-negative flora. We investigated alterations in canine granulopoiesis following suppression of bacterial flora by antibiotic treatment. Beagles were decontaminated in sterile isolation with laminar air flow, by an antifungal and antibiotic regimen. Skin and fecal specimen cultures were usually negative after 4 days. The reduction of gram-negative bacteria resulted in a significant decrease in plasma colony-stimulating factor (CSF) levels, marrow CFU-c concentration, and the cytopoietic activity of marrow-derived diffusion chamber (DC) progenitor cells. The period of conventionalization was characterized by a significant although delayed increase in plasma CSF as well as marked increases in marrow CFU-c concentration and cytopoietic activity of marrow DC progenitors. There was also mobilization of marrow DC progenitors into the circulation. All parameters returned to control values within 7 days of conventionalization. These data supported the hypothesis that the gram-negative bacteria of the gut play a significant role in the regulation of normal canine granulopoiesis.


Differential effects of red cells on the formation of normal and neoplastic mouse B lymphocyte colonies in vitro. Intact sheep red cells potentiated mouse B lymphocyte colony growth in agar but red cell membranes or lysates exhibited no comparable ability. For maximum colony formation red cells had to be present throughout the entire culture period. Red cells added to cultures late in the culture period did not potentiate growth. Intimate contact between colony-forming cells and red cells was not essential for potentiation to occur. Red cell lysates inhibited normal B lymphocyte colony formation in cultures containing intact red cells, but did not inhibit colony formation by cells of the B lymphoid leukemia ABE-8. This differential effect may provide a means of differentiating normal from neoplastic colony-forming B lymphocytes in the mouse. Eight different tumors were also examined. Intact red cells potentiated colony formation by all of them. Lysed red cells did not potentiate the growth of any of the tumor lines. The mastocytoma P815 was the only tumor whose colony formation was inhibited by the addition of intact and lysed red cells.


Regulation of enzyme secretion by mononuclear phagocytes: studies with macrophage plasminogen activator and lysozyme. Lysozyme and plasminogen activator (PA) are independently regulated secretion products of the macrophage. Lysozyme is released constitutively by all types of macrophage, whereas PA is induced during macrophage activation by nonspecific stimuli or by an immunologically specific pathway under control of sensitized T lymphocytes and antigen. Production of PA is closely related to the ability of the macrophage to proliferate in the presence of colony stimulating factor (CSF). Production of lysozyme is often extinguished after hybridization of macrophages with other cells, but may persist and serve as a useful marker for expression of the differentiated macrophage phenotype in somatic cell hybrids.


Serotonin metabolism in patients with carcinoid tumors: incidence of 5-hydroxytryptophan-secreting tumors. The urinary excretion of 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, serotonin, tryptamine, and tyramine and the serum serotonin concentration were determined in 38 consecutive patients with metastatic carcinoid tumors. Four of the 23 patients with the carcinoid syndrome (15%) had markedly elevated excretion of 5-hydroxytryptophan. None of the patients had markedly elevated excretion of tryptamine or tyramine; a substantial number of patients had moderately low urinary excretion of these amines. All of the patients with the carcinoid syndrome had elevated urinary 5-hydroxyindoleacetic acid excretion; 2 of these patients had normal serum serotonin concentrations, suggesting that quantitative 5-hydroxyindoleacetic acid excretion is the most reliable test for the carcinoid syndrome. Although tryptamine secretion by carcinoid tumors is rare, 5-hydroxytryptophan secretion may be more common than is recognized.


Vitamin D dependence of in vivo calcium transport and mucosal calcium binding protein in rat large intestine. Dependence of large intestinal calcium transport on vitamin D has been examined in vitro in colon only. The authors studied calcium fluxes in cecum and colon in vivo by perfusion with 1.6 mM calcium chloride in saline. Tracer 45Ca either was injected parenterally 24 hr before study or was added to the perfusates. For 8--10 wk after weaning, rats had been fed a rachitogenic diet; 48 and 24 hr before study, 50% of the animals were treated with 20,000 IU vitamin E2. In a separate set of animals, mucosal calcium binding protein was analyzed by the Chelex assay method. In comparison with vitamin D-deficient rats, the colon of vitamin D-treated rats showed higher lumen-to-plasma flux and lower plasma-to-lumen flux and net absorption instead of net secretion. In cecum, calcium transport was not significantly altered by vitamin D treatment. Mucosal calcium binding protein was higher in cecum than in colon in both groups and was higher in vitamin-D-treated than in vitamin D-deficient animals in both segments. The current study shows that in the rat colon calcium fluxes both into and out of the lumen as well as net transport are significantly by vitamin D treatment, but that cecal transport rates are not affected. In both cecum and colon, mucosal calcium binding protein increases with vitamin D treatment.


[Pathomechanisms, signs, symptoms and management of amniotic fluid embolism (author's transl)]. The rare, acute and dramatic event of amniotic fluid embolism is increasing in relative importance as a cause of maternal mortality. Recent findings based on the estimation and characterization of circulating fibrin, fibrinogen content and fibrin-fibrinogen degradation products indicate that the coagulation disorder is caused by intravascular coagulation and extensive fibrinolysis and fibrinogenolysis. The program of treatment consists of: 1. Management of the acute respiratory insufficiency syndrome by early intubation and ventilation with positive end-expiratory pressure (PEEP). 2. Intensive therapy of shock and rapid restoration of blood volume with blood transfusion (fresh whole blood) and infusion of other fluids. 3. Treatment of the coagulation disorder with fibrinogen, antifibrinolytic agents (aprotinin--Trasylol), platelet transfusion and fresh frozen plasma.


Lymphocyte subpopulations in adult coeliac disease. Rosetting techniques were used to estimate T and B cell subpopulations in the peripheral blood in patients with treated and untreated adult coeliac disease and in control subjects. In patients with untreated coeliac disease, T cell numbers were significantly lower than in controls or treated patients, although there was no difference in total lymphocyte counts. There was no significant difference in B cell numbers between treated and untreated patients, and the subpopulation which increased to replace the T cells in untreated patients comprised cells not identified by B or T cell markers. Total lymphocyte counts and lymphocyte subpopulations were affected by splenic atrophy. It is suggested that these effects might be caused by the loss of lymphocytes from the gastrointestinal tract in untreated coeliac disease.


Selective transplenic decompression of oesophageal varices by distal splenorenal and splenocaval shunt. The usefulness of selective transplenic decompression of oesophageal varices by distal splenorenal shunt and splenocaval shunt was evaluated in the control of gastrointestinal haemorrhage in patients with portal hypertension of varied aetiology. (Decompression was successful in 69 out of 78 cases.) It was shown that it is superior to total portosystemic shunts, as the incidence of encephalopathy was very low compared with the data from our series of portocaval shunts. The operative mortality has been progressively lowered and has now reached levels comparable with portocaval shunt. Distal splenorenal shunt when performed as an emergency procedure to arrest bleeding has limited usefulness but when performed as an elective or prophylactic procedure its results are comparable with those of portocaval shunt without the untoward complications such as encephalopathy. A modified selective decompression of varices has been described in which the distal end of the splenic vein is anastomosed to the inferior vena cava. Though no long term follow-up studies are available, we believe that this shunt is likely to prove superior to distal splenorenal shunt as it has both the advantages of the distal splenoral and the haemodynamic advantage of end-to-side portocaval shunt. We conclude that in patients with portal hypertension of varied aetiology, who have not had a haemorrhagic episode but in whom varices have been demonstrated or who have had one episode of haemorrhage from varices, the splenocaval shunt when feasible or the distal splenorenal shunt offers the optimal method of management at present in India.


[Analgetic and antipyretic activity of SL-573 (author's transl)]. Potency of analgetic activity of SL-573 was between that of indomethacin and aminopyrine in chemical stimulation tests. The analgetic activity of SL-573 was 3.2 times as potent as that of aminopyrine in the phenylquinone writhing test, 4.1 times as potent as aminopyrine in the acetic acid writhing test and 6.3 times as potent as aminopyrine in the Randall and Selitto test. Thus the analgetic activity of SL-573 appears to be comparable etic to that of codeine. SL-573, unlike narcotic analgesics, showed common properties to known antipyretic analgesics and anti-inflammatory agents in the following points. (1) Analgetic activity was not evident in the mechanical stimulation or in the heat stimulation tests. (2) The analgetic activity was not antagonized by naloxone. (3) SL-573 showed no antagonistic effect to morphine. (4) Tolerance to the analgetic activity of SL-573 was not observed after a one week pretreatment with this compound. (5) SL-573 had no effect on the evoked potentials recorded from cells in the pain pathway of CNS and the site of action of analgetic effect was considered to be in peripheral sites of the sensory neurons. The antipyretic activity of SL-573 was equal to that of aminopyrine in febrile rabbits and 4 times as potent as that of aminopyrine in febrile rats. This compound did not affect normal body temperature of rabbits and rats, this observation being similar to that noted with antipyretic analgesics and nonsteroidal anti-inflammatory agents.


[Calcifying coronary sclerosis. Incidence and clinical importance of radiographically visible coronary sclerosis in the light of new study methods]. Since introduction of the new image intensifier generation coronary calcification has become a common finding during fluoroscopy. Nearly one quarter of all patients over 40 years have calcified coronary vessels, men twice as often as women. More than two thirds of all these patients have coronary heart disease. Patients with coronary calcification suffer more often than those without from risk diseases of atherosclerosis, especially of coronary heart disease. The calcification means in most cases a lumen reduction of the vessel and is predominantly located in the left coronary artery. Other uncalcified stenoses exist very often, i.e. multiple vessel disease is a very common finding in these patients. The x-ray sign confirms the diagnosis "coronary heart disease" if there are other suspicious findings but it has not rarely its own value in comparison with other non-invasive examination methods in the diagnosis of coronary heart disease.


The immunopathology of myasthenia gravis. Experimental autoimmune myasthenia gravis, induced by immunization with solubilized acetylcholine receptors, has proven an excellent animal model for the study of myasthenia gravis. The role of the thymus in myasthenia gravis is not yet known. Its content of skeletal muscle elements and acetylcholine receptors and the presence of germinal centers in myasthenia gravis suggest that the thymus could be a site of autoimmunization. An effector role has not been demonstrated for T cells in the pathogenesis of experimental autoimmune or clinical myasthenia gravis, but helper T cells participate in the rat's autoantibody response to acetylcholine receptors. Antibodies and lymphocytes reactive with acetylcholine receptors are demonstrable in the peripheral blood of patients with myasthenia gravis and appear to be specific for this disease. Parallel studies of both experimental autoimmune and clinical myasthenia gravis have provided evidence for an autoimmune basis for the pathophysiology in myasthenia gravis. Antiacetylcholine receptor antibodies appear to play a central role in impairing neuromuscular transmission. Numerous antibody specificities have been described, but none seems to be directed at the acetylcholine binding site of the receptor. Addition of antiacetylcholine receptor antibodies to cultured muscle cells, in the absence of complement, causes redistribution of the receptors on the membranes of myotubes, accelerated receptor degradation, apparent impairment of ionophore function, and loss of sensitivity to acetylcholine. In vivo complement appears to be an important mediator of antiacetylcholine receptor antibody pathogenicity. Its presence is essential for the passive transfer of experimental autoimmune myasthenia gravis with antibodies. In muscle biopsy specimens from patients with myasthenia gravis, IgG and C3 have been demonstrated on the postsynaptic membrane and on degenerated fragments of membrane in the synaptic cleft. This suggests that complement activation in vivo is associated with focal lysis of the postsynaptic membrane. A causal relationship appears to exist between the binding of antibody to acetylcholine receptors, the reduction in muscle acetylcholine receptors, and impairment of neuromuscular transmission.


Evidence for the involvement of corticosterone in the ontogeny of the cellular immune apparatus of the mouse. The effects of corticosterone deprivation in the cellular immune system of the mouse have been studied. Adrenalectomy was performed from three weeks after birth; at an earlier age oral administration of aminoglutethimide phosphate (AGP) had to be used. Three effects could be recognized: (1) Adrenalectomy or AGP treatment, at any age studied, resulted in an enhanced delayed hypersensitivity (DH) to sheep red blood cells (SRBC). This effect has previously been ascribed to monocytes. (2) An altered T lymphocyte distribution was observed as consequence of early adrenalectomy or continuous AGP administration. The lymph nodes were depleted whereas the thymus was increased in size and blood-leucocytes increased in number. This effect appeared reversible on restoration of adrenal function. (3) Irreversible damage to the cellular immune system following early AGP intake was observed in DH after recovery of the adrenal function. As corticosterone is the principal glucocorticoid produced by mice the effects described under (2) and (3) may be ascribed to this hormone. Our results suggest that thymic involution during life, is at least partially, under adrenal control.


Activation of human B lymphocytes induced by Robinia pseudoacacia lectin in the presence of T cells. Robinia pseudoacacia seed lectin is a potent human lymphocyte activator which is capable of activating pure T cells but not pure B lymphocytes. However, when B and T cells were cultured together, the thymidine incorporation was found to be higher than that expected from B- or T-cell cultures alone. Killing of T cells by anti-human-T-lymphocyte antigen (HTLA) serum and complement at the time of thymidine incorporation was found to be unable to suppress completely the thymidine uptake whereas treatment by anti-human-B-lymphocyte and monocyte antigen (HBLMA) serum reduced the response to some extent. Moreover, stimulated lymphoblasts were shown to bear B-cell markers (surface Ig and complement receptors) in about the same proportion as B lymphocytes present in the cultures. These results show that B cells proliferate in the presence of T cells and Robinia lectin. Finally, activation of B cells by Robinia lectin in the presence of T cells led to their maturation to plasma cells in the same way as PWM.


Mitogenicity of Mycoplasma fermentans for human lymphocytes. The in vitro stimulation response of human lymphocytes to Mycoplasma fermentans was examined. M. fermentans stimulated DNA synthesis in blood lymphocytes from all of 20 healthy subjects examined. Only one of these subjects had complement-fixing antibodies to M. fermentans. Lymphocytes from 21 of 22 adenoids and from 1 spleen were also stimulated to DNA synthesis by M. fermentans. The organism induced DNA synthesis in both B and T lymphocytes from adenoids and spleen and preferentially in T lymphocytes from blood. M. fermentans was shown to activate adenoid lymphocytes to non-amtogem-specific antibody secretion demonstrable by a hemolytic plaque assay. It is concluded that M. fermentans can have a mitogenic effect on both B and T lymphocytes.


Experimental murine candidiasis: pathological and immune responses in T-lymphocyte-depleted mice. Mice depleted of T-lymphocytes by thymectomy and irradiation (TXB) and immunologically competent mice were compared for gross and histological pathology as well as immune responses after cutaneous and/or intravenous challenge with Candida albicans. In response to a first cutaneous inoculation with viable Candida, TXB, sham-operated (SXB), and unmanipulated (normal) mice, all developed lesions of comparable size, duration, and histopathology. When challenged a second time cutaneously, normal and SXB mice developed lesions which were greatly increased in size when compared with those produced by a first cutaneous infection, whereas TXB mice developed lesions comparable in size to those initiated by the first infection. Histologically, the first and second lesions in all animals were acute abscesses predominantly comprised of polymorphonuclear leukocytes. The larger second lesions in SXB and normal mice were accompanied by detectable circulating antibody and by delayed hypersensitivity. Neither circulating antibody nor delayed hypersensitivity were stimulated in the TXB mice. When challenged intravenously, all previously uninfected mice, regardless of T-cell status, were equally susceptible to C. albicans. Contrary to SXB or normal mice, however, TXB mice which had been infected cutaneously were not more resistant to a subsequent intravenous challenge as judged by 6-week survival. The results suggest that T-cells do not play a significant role in innate resistance of mice to systemic candidiasis, but that such cells are important in the development of acquired resistance.


Histoplasma capsulatum infection in nude mice. Congenitally athymic nude (nu/nu) mice, when injected intraperitoneally with Histoplasma capsulatum, developed a rapidly fatal disseminated infection characterized by heavy parasitization of reticuloendothelial tissues. In contrast, their heterozygous (nu/X) littermates, which possessed a functioning thymus, developed only a low-grade infection which was apparently self-limited and rarely fatal. Transplantation of thymic tissue into nu/nu mice diminished greatly the severity of infection and reduced mortality by about 50%. These studies emphasize the importance of cell-mediated immunity in host defense against histoplasmosis and suggest that the nude mouse may be a valuable model for the study of this chronic intracellular infection.


The comparative radiosensitivity of T and B lymphocytes. This study deals with the comparative effects of gamma irradiation on T and B lymphocytes in mice. Quantitatively, splenic T cells appeared substantially more radioresistant than B cells. However, in the thymus, the mesenteric lymph node and peripheral blood, both cell types were highly radiosensitive. No repair processes could be detected with respect to lymphocyte killing, since reducing the dose rate or fractionating the dose resulted in no reduction in cell destruction. Splenic B cells which remained intact 3 days after doses of 600 R or larger were impaired in their ability to form caps, whereas T cells capped normally. Spleen cells which were viable 3 days after irradiation bore latent radiation damage which was manifested as a reduced ability to survive and generate plaque-forming cells in vitro. Attempts to separately assess irradiated T and B cell immunocompetence in vitro suggested that at doses of 300 R and below, surviving B cells were more impaired than T cells. After a 600 R dose, neither cell type appeared to be functional.


Plutonium-239 deposition in the skeleton of the mouse. Using the technique of neutron-induced autoradiography, together with computer-based methods of data reduction, the distribution of intravenously injected plutonium-239 in the skeleton of the female CBA mouse, 24 hours after injection, has been investigated. With these techniques, it is possible to measure the localization of 239Pu on the endosteal and periosteal surfaces of the bone to an accuracy of approximately +/- 2 x 5 micrometer. Results are reported for the distribution of 239Pu in the third lumbar vertebra, a central caudal vertebra, the right ilium and the right femur. Radiochemical analyses of the 239Pu in other comparable bones of the skeleton are also reported.


Factors affecting the mobility of plutonium-238 dioxide in the rat. A major factor influencing the movement of plutonium-238 from the lungs to blood after the intubation of oxide suspensions is the presense of 0.001 micrometer diameter particles. In a polydisperse suspension of particles this fraction increases with time, due it is thought, to fragmentation of larger particles induced by alpha decay. The rate of this process could account for the greater transportability in vivo of plutonium-238 relative to plutonium-239 when the oxides are inhaled. In blood, 0.001 micrometer diameter plutonium-238 oxide particles undergo a rapid reaction to form a low molecular weight species before plutonium is complexed with transferrin and citrate ions. The filtration of this species through the kidneys may explain the observed enhanced urinary excretion of plutonium relative to administered plutonium citrate. The mechanism of urinary excretion and relationship between cumulative urinary excretion and body content for plutonium-238 is similar to that previously observed for plutonium-239, even though different methods of preparation of the oxides were used.


The uptake and redistribution of 241pu within the gonads. Male and female hamsters and a female rabbit were injected with 241Pu citrate. The hamsters were killed serially at 15 min, 2 hours, 1 day and 10 days after injection, and the rabbit 1 week after injection. The gonads were examined for 241Pu by tissue-section autoradiography. Soon after injection the plutonium was concentrated by the contents of atretic Graafian follicles and by thecal rings in the ovary, but was found to be dispersed throughout the testes. It is suggested that the disperse distribution in the testes which is only seen soon after injection may be an artefact of tissue processing. One day after injection, plutonium was accumulated by macrophages in both the follicles of the ovary and in the interstitial tissue of the testes. Macrophages containing plutonium later migrated away from the aretic ovarian follicles towards the ovarian medulla. This pattern of distribution and redistribution in the ovary is regarded as likely to lower the effective dose from a-emitting plutonium isotopes to the viable oocytes. No migration of macrophages was seen in the testes. Histochemical staining methods revealed the presence of acid protoglycans, including chondroitin sulphate, and glycoproteins at the sites of plutonium concentration in the ovary. These molecules are regarded as likely receptor sites for plutonium. In the testes no acidic carbohydrates were found, and it is suggested that the initial binding site for plutonium may be a compound lipid. This was deduced from the apparent inability of the interstitial tissue of the testes to bind plutonium in situ.


Irradiation of micro-organisms with mono-energetic X-rays; biological consequences of the Auger effect. The radiation resonance effect reported previously for isolated biomolecules has now for the first time been observed in a cellular system. Dried bacteria, Micrococcus denitrificans, in which TdR in DNA was partially substituted by BUdR, were subjected to mono-energetic X-rays of energies below or above the K-edge for Br. Subsequently, the colony-forming ability was assayed. For photon energy slightly above the K-edge, the lethality/rad was greater than that below the K-edge. This is interpreted in terms of the Auger effect initiated selectively by photo-absorption in constituent Br atoms. The differential absorption of low-energy photons in constituent atoms of DNA is also discussed.


The absence of an effect of photoreactivation on sub-lethal damage accumulation in a photoreactive wallaby cell-line. Monolayer cultures of JU56 wallaby cells were exposed to germicidal U.V. and/or photoreactivating (PR) light. The U.V. exposures induced dose-dependent cell-death. The survival data are consistent with a common extrapolation number (n) of 6 x 17 +/- 0 x 98 with a D(0) of 123 x 0 +/- 6 x 8 erg/mm2 for photo-reactivated cells and a D0 of 87 x 3 +/- 4 x 9 erg/mm2 for non-photoreactivated cells; the photoreactivation protected the cells with a dose-modification factor of 1 x 41 +/- 0 x 02. Therefore PR is not a shoulder phenomenon and so has no relationship to the repair of sub-lethal damage.


Radioprotective effect of 5-hydroxytryptamine and 5-hydroxytryptophan on mammalian cells irradiated in vitro. The radioprotective effect in vitro of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (k-HTP) was studied with cultured mammalian cells of three cell lines: 5-HT-synthesizing FMA and 5-HT-non-synthesizing FM3A and B16-C2W. In these cells, the addition of 5-HT to the suspending medium induced only a weak protection or no protection at all. The increase in the 5-HT content of these cells at the time of irradiation was negligible. Pre-incubation of cells for 40 min in a 5-HTP-containing medium resulted in an elevation of the 5-HT content concomitantly with an increase in the radioresistance of FMA cells, where the DRF at 1 per cent was 1 x 8. In FM3A and B16-C2W cells such an effect was not observed. The same relationship between 5-HT content and radioresistance was also observed in FMA cells which were cultured in different densities or with reserpine. These results strongly suggest that the substance playing the main role in the induction of radioresistance in cells in vitro is the 5-HT that exists in the cells.


The r.b.e. of different-energy neutrons as determined by human bone-marrow cell-culture techniques. The effect of X-rays and different-energy neutrons on human bone-marrow cells was studied using two different cell-culture techniques--diffusion chamber (DC) growth and colony formation in vitro (CFU-C). Based on the survival of proliferative granulocytes in DC on day 13, the D0 value was 80 rad with X-rays, and 117 rad as measured by the CFU-C assay. The D0 values for neutrons depended on the radiation source and the energy level. The r.b.e. values, which dropped with increasing energy levels of mono-energetic neutrons, were (i) 0.44 MeV; DC 3.7, CFU-C 4.1; (ii) 6 MeV; DC 1.8, CFU-C 2.0; (iii) 15 MeV; DC 1.6, CFU-C 1.6; (iv) fission neutrons; DC 2.6, CFU-C 2.4.


Photodynamic activity of dyes with different DNA binding properties I. free-radical induction in DNA. The photosensitizing efficiencies of eight dyes have been compared; two acridines, two xanthene derivatives, one sulphur-containing dye and three chemotherapeutic agents. The analysed reaction was the photosensitized induction of free radicals in calf-thymus DNA at low temperature. The binding of these dyes to DNA was first measured. Both strong (process I) and weak (process II) binding, with different intensities, either alone or together, were observed as mode of fixation. Whatever the nature of their binding, all the dyes used revealed a photosensitizing power as inducers of peroxide radicals in DNA. Their relative efficiencies, expressed as a function of the amount of dye molecules bound to DNA, were found to be very different. Intercalation, however, appeared to favour the free-radical induction as the first strongly bound molecules were more efficient.


Photodynamic activity of dyes with different DNA binding properties II. T4 phage inactivation. The photosensitizing efficiency of six dyes--proflavine, 9-aminoacridine, ethidium bromide, thiopyronine, pyronine and acridine red--have been compared on the basis of the inactivation of sensitized T4 phage caused by light irradiation. This reaction was only measurable after diffusion of the dye through the phage capsid and was not observed in the presence of either chloroquine or quinacrine; it followed a single-hit kinetics as a function of the irradiation time. With each dye, a double reciprocal plot of the inactivation constant versus the dye concentration present gave rise to a linear relationship. From this relation, parameters were deduced which expressed the relative photosensitizing efficiencies. Dye-binding to the phages was measured and the proflavine-mediated inactivation appeared to be related to the amount of strongly bound molecules. Such a conclusion could not be reached in the case of 9-aminoacridine and ethidium bromide, which were much less efficient photosensitizers than proflavine, but which were also strongly bound to the phages. Thiopyronine was weakly bound to the phages; it had, however, the highest photosensitizing activity observed. These results indicate that various mechanisms are involved when the phage photosensitization is due to one dye or another.


Thermal enhancement of the effectiveness of gamma radiation for induction of reproductive death in cultured mammalian cells. The induction by gamma radiation of reproductive death in cultured cells derived from a rat ureter carcinoma (RUC-2) and from Chinese-hamster lung tissue (CH-V79) was shown to be enhanced by hyperthermic treatments at 41, 43 and 45 degrees C. The degree of enhancement was found to depend on the line of cells studied, the temperature employed and the level of damage considered. The influence of accumulating sublethal damage was decreased by hyperthermia, and the final slope of the radiation survival curve was increased. The degree of enhancement of lethal damage was found to depend on the time interval between the heat treatment and irradiation, especially at 41 degrees C.


Interaction of ascorbate with the radioprotective effect of mercaptoethylamin. An exploratory study in mice, whole animals and cell cultures. The injection of ascrobate together with cysteamine (beta-mercaptoethylamin or MEA) was shown to cause a partial reversion of the radioprotective action of MEA in mice, and simultaneously of the suppressive action of MEA on RNA synthesis in bone marrow cells. In mouse spleen lymphocytes stimulated by concanavalin A in vitro, MEA and ascorbate exhibited a strong antagonism, neutralizing each other's inhibitory action on RNA synthesis. The latter effect failed to appear after chelation of trace metals, and it is indicated that the ability of ascorbate to counteract the effects of MEA on radiosensitivity and metabolism requires the formation of oxidized products, probably monodehydroascorbate, in agreement with previous observations on bacteria.


Late effects of successive massive doses of radiation on parabiont rat pairs. Parabiosis of rats permits one partner to survive 1000 R X-radiation if the other is shielded. This dose to the previously shielded partner after intervals of 5, 10 or 30 days tests the ability of the first irradiated partner to recover and, in turn, support the second. The effectiveness of this can be measured by the late effects induced in the pair. Lifespan was shortened by 100--150 days following a 5-day interval, by 30 days following a 10-day interval and not shortened following a 30-day interval. The incidence of leukaemia was about 6 per cent in each group, close to that in control pairs. Shortening the interval between the irradiations decreased the average age of death from leukaemia. No solid lymphoid tumours were induced in the doubly irradiated pairs. The incidence of osteogenic sarcoma was 1.6 per cent in controls and 12.9 per cent in the pairs with both partners irradiated.


The effect of ubiquinone-7 and its metabolites on the immune response. IV. Chemical structure-adjuvant activity relationship of quinonyl derivatives on humoral immune response. The effects of the emulsion of quinonyl acids (QS-n, ES-n, KS-n) and related compounds (QSA-n) in Freund's incomplete adjuvant on the humoral immune response to bacterial alpha-amylase were assayed, and their structure-adjuvant activity relationships were discussed. All the quinonyl acids tested (500 microgram/mouse) enhanced the humoral immune response two to seven times as much as that of the control group, five weeks after immunization. 3'-Methyl and 2', 3'-double bond in the carboxy side chains of ubiquinone metabolites (Q acid-I, -II) were not essential for the adjuvant activity. The conversion of methoxyls on the quinone ring into methyls, and that of benzoquinone into phenol also did not affect the activity, but the activity seemed to depend on the carbon number of the carboxy side chain, and the prominent adjuvant activity was observed in the carboxylates having the carboxyalkyl chain of five to seven carbons. High doses (1 or 5 mg/mouse) of ubiquinone-7 and -2 enhanced the humoral immune response two to three times as much as that of the control group, and quinonyl alcohols (QSA-n) enhanced that with low dose (500 microgram/mouse).


[Giant hypertrophy of the gastric antrum (localized Menetrier's disease) as a cause of recurrent intestinal hemorrhage]. A case of discrete, localised Morbus Ménétrier is reported, with pitting of a giant mucosal fold at the antrum, where the patients' main symptom was recurrent gastric haemorrhage. The presentation posed considerable diagnostic difficulties that were only clarified through a partial gastric resection and subsequent histological examination.


[Azygoportal interruption, fundoplication and vagotomy in hemorrhagic esophageal varices]. A vascular interruption to the azygoportal zone, achieved by devascularisation about the cardia and a closed transmural ligation of the varices is described, which is combined with a simultaneous truncal vagotomy, pyloroplasty procedure and a fundoplication. This fourfold method combats the bleeding varices at several points: a direct disruption of vascular paths, haemodynamic control, reduced influence of peptic factors, the management of coincident ulcer pathology and the prevention of gastro-oesophageal reflux. The results from 5 patients are encouraging. This abdominal operation is swift, comparatively atraumatic and may be undertaken in emergency cases and in at-risk patients on an elective basis.


Immune status in children with acute lymphocytic leukemia. Observations in 67 cases. 67 children affected with acute lympocytic leukemia were immunologically evaluated for lymphocytic markers, serum immunoglobulins and delayed hypersensitivity skin tests at the onset, in remission and after cessation of therapy. E, EA rosettes and surface Ig assayed significantly lower in leukemic children than in matched controls, except for three cases of T-cell leukemia in which E rosettes were very high. After cessation of therapy almost normal results were obtained. As for serum Ig, the only abnormal finding was that of low IgM during therapy. The skin tests with Varidase, Candidine, Mumps antigen and DNCB were not significantly different at onset and in remission. As for DNCB test, the negative responses at onset often became positive in remission, but only when the test was performed before any treatment (anamnestic-like response?). One of the three patients with T-cell leukemia relapsed after 8 months: strangely enough, no surface marker could be detected on that occasion. We could not find any relationship between various immunological tests, or between these tests and prognosis; chemotherapy proved active in suppressing cellular immunity, especially the primary cellular response.


[Juvenile Sharp syndrome (mixed connective tissue disease)]. Five children with Sharp syndrome are described presenting a non-erosive polyarthritis, hand and finger swelling, Raynaud phenomenon, myositis, dermatomyositis or SLE-like rash. Characteristic laboratory findings are, apart from elevated sedimentation rate, anemia and leucopenia, high titer IgM rheumatoid factors and antinuclear antibodies (ANA). The latter show speckled pattern, contain IgG, bind complement components and are directed against ribonuclease-sensitive nuclear antigens. All patients have antibodies against the so-called extractable nuclear antigens (Anti-ENA) and antibodies against ribonucleoproteins (Anti-RNP). Since children with Sharp syndrome rarely show renal or cerebral involvement, the prognosis seems to be fairly good.


Comparison, by freeze-fracture electron microscopy, of chromatophores, spheroplast-derived membrane vesicles, and whole cells of Rhodopseudomonas sphaeroides. By using freeze-fracture electron microscopy, chromatophores and spheroplast-derived membrane vesicles from photosynthetically grown Rhodopseudomonas sphaeroides were compared with cytoplasmic membrane and intracellular vesicles of whole cells. In whole cells, the extracellular fracture faces of both cytoplasmic membrane and vesicles contained particles of 11-nm diameter at a density of about 5 particles per 10(4) nm2. The protoplasmic fracture faces contained particles of 11 to 12-nm diameter at a density of 14.6 particles per 10(4) nm2 on the cytoplasmic membrane and a density of 31.3 particles per 10(4) nm2 on the vesicle membranes. The spheroplast-derived membrane fraction consisted of large vesicles of irregular shape and varied size, often enclosing other vesicles. Sixty-six percent of the spheroplast-derived vesicles were oriented in the opposite way from the intracellular vesicle membranes of whole cells. Eighty percent of the total vesicle surface area that was exposed to the external medium (unenclosed vesicles) showed this opposite orientation. The chromatophore fractions contained spherical vesicles of uniform size approximately equal to the size of the vesicles in whole cells. The majority (79%) of the chromatophores purified on sucrose gradients were oriented in the same way as vesicles in whole cells, whereas after agarose filtration almost all (97%) were oriented in this way. Thus, on the basis of morphological criteria, most spheroplast-derived vesicles were oriented oppositely from most chromatophores.


Studies on the substrate specificity of Taka-amylase A1. XIV. Preparation of 6-deoxy-6-halogenomaltotrioses and their hydrolysis by Taka-amylase A. 1. O-6-Deoxy-alpha-D-glucopyranosyl-(1 leads to 4)-O-alpha-D-glucopyranosyl-(1 leads to 4)-D-glucopyranose, O-6-chloro-6-deoxy-alpha-D-glucopyranosyl-(1 leads to 4)-O-alpha-D-glucopyranosyl-(1 leads to 4)-D-glucopyranose, O-6-bromo-6-deoxy-alpha-D-glucopyranosyl-(1 leads to 4)-O-alpha-D-glucopyranosyl-(1 leads to 4)-D-glucopyranose, and O-6-deoxy-6-iodo-alpha-D-glucopyranosyl-(1 leads to 4)-O-alpha-D-glucopyranosyl-(1 leads to 4)-D-glucopyranose were prepared, taking advantage of the substrate specificities of Taka-amylase A and glucoamylase, and the action of Taka-amylase A on these substrates was investigated. 2. The Michaelis constant Km and the molecular activity ko were determined at 37 degrees C and pH 5.2 using the modified maltotrioses. The values of Km and ko decreased upon modification of maltotriose and those of ko/Km were in agreement with the comparative initial rates for the corresponding derivatives of phenyl alpha-maltoside at low substrate concentrations. This result suggested that a subsite of the enzyme may have a specific interaction with halogen atoms in the substrate. 3. All halogenomaltotrioses examined showed substrate inhibition at high substrate concentrations.


Purification and some properties of two proteinases from Crotalus adamanteus venom that inactivate human alpha 1-proteinase inhibitor. Two proteinases (proteinases I and II) have been purified from Crotalus adamanteus venom to the stage of electrophoretic homogeneity and proteinase II has been crystallized. The proteinase differ slightly in molecular weight and amino acid composition. Both are metalloenzymes requiring Zn2+ or Ca2+, or both; neither requires thiol compounds for activation. The proteinases are free of esterolytic activity against benzoly-L-arginine ethyl ester and benzoyl--tyrosine ethyl ester. Proteinase II cleaves the oxidized B chain of insulin at the bonds Phe1-Val2, His5-Leu6, His10-Leu11, Ala14-Leu15, Leu15-Tyr16, and Tyr-16-Leu17. Digestion of polylsine and polyarginine by proteinase II liberates products ranging from dodecapeptides to hexapeptides. Proteinases I and II catalytically inactive human plasma alpha 1-proteinase inhibitor (54,000 daltons). Electrophoretic analysis of the reaction of proteinase II with alpha 1-proteinase inhibitor reveals that an inactivated inhibitor species of 50,000 daltons is formed, and a peptide of 4,000 daltons is released. The gradual disappearance of the native inhibitor results in the corresponding loss of inhibitory activity against trypsin and chymotrypsin.


The participation of a second molecule of adrenodoxin in cytochrome P-450-catalyzed 11beta hydroxylation. We have utilized 11beta-hydroxylase activity and visible absorption spectrophotometry to detect possible complex formation among adrenodoxin reductase, adrenodoxin, and cytochrome P-450(11)beta. At low ionic strength, a 1:1 complex between adrenodoxin reductase and adrenodoxin occurs but does not support maximal rates of 11beta hydroxylation; at least 1 additional molecule of adrenodoxin in excess of the 1:1 complex is required for full hydroxylase activity. Spectrophotometric titration of a mixture of adrenodoxin reductase and cytochrome P-450(11)beta with adrenodoxin indicates sequential formation of 1:1 complexes between adrenodoxin reductase and adrenodoxin and then between a second adrenodoxin and cytochrome P-450(11beta; the adrenodoxin-cytochrome P-450(11)beta complex is only detectable when the concentration of adrenodoxin exceeds that of adrenodoxin reductase.


Interaction of platelet membrane receptors with von Willebrand factor, ristocetin, and the Fc region of immunoglobulin G. The agglutination of human platelets by ristocetin and von Willebrand factor was inhibited by aggregated immunoglobulin (Ig)G and by Fc fragments of IgG, but not by Fab, F(ab')(2) or pFc fragments of IgG. Because this inhibition occurred with formalin-fixed platelets as well as with normal platelets, a generalized aggregation of fluid membrane components by Fc fragments was not responsible for this inhibition of ristocetin and von Willebrand factor-induced agglutination. Reciprocal inhibition of platelet Fc receptors was produced by prior incubation of platelets with von Willebrand factor and ristocetin. Sucrose density gradient ultracentrifugation studies demonstrated that aggregated IgG did not form fluid-phase complexes with von Willebrand factor and ristocetin. Furthermore, passage of von Willebrand factor and ristocetin through a column of immobilized heat-aggregated IgG did not alter platelet agglutinating activity which indicates that aggregated IgG did not inactivate von Willebrand factor or ristocetin. Thus, it was likely that the IgG-mediated interference with platelet agglutination by ristocetin and von Willebrand factor did not occur in the fluid phase but at the platelet surface. These studies suggest that the platelet membrane Fc receptor may be either a part of, or sterically related to, the membrane glycoprotein I complex that interacts with von Willebrand factor, and that occupation of one of these surface components blocks the availability of the other.


A direct binding assay for rheumatoid factor serum antiglobulins using fluorescein-labelled Fc fragment of human immunoglobulin-G. A simple routine method is described for the quantitation of antiglobulin (rheumatoid factor) in human serum irrespective of its immunoglobulin class. Papain Fc fragment of human IgG is labelled with fluorescein isothiocyanate and incubated with the serum. Bound Fc is separated from free Fc by precipitation with polyethylene glycol and measured by the fluorescence of the precipitate. Results are expressed as a percentage of the binding obtained with a normal pool serum. About 60% of seronegative rheumatoid sera and 96% of seropositive rheumatoid sera gave results more than 2SD above the mean value for normal sera. Only 17% of osteoarthritis sera gave positive results by the same criterion. A relationship is also deduced to show that if the test is carried out at a number of Fc concentrations a double reciprocal plot of bound Fc against free Fc enables both the total antiglobulin and the ratio of binding constants of antiglobulin for Fc and for IgG to be calculated. This ratio is approximately unity. Under the standard conditions the results correspond to a measurement of approximately 30% of the total antiglobulins present.


Decreased serum thymic factor activity in asthmatic children. Serum thymic factor (STF) activity was assayed in 26 young asthmatic patients and in 20 age-and sex-matched controls, in view of the increasing importance attributed to this thymic product in regulating several immune mechanisms. Determinations of total and specific IgE and of other immunoglobulins and skin tests were also performed. Decreased STF activity and high total and specific IgE concentrations were observed in the majority of asthmatic patients. In controls, STF activity was within normal limits in all cases and total and specific IgE concentrations were increased only on one case. The decreased STF activity may be responsible for a possible impairment of cell-mediated immunity and for the increased stimulation of the reaginic system observed in asthmatic patients, via its effects on some T cell subpopulation, namely, suppressor T lymphocytes, which seem particularly sensitive to STF variations. On the basis of these data and of the results of our study, a possible, although speculative, correlation between reduced STF activity and high IgE concentrations in asthmatic patients may be postulated. The reported increased occurrence of autoimmune phenomena in asthmatic patients is in agreement with the hypothesis of a STF-mediated suppressor T-lymphocyte quantitative and/or qualitative defect in this disease.


Cytotoxic T lymphocyte sequential killing of immobilized allogeneic tumor target cells measured by time-lapse microcinematography. Sequential killing of allogeneic target cells by immune cytotoxic T lymphocytes (CTL) was directly observed by time-lapse microcinematography. Target cells (EL4 lymphoma cells from C56BL/6 mice), coated with Fab fragments of goat antibody to EL4, were immobilized by binding to the floor of a polystyrene tissue culture flask that had been precoated with specifically purified anti-goat Fab. On adding immune BALB/c spleen CTL to such target cell monolayers it could be verified by direct observation that individual CTL could sequentially kill several target cells, that the CTL usually separated from the target cell before target cell death, that not all contacted target cells were killed, and that duration of contact was variable and not correlated with subsequent target cell death.


Tumor-associated antigens of rat moloney sarcoma cells. II. Cytosol antigens. Rat Moloney sarcoma cells (MST) were pulsed with 35S-L-methionine for 10 and 60 min and lysed by vortexing in 0.5% deoxycholate, 0.5% NP40, 0.02 M Tris, 0.05 M NaCl, pH 7.5, for 30 sec. The lysate was centrifuged at 16,300 X G for 10 min and the supernatant was co-precipitated with Ig fractions of normal BN serum, normal Lewis serum, BN antiserum to Moloney sarcoma cells (BNaMST), BN antiserum to tumor-associated antigens (BNaTAA), BN antiserum to murine leukemia virus (BNaMuLV), BN antiserum to p30 (BNap30), BN antiserum to gp70 (BNagp70), Lewis antiserum to BN (LeaBN), and BN antiserum to BC5 tumor (BNaBC5). With BNaTAA and BNaMST, a cytoplasmic TAA with m.w. 85,000 was detected. In addition, BNaTAA detected three other species of cytoplasmic TAA with m.w. 220,000, 170,000 and 39,000.


Identification and cytotoxic reactivity of inflammatory cells recovered from progressing or regressing syngeneic UV-induced murine tumors. Most tumors induced in C3H mice by ultraviolet (UV) light are immunologically rejected by normal syngeneic recipients, but will grow progressively in immunosuppressed mice and in mice treated with UV light. In this study we compared the composition and cytotoxic activity of the inflammatory cell infiltrate from tumors transplanted into syngeneic UV-irradiated or unirradiated mice. Tumor fragments were implanted in either normal (regressor) or UV-treated (progressor) mice, and removed on various days after implantation and mechanically dissociated. The cells were examined by immunofluorescence for theta and immunoglobulin markers, stained for morphologic examination, and tested for cytotoxicity against the tumor. No significant differences were noted in numbers of macrophages, granulocytes, or B cells recovered from progressing or regressing tumors on day 6, the time of greatest activity. However, the numbers of T cells recovered from tumor fragments implanted in normal mice was approximately 3-fold that recovered from tumor fragments implanted in UV-treated mice. Lymphocytes recovered from regressing tumor fragments were specifically cytotoxic for that tumor in a microcytotoxicity test; those from progressing tumor fragments were not cytotoxic.


In vitro growth of murine T cells. I. Production of factors necessary for T cell growth. Supernatants of murine lymphoid cultures stimulated with Concanavalin A contain factor(s) capable of sustaining continuous growth of murine lymphoid cells in vitro. Methods for the optimal generation of these growth factors (GM) have been defined, including number of cells required, optimal concentration of Concanavalin A, incubation time, and strain differences in GM production. With GM, cells have been grown for over 15 10-fold generations over a 2-month period. The growing cells express the theta surface marker and do not express surface Ia antigens.


In vitro growth of murine T cells. II. Growth of in vitro sensitized cells cytotoxic for alloantigens. Growth factors (GM), produced by murine lymphoid cells incubated with Concanavalin A, have been used to grow cytotoxic lymphoid cells in culture. C57BL/6 and DBA/2 lymphoid cells were sensitized against each other in primary, secondary, and tertiary in vitro cultures. These sensitized cells were grown in vitro in GM and retained their cytotoxic properties. Cells grew in culture about 10-fold every 5 to 7 days for over 2 months. Initial growth of cytotoxic cells in GM resulted in marked enhancement of specific cytotoxicity that returned to original levels after subsequent subcultures. After five 10-fold cell culture generations some nonspecific cytotoxicity directed against the responding target cell strain appeared in continuous cultures. This technique for growing large numbers of cytotoxic cells may be of value in the development of adoptive immunotherapies.


Enhancement of T cell cytotoxic responses by purified human fibroblast interferon. Purified polyribonucleotide-induced human fibroblast interferon (HFIF) was tested for its effects on proliferative and cytotoxic human T cell responses to alloantigens. The addition of HFIF (100 to 400 IFU/ml) to mixed leukocyte cultures decreased alloantigen-induced lymphocyte proliferative responses as determined by both recovery of responding cells and by 3H-thymidine incorporation into responding cells. However, HFIF, but not the mock interferon preparation, increased the cytotoxic response of T cells to allogeneic cells by 4- to 5-fold when expressed in terms of lytic units. Although fibroblast and leukocyte interferons have different physicochemical and biologic properties, the results reported here are in concert with previous findings concerning the effects of virus-induced leukocyte interferon on human T cell functions.


Types of cells involved in antigen-stimulated and spontaneous rosette formation with Toxoplasma gondii. Antigen-binding cells were identified by using rosette formation of Toxoplasma gondii and defined lymphoid populations under different experimental conditions. Treatment of immunized spleen cell suspensions with anti-Thy 1 serum plus complement inhibited 5 to 29% of the rosette-forming cells (RFC). Higher numbers of thymus-derived lymphocyte-RFC were obtained after incubation at 4 degrees C and by the centrifugation method than by simple incubation at 20 degrees C. RFC were also observed with thymocytes. Combined treatment with anti-Thy 1 serum plus complement and depletion of adherent cells indicated that the major proportion, 46 to 70%, of RFC were B cells. Spleenocytes of nu/nu mice formed similarly high numbers of rosettes. Spontaneous RFC were observed in nonimmunized mice with both spleen and thymus populations. Numbers of rosettes varied considerably depending on the method and the source of cell population used. Removal of adherent cells from spleen suspensions resulted in RFC reduction of 14 to 25% in immunized and 14 to 33% in nonimmunized animals. Pretreatment with anti-mouse immunoglobulin inhibited completely the spleen and spontaneous thymus RFC and partially the thymus RFC in immunized animals.


Regulation of antibody response in different immunoglobulin classes. V. Establishment of T hybrid cell line secreting IgE class-specific suppressor factor. Establishment of a mouse T hybrid cell line secreting suppressor factor(s) specific for the IgE antibody response is described. Fusion was made with polyethyleneglycol between AKR-derived T lymphoma cells (BW5147) and T cells from mice sensitized with DNP-Mycobacterium. Treatment of spleen cells with nondialyzable factor(s) in the culture supernatants of the T cell hybrid clone, 26-M10, showed a suppressive effect on IgE formation but not on IgG formation in adoptive transfer experiments. The suppressive effect was exerted through inactivation of normal or antigen-primed B cells responsible for IgE formation. It was also shown by direct cytotoxic test that the hybrid cells expressed H-2 and Thy-1 antigens derived from both parental cells on their surface. Karyotype analysis of the hybrid cells revealed that the number of chromosomes was less than the sum of the two parental cells' and the average was 50 (45 to 55). Although the 26-M10 hybrid cells lost the ability to secrete active suppressive factor(s) into culture medium 21 weeks after hybridization when the number of chromosomes in most of the cells was less than 41, recloning of the 26-M10 cells successfully recovered active suppressive clones.


Radiosensitivity of the helper cell function. The helper function of T cells primed and irradiated in vivo was tested in vitro by the Mishell-Dutton technique. Spleen cells from mice carrier-primed with HRBC and exposed to 50 to 2000 rads of x-radiation were assayed for their ability to help syngeneic normal spleen cells to mount an in vitro anti-hapten antibody response after stimulation with the conjugate TNP-HRBC. The anti-TNP response was evaluated by the Jerne technique. The helper activity was titrated by adding graded numbers of carrier-primed spleen cells to a constant number of normal spleen cells. The slope of the initial linear portion of the response-cell dose titration curve was taken as an estimated of the helper activity and found to decrease with increasing the x-ray dose. The curve describing the remaining helper activity as a function of the radiation dose shows the presence of two components, one radiosensitive, the other, radioresistant. This suggests the existence either of helper cells at different stages of activation or of two cell subpopulations participating in the helper function.


Modulation of age-related development of contact sensitivity in mice by adult thymectomy. The effect of adult thymectomy on antibody production and on the development of contact sensitivity to picryl chloride in mice of different ages was studied. An age-dependent decline in the ability to develop contact sensitivity was found to be counteracted by thymectomy. In contrast, antibody production was regularly decreased by thymectomy in mice of all ages. A hypothesis is put forward in which the development of contact sensitivity may be regulated by long-lived thymus-dependent suppressor cells which do not affect antibody formation.


Characterization of mononuclear cell infiltrates in psoriatic lesions. The dermal mononuclear cell infiltrates of psoriatic lesions were characterized by receptors for sheep erythrocytes (T-lymphocytes), C3b receptors (macrophages and B-lymphocytes) and C3d receptors (B-lymphocytes), using hemadsorption to cryostat sections in a closed chamber. T-lymphocytes and macrophages were the predominant inflammatory cells. Very few B-lymphocytes were detected. These findings are discussed in relation to the possible pathogenetic signficance of cellular immunity in psoriasis.


Role of immunity in the clearance of bacteremia due to Haemophilus influenzae. The role of antibodies to capsular and somatic antigens in the clearance of Haemophilus influenzae was investigated by active and passive immunization. The clearance index (k) and the proportion of strain b organisms cleared 30 min after intravenous administration (deltaY30) were greater in eight-week-old actively immunized rats (k = 0.693, deltaY30 = 4.07) than in nonimmune animals (k = 0.075, deltaY30 = 0.95)(P less than 0.025 for all); however, clearance correlated imprecisely with titers of bactericidal or anticapsular antibody. In three-week-old rats, intranasal immunization with strain b or U significantly increased (P less than 0.005) the rate of clearance of strains b and U. Passive immunization with antibodies to somatic or capsular antigens significantly increased the rate of clearance (P less than 0.001) and the proportion of bacteria cleared (P less than 0.05) with all test strains. The increased clearance associated with passive immunization correlated with increased splenic uptake of 32P-labeled H. influenzae (r = 0.83, P less than 0.025). Analysis of the disappearance of viable organisms and bacterial 32P suggested that bacteriolysis of H. influenzae did not occur during clearance of the bacteremia. Either antibody to capsular antigen or antibody to somatic antigen, administered or evoked in rats, accelerates intravenous clearance of H. influenzae by promotion of reticuloendothelial phagocytosis.


Significance of thymus-derived lymphocytes in immunity elicited by immunization with ribosomes or live yeast cells of Histoplasma capsulatum. The lymphoid cells responsible for protective immunity to histoplasmosis were characterized. Adoptive transfer of spleen and peritoneal cells treated with antiserum to theta-antigen from mice immunized with ribosomes or live yeast cells of Histoplasma capsulatum abrogated the ability of these cells to protect the syngeneic recipients, whereas treatment of lymphoid cells with antiserum to IgG did not affect the immunity. Prior removal of glass-adhering cells from spleen and peritoneal cell suspensions did not alter their protective activity. Treatment with mitomycin C, an antimitotic agent, ablated the capacity of immune lymphocytes to protect the syngeneic recipients. These results indicate that the immune spleen and peritoneal cells that confer immunity to histoplasmosis are thymus-dependent (T) lymphocytes and that their active proliferation in the recipients is necessary for expression of the protective immunity. Furthermore, the immunity elicited by immunization with histoplasma ribosomes and live yeast cells is mediated by a similar mechanism.


Colony-stimulating activity in serum and bone-conditioned medium of 89Sr marrow-ablated mice. We evaluated the levels of CSA in the serum of and in the medium conditioned by marrow-free femurs of 12 to 16-week-old female CAF1 mice whose marrows had been ablated with the bone-seeking radionuclide, 89Sr. Intact mice were studied 10 to 56 days after 89Sr injection, and mice splenectomized on days 14 and 42 after injection of 89Sr were studied on days 21 and 56, respectively. Control mice were injected with cold 89Sr; sham-splenectomized mice were used when appropriate. None of the mice had any significant levels of CSA in the serum, even the leukopenic splenectomized 89Sr-treated mice. Femur-conditioned medium from all groups contained sizable, but approximately equal, amounts of CSA; thus 89Sr marrow ablation did not adversely affect the capacity of femurs to elaborate CSA. Intraperitoneal injection of endotoxin effected an increase in serum CSA in both intact and splenectomized 89Sr marrow-ablated mice which was equal to that found in the control mice.


Effect of shear rate on platelet interaction with subendothelium in citrated and native blood. I. Shear rate--dependent decrease of adhesion in von Willebrand's disease and the Bernard-Soulier syndrome. Previous studies have demonstrated impaired adhesion of platelets to the subendothelium in von Willebrand's disease. These studies were performed by circulating (in a closed system) citrated whole blood through a chamber containing everted segments of rabbit aorta from which the endothelium had been removed by balloon catheter. The average wall shear rate was 800 sec-1, and the perfusion time was 10 min. In the present study we measured the interaction of platelets with subendothelium in native (nonanticoagulated) blood, using a recently described technique in which the vessel segments are perfused with directly sampled venous blood. The system was open; that is, the blood was not recirculated. We used blood flow rates of 20, 40, and 50 ml/min, which correspond to calculated shear rates of 1300, 2600, and 3300 sec-1 and perfusion times of 3, 2, and 2 min, respectively. For comparison, parallel studies at 1300 sec-1 were also obtained with citrated blood. In normal subjects, at a shear rate of 1300 sec-1, platelet adhesion was less in native blood than in citrated blood, but thrombus formation was greater. Platelet adhesion in five patients with von Willebrand's disease was decreased in both citrated and native blood. The magnitude of the adhesion defect was strongly dependent on the shear rate. Thus, in citrated blood studied at a shear rate of 1300 sec-1, adhesion was 75% less than in normal subjects, whereas in previous studies at 800 sec-1 the reduction in adhesion was 29%. In native blood, adhesion in von Willebrand's disease was normal at a shear rate of 1300 sec-1, whereas 53% and 77% reductions in adhesion were obtained at shear rates of 2600 and 3300 sec-1, respectively. The latter shear rates studied, adhesion of platelets in native blood was also decreased in the Bernard-Soulier syndrome but was normal in hemophilia and afibrinogenemia. Our findings with native blood provide further evidence that impaired adhesion of platelets to the vessel wall accounts for the hemostatic defect in von Willebrand's disease. In addition, this adhesion defect is shear rate-dependent.


Failure to respond to influenza vaccine in the aged: correlation with B-cell number and function. Failure to respond to influenza vaccination correlated with a decreased number and percentage of IgD-bearing PBL and a dampened lymphocyte response to PWM in a subset of healthy aged volunteers. These subjects had normal levels of serum immunoglobulins, intact T cell function, and normal numbers of E-rosetting cells.


Arachnoiditis presenting as a cerebello-pontine angle tumour. Two cases are reported in which arachnoiditis presented as tumours of the cerebello-pontine angle. The possible aetiological factors are briefly discussed.


Initiation of parturition in the goat: evidence for control by foetal glucocorticoid through activation of placental C21-steroid 17alpha-hydroxylase. Infusion of dexamethasone into chronically catheterized foetal kids induced delivery in 41--65 h. Changes in the concentrations of placental and ovarian steroids in the maternal circulation at dexamethasone-induced delivery mimicked those preceding spontaneous kidding at term; in both instances the peripheral concentration of progesterone fell and the concentration of oestradiol-17beta rose. The concentration of cortisol in the foetus was low at dexamethasone-induced delivery. Metabolism of pregnenolone, progesterone, 17alpha-hydroxyprogesterone and androst-4-ene-3,17-dione by extracts of foetal placenta was investigated in late pregnancy, after premature parturition induced with dexamethasone or prostaglandins and after spontaneous parturition at term. In placenta obtained before the onset of labour (or from animals induced to kid by administration of prostaglandins), the main product of progesterone metabolism was a 5beta-pregnane-3,20-diol. In contrast, placentae from animals in which the foetal level of glucocorticoid had been raised (after spontaneous parturition or by administration of dexamethasone to the foetus) were able to 17alpha-hydroxylate and progesterone was metabolized to 5beta-pregnane-3alpha/3beta,17alpha,20alpha-triols and 17alpha,20alpha-dihydroxypregn-4-en-3-one. The appearance of placental 17alpha-hydroxylase was correlated with raised maternal concentrations of 17alpha,20alpha-dihydroxypregn-4-en-3-one and androstenedione. The induction or activation of placental 17alpha-hydroxylase may represent the mechanism by which foetal glucocorticoid controls the onset of labour in the goat.


Static pressure-volume curves for the lung of the frog (Rana pipiens). 1. Static pressure/volume curves have been determined for isolated frog lungs inflated with either air or saline. In both cases a hysteresis was present: the pressure required to produce unit change of volume being greater during inflation than deflation 2. The pressure necessary for a given volume change was less for the saline-filled than the air-filled lungs. The difference between these curves is due to the surface tension at the air/lung interface. 3. Pressure/volume curves for air-filled lungs in situ were similar to curves for isolated lungs. However, a greater pressure was required for the same volume change during both inflation and deflation. 4. Compliance was calculated from different parts of air pressure/volume curves and gave values greater than those obtained using similar calculations for higher vertebrates. 5. These observations support other evidence for the presence of a surfactant in the lung lining of frogs in spite of the relatively large diameter of their 'alveoli.' The precise role of such a lining is uncertain and it is concluded that similar forces may be involved during the inflation and deflation of lungs of frogs and higher vertebrates in spite of differences in gross morphology.


Adult idiopathic communicating hydrocephalus with and without shunting. The outcome in 37 adult patients with idiopathic communicating hydrocephalus treated by ventriculoatrial shunting is presented. Only 33% showed definite improvement, and no diagnostic procedures accurately predicted the outcome of surgery. These were compared with a "control" group of 12 patients who were not shunted; 50% of these were stable for up to 36 months. These findings, and the high frequency of serious complications (35%), suggest caution in recommending a shunt procedure.


Gastric heterotopia in the ileum causing hemorrhage. Two cases of infants with heterotopic gastric mucosa in the ileum causing hemorrhage and massive bleeding per rectum are presented. Preoperative Technetium 99 m scanning was valuable as a means to the diagnosis. Successful operative treatment was achieved by segmental resection with end to end anastomosis.


Effect of surfactants on percutaneous absorption of naproxen II: in vivo and in vitro correlations in rats. The effect of surfactants on percutaneous absorption of naproxen was studied using rat in vivo models. The in vivo normalized relative absorption rates were in good agreement with the in vitro relative flux. An antipyretic model in the rat could not show relatively small increases in percutaneous absorption caused by the surfactants. Based on these results, it is apparent that reliance on the rat, using either in vitro or in vivo models, may lead to erroneous conclusions when considering the effect of surfactants on human percutaneous absorption of drugs such as naproxen.


Fading: a new cytofluorimetric measure quantifying serotonin in the presence of catecholamines at the cellular level in brain. A new histopharmacological approach to the study of serotonergic neurons is described. Using a computerized microspectrofluorimeter, we demonstrated that a measure of fluorescence fading reliably detects changes in serotonin even in the presence of catecholamines. This "fading measure" was validated with model droplets containing serotonin, norepinephrine or mixtures of the two, and with in vivo studies using pargyline to increase brain serotonin. After various doses of pargyline, a correlation of 0.927 was found between our intraperikaryal fading measure and a standard florimetric measure of serotonin in dissected samples of the raphe. Further experiments were designed to test the feasibility of the cytofluorimetric fading measure for quantifying differential changes in serotonin in intraperikaryal and extraperikaryal regions. Both LSD (75 and 150 microgram/kg) and a low dose of the monoamine oxidase inhibitor pargyline (25 mg/kg) increased intraperikaryal serotonin without affecting extraperikaryal fluorescence. Conversely, the serotonin reuptake inhibitor fluoxetine produced the opposite effect of selectively increasing extraperikaryal serotonin. Another inhibitor of serotonin reuptake, chlorimipramine, which also blocks reuptake of norepinephrine in vivo, markedly increased both intraperikaryal and extraperikaryal serotonin. These results confirm the utility of cytofluorimetric measures of serotonin within raphe cell bodies from untreated rats, and indicate that changes in the intracellular and extracellular concentrations of serotonin can be differentiated.


Mammary gland hyperplastic alveolar noduligenesis in the LEW/Mai rat in relation to mitotic activity, estrous cycle status, and age. Spontaneous mammary hyperplastic alveolar noduligenesis was studied in nulliparous female LEW/Mai rats in relation to age, estrous cycle status, and mammary gland mitotic activity. The morphometric composition of the mammary gland and the incidence of hyperplastic alveolar nodules (HAN) and dysplasias were determined by examination of stained wholemount preparations of one of the inguinal mammary glands. Mitotic activity in the contralateral mammary gland rose almost linearly from 30 to 108 days of age and then fell progressively thereafter, although mitotic activity remained significantly elevated compared to that in mammary glands of rats less than 100 days old. Mitotic activity was nonrandomly distributed in the mammary glands of young pubertal rats in contrast to that in glands of prepubertal rats and in rats in persistent estrus, in which it tended to be randomly distributed. HAN were present in some rats by 150 days of age and were frequent in the mammary glands of most rats older than 200 days. All animals with HAN were in persistent vaginal estrus and had significantly increased pituitary weights. This association suggested that hormone imbalance may be an important etiologic factor in spontaneous hyperplastic alveolar noduligenesis in the rat.


Aspirin and gastrointestinal bleeding.

Aspirin and gastrointestinal bleeding. There is no other over-the-counter (OTC) drug having the widespread use of aspirin. Evoking the well-established analgesic, antipyretic, and anti-inflammatory activities with an amazingly low degree of toxicity, its use has increased in this country to the astounding figure of more than 20 tons daily. The observation that comparatively small daily doses of aspirin may serve as a means of preventing certain types of cardiovascular disasters may lead to even more widespread use of the drug. The most frequent untoward side effect of aspirin is gastric discomfort with or without microbleeding. The amount of bleeding is usually quite small but owing to the long interest of the author in buffered aspirin, it is prudent to determine whether or not this action of aspirin is serious.


Late results of bladder stimulation in 11 patients: followup to 4 years. Direct stimulation of the detrusor muscle offers the best possibility to evacuate the bladder in highly selected patients. During the last 4 years 11 patients have undergone implantation of a bladder pacemaker; followup revealed that 1 patient could void only during stimulation, while 7 patients had reflex evacuation and 3 had no function at all. An exceptional case report is presented.


Studies on the adjuvant effect of water-in-oil-in-water (w/o/w) emulsion of sesame oil. 2. Mode of action of the w/o/w emulsion. The water-in-oil-in-water (w/o/w) emulsion showed potent adjuvant effect on the antibody formation to thymus-dependent antigens, but not to thymus-independent antigens. In hapten-carrier system the priming with carrier in the w/o/w emulsion enhanced more effectively the carrier specific helper function than did the priming with carrier in free solution. The cells responsible for the helper function were radioresistant. In the adoptive cell transfer system, the w/o/w emulsion was shown to enhance helper cell function. It is discussed that our w/o/w emulsion exerts the adjuvant effect by enhancing helper T cell activity.


Inhibitory effects of cadmium on the release of acetylcholine from cardiac nerve terminals. The effect of stimulation of the vagaosympathetic trunk or the vagal nerve on the cardiac interval of the spontaneously beating heart of the bullfrog was studied in the presence and absence of Cd. The prolongation of the cardiac interval following the nerve stimulation was abolished by Cd (5 micrometer). Such an effect of Cd was completely antagonized by increasing the external Ca to 10 times the normal concentration. Cd (10 micrometer) did not alter the compound action potential of the nerve trunk, nor did it affect the pacemaker activity of the heart. Bioassay of acetylcholine in the effluent from the heart after cardiac nerve stimulation showed that Cd reduced the acetylcholine release from the cardiac nerve. It is concluded that Cd may act on the cardiac nerve terminals where Cd suppresses the release of acetycholine.


[Changes in clinical and immunological laboratory parameters of healthy adults after exposure to a one-hour 40 degree C-whole-body hyperthermia (author's transl)]. There are no signs of organ lesions in healthy subjects exposed to an 1-hour 40 degree C whole-body hyperthermia, induced by radiofrequency or infrared light. As to the immunological in vitro parameters, only a slight decrease of the relative T-cell count is seen, T-cell functions however being normal. A leukocytosis appearing during infrared-induced hyperthermia is probably related to the erythema caused by skin heating. About possible indications and clinical values of this treatment, nothing can however be said so far.


HLA-B27, antinuclear antibodies and drug-induced agranulocytosis. Eight female patients with drug-induced agranulocytosis (five patients with definite seropositive rheumatoid arthritis (RA), three patients with upper respiratory infections) were studied for the presence of HLA-B27 and antinuclear antibodies (ANA). Five of eight patients were found to be HLA-B27 positive and all RA patients had ANA in their serum. The frequency of HLA-B27 and ANA was found to be significantly different from control groups. It is concluded that the occurrence of HLA-B27 and ANA was found to be significantly different from control groups. It is concluded that the occurrence of HLA-B27 in female patients with seropositive RA (especially in those with ANA) and of HLA-B27 alone in other individuals could reflect an increased risk for drug-induced agranulocytosis.


Studies in valine biosynthesis. X. The acetolactate synthase from Rhodopseudomonas spheroides. The first committed enzyme in valine biosynthesis, acetolactate synthase, in the photosynthetic bacterium, Rhodopseudomonas spheroides, required added pyruvate (apparent Km--4.5 mM), Mg2+ (Km--1.01 mM), diphosphothiamine (Km--29.6 micrometer), flavin adenine dinucleotide, and a buffer pH of 7.2--7.4 for enzymatic activity. The synthase was affected by L-valine, an end-product inhibitor, in a competitive manner. The presence of acetolactate synthase, along with other earlier observed enzymes, completes the identification of the valine biosynthetic pathway in this photo-organotroph.


Evidence that the malignant lymphoma of Sjögren's syndrome is a monoclonal B-cell neoplasm. We studied the malignant lymphomas that developed in patients with Sjögren's syndrome and the antecedent benign salivary-gland lesions to determine their cellular characteristics. We used an immunoperoxidase technic that identified intracellular gamma, alpha and mu heavy chains and kappa and lambda light chains. In six of nine patients, the lymphomas were composed of cells containing intracytoplasmic immunoglobulin that was exclusively IgMK. The benign lymphoepithelial salivary-gland lesions preceding these malignant tumors consisted of approximately equal numbers of lymphoid cells containing either kappa or lambda light chains. Thus, in some patients with Sjögren's syndrome, there may be a progression in the lympho-proliferative lesions from a polyclonal infiltrate to a monoclonal neoplasm. Intracytoplasmic immunoglobulin identifies six of the nine cases as being B-cell in origin.


[A case of choroid plexus papilloma at the right cerebello-pontine angle (author's transl)]. A rare case of the choroid plexus papilloma originating from the extraventricle was reported. A 48-hear-old woman began not to walk well about two years ago. Then, she was complained of vertigo, hearing disturbance of the right ear and nausea. These symptoms gradually increased. On admission she had papilledema, Brun's nystagmus, hearing disturbance of right ear and cerebellar ataxia. Cerebral angiogram and CT scan showed dilated ventricles and a large tumor in the posterior fossa. At operation, tumor was found in extramedullary space at the right cerebello-pontine angle and extended to the foramen magnum. This was removed totally. Histological examination revealed choroid plexus papilloma. Her postoperative course was satisfactory and shunting procedure was not necessary. According to the electron microscopic findings, the ultrastructure of tumor was similar to that of normal choroid plexus. We could not clear the morphological features which were considered essential for overproduction of CSF in the tumor.