Variation with age and disease of an amyloid A protein-related serum component. Using the radioactively-labeled alkaline-degraded acid-soluble fraction of amyloid ([ 125I ]DAA), we developed a radioimmunoassay for the previously described amyloid-related component of the human serum (SAA). Screening the sera of 228 normal individuals and of 297 patients with a variety of illnesses, we found that SAA is a component of all human sera, including cord blood (mean 94 plus or minus 57 ng/ml). The concentration of this component increases significantly with the aging process, reaching very high levels in the eighth and nine decades. It is also elevated in all cases of amyloidosis (except for those associated with nephrotic syndrome) as well as in many patients with myeloma, macroglobulinemia, lymphoma, carcinoma, rheumatoid arthritis, and tuberculosis. A marked increase was noted in the early stages of a variety of acute inflammatory and infectious states with a return to normal levels paralleling clinical improvement and faster than the erythrocyte sedimentation rate. The possible implications of this component in the genesis of amyloid and in the immune process are discussed.


Association of tissue factor activity with the surface of cultured cells. Tissue factor occurs in a dormant state on the surface of cultured normal human fibroblasts and WISH 1 amnion cells. The activity of undisturbed monolayers or cells lifted with brief trypsin treatment (0.125 per cent trypsin for 1 min) increases up to 60-fold upon prolonged digestion with dilute trypsin (0.0025 per cent trypsin for 30 min); activity appears subsequent to cell detachment. Up to 70 per cent of the total cellular tissue factor becomes active under these conditions and is released from the cells. The ruthenium red staining coat of the cells is lost during detachment, but cell viability (more than 90 per cent exclude trypan blue) and cell morphology do not change during the subsequent development of tissue factor activity. Furthermore, less than 10 percent of four intracellular enzymes and less than 20 per cent of two plasma membrane enzymes are released during this period of time. We therefore conclude that cells in culture do have tissue factor activity, that it exists in a latent form, and that total cell disruption is not necessary for this activity to initiate blood coagulation.


Immunochemical heterogeneity of calcitonin in plasma of patients with medullary thryoid carcinoma. Marked discrepancies (values up to four times higher in on assay than in the other) were observed when the plasma concentration of immunoreactive human calcitonin (iCT) was measured by two radioimm8noassays in 18 patients with medullary thyroid carcinoma. The two antisera used had different binding affinities for the NH2- and COOH-terminal regions of synthetic calcitonin monomer (CT-1-32). Except for this difference, the assays were identical and reacted equally with CT 1-32. Plasma samples from patients with medullary thyroid carcinoma were gel filtered on columns of Bio-Gel P-150, and the immunoreactivity in column effuent fractions was measured with both assays. The one utilizing the antiserum with prominent NH2-terminal binding affinity (and giving higher iCT values) recognized at least five molecular species that eluted with or before CT 1-32. The other assay, utilizing the antiserum with a COOH-terminal binding affinity, recognized two fo these molecular species-one eluting with CT 1-32 and the other in a position consistent with a dimer. A mixture of athreotic asthma and added CT 1-32 contained a single immunologic species that was recoqnized equally by both antisera. No forms smaller than CT 1-32 were detected in any study. The results suggest that iCT circulating in the plasma of patients with medullary thryoid carcinoma is hetergeneous. The absolute iCT concentration measured by radioimmunoassays depends on recognition of these distinct molecular species as well as on the specific binding affinities of the antiserum used to detect them. These observations may partially explain the variations among iCT values reported by different laboratories.


Orcein staining of hepatitis B antigen in paraffin sections of liver biopsies. Liver biopsies from 97 hepatitis B antigen (HBsAG)-positive patients were stained by a modified orcein method described by Shikata et al (1974) in order to detect the antigen in liver tissue. The results were consitently negative in acute hepatitis, but positive in nearly two-thirds of biopsies from 53 patients with chronic liver disease. The distribution of positive staining was frequently irregular so that there is a problem of sampling error in needle biopsies. The deposits were seen in the cytoplasm of liver cells and occasionally in Kupffer cells, but never in nuclei. There was an inverse relationship between staining and parenchymal necrosis. Biopsies from asymptomatic HB(s)Ag carriers were often strongly positive, as were "ground-glass" hepatocytes in carriers and patients with chronic liver disease. The mechanism of staining is unclear but may be related to the presence of disulphide bonds in (HBsAG. The technique is simple and of use both in fresh and stored material.


Organochlorine content of milks, dairy products and animal feed ingredients: Ireland 1971-1972. Milks (bovine and human) and dairy products (butter, cheese, skim and whey powders, calf-replacer, casein, butter-oil and dietetic food) were collected during 1971/2 throughout Ireland together with a more limited samples of the 10 major animal feed ingredients, and analysed for organochlorine insecticide residues using electron-capture gas chromatography. The different materials contained low or negligible levels of chlorinated insecticides. Apart from some of the animal feed ingredients the DDT residues were generally the predominant contaminants detected together with lower levels of gamma-BHC (lindane), aldrin/dieldrin and heptachlor/heptachlor epoxide. The maximum levels of these insecticides in the bovine milk and dairy products (511, 100, 62 and 21 mug/kg fat respectively) constitute only 50% or less of the Codex Tolerance Limits. The correspondingly low residue levels in the human milk (maxima of 128, 1, 1, and 5 mug/kg fat respectively) which at most represent insecticidal ingestion by infants equivalent to 13, 0-05, 5 and 5% respectively of the WHO/FAO acceptable daily intake for DDE, gamma-BHC, aldrin/dieldrin and heptachlor/heptachlor epoxide again pose no obvious health hazards and are strongly indicative of negligible organochlorine contamination in the general diet. The samples of animal feed ingredients examined also contained trace levels of ogranochlorines (maxima of 0-9, 0-1, 1-6 and 1-0 mug/kg respectively). More extensive monitoring of the residues in animal feed ingredients (the most probable source of milk contamination is advocated, and the desirability of tolerance limits for insecticides in animal feeds discussed.


Group/audiovisual instruction for patients with diabetes. Learning achievements and time economics. Patients with diabetes receiving instruction in group classes utilizing audiovisual teaching techniques achieved significantly higher post-test scores than those taught individually in the traditional bedside manner. In addition to the significantly greater learning, the dietitian's time was reduced by 100 per cent, based on classes of eight patients. The study was conducted by randomly allocating forty-five qualified patients to control or experimental groups, pre-testing them using a questionaire-interview, giving bedside or class dietary instruction, and post-testing, using the same questionaire. Various personal characteristcs of the participants, as well as data relating to the diabetic state, were also examined for possible relationships to test scores and to one another.


Lack of B lymphocyte depletion from murine spleen cell populations by a human gamma-globulin, anti-human gamma-globulin column system. It has been reported previously that enriched populations of mouse thymus-dependent (T) lymphocytes could be prepared by the use of a column procedure that is believed to remove selectively cells with receptors for antigen-antibody complexes. In our hands, this procedure does not selectively remove B lymphocytes but rather masks the surface immunoglobulin. Analysis of the column-passed cells revealed an apparent decrease in the percentage of immunoglobulin-bearing cells but little decrease in either the percentage of complement receptor lymphocytes or the mitogenic response to lipopolysaccharide. Furthermore, rabbit immunoglobulin could be detected on the surface of 35 to 45% of the cells emerging from the columns prepared with rabbit anti-human gamma-globulin (HGG). After overnight incubation, 30 to 40% of the emerging cells reexpressed mouse immunoglobulin on their surfaces. Adsorption of the antisera used to make the columns with mouse gamma-globulin (MGG) diminished the depleting capacity of the columns. We conclude from these observations that antibodies in the anti-HGG sera, cross-reactive with mouse immunoglobulin, account for the spacious depletion of B lymphocytes observed when cells are passed over these antigen-antibody complex columns.


Experimental allergic encephalomyelitis in resistant and susceptible guinea pigs: in vivo and in vitro correlates. Strain 2 guinea pigs develop less severe experimental allergic encephalomyelitis than do strain 13 and Hartley guinea pigs when sensitized with equivalent amounts of homologous myelin basic protein (BP) in complete Freund's adjuvant. In vivo and in vitro correlates of delayed hypersensitivity to myelin basic protein are depressed in the strain 2 guinea pigs relative to the two susceptible strains. The incidence of circulating anti-BP antibodies is also lower in sera from strain 2 guinea pigs than in sera from strain 13 or Hartley guinea pigs. There was no difference among the three strains in their ability to mount delayed hypersensitivity to tuberculin, nor in the response of their cells to PHA in vitro.


The location of regions in guinea pig and bovine myelin basic proteins which induce experimental allergic encephalomyelitis in Lewis rats. Myelin basic proteins and peptides derived from them by limited cleavage with pepsin were tested for their ability to induce experimental allergic encephalomyelitis (EAE) in Lewis rats. The encephalitogenicity of the weakly active bovine protein was found to be associated with both halves of the molecule, peptides (1-88) and (89-169). Of the four smaller derivates of peptide (1-88), peptides (1-36), (43-88), (1-42), and (37-88), only the last two were active. This demonstrated that the overlap region consisting of residues 37-42 (sequence Asp-Ser-Leu-Gly-Arg-Phe) constitutes an encephalitogenic determinant. Of the two smaller derivatives of peptide (89-169), peptides (111-169) and (89-152), only the last was active. This indicated that the second encephalitogenic determinant begins between residues 88 and 111 and ends before residue 153. This region contains the sequence Leu-Ser-Leu-Ser-Arg-Phe (residues 108-113), which is strikingly similar to that of the first encephalitogenic determinant. Studies involving the extremely encephalitogenic guinea pig protein demonstrated that virtually all of the activity was recovered in the peptides corresponding to bovine peptides (37-88) and (43-88). These peptides, but not those comprising the remainder of the protein, were active in inhibiting the passive transfer of EAE with lymph node cells from donors immunized with guinea pig spinal cord.


Macrophage requirement for production of guinea pig migration inhibitory factor (MIF) in vitro. Methods devised for generation and assay of migration inhibitory factor (MIF) on a reduced scale have permitted the performance of experiments which demonstrate that glass bead column-purified guinea pig lymph node lymphocytes do not produce MIF or proliferate in response to antigen. Evidence that the macrophage is the essential cellular element eliminated by the purification procedure is demonstrated by the restoration of both lymphocyte responses upon addition of 5% macrophages to the purified lymphocytes. Autologous, immune and syngeneic, non-immune peritoneal exudate macrophages were equally effective in restoring MF production by purified lymphocytes. Supernatants which inhibited the migration of peritoneal exudate macrophages had only minimal or no effect on the migration of alveolar macrophages, confirming that the inhibitory effects studied were attributable to MF and not cytophilic antibody.


Competition for antigen by cell populations having receptors with the same specificity but of different idiotype. All normal A/J mice immunized with keyhole limpet hemocyanin-p-azophenylarsonate (KLH-Ar) produce anti-Ar antiboides, some of which share a cross-reactive idiotype. The present results indicate that the biosynthesis of antibody molecules bearing this idiotype does not occur in mice having an excess of lymphoid cells with receptors for Ar that lack the idiotype. This was shown, first, by introducing into normal, nonirradiated mice lymphoid cells from mice which had been suppressed with respect to production of the idiotype and then immunized with KLH-Ar. The recipients failed to express the idiotype upon immunization. Alternatively, cells from suppressed, mice were transferred into lethally irradiated syngeneic recipients, followed 17 days later by normal cells. All recipients expressed the idiotype upon immunization. If, however, the recipients were challenged with antigen between the two cell transfers, antibodies bearing the idiotype were not produced during subsequent immunization. Arguing against active, cell-mediated suppression was the production of the idiotype by normal cells in the presence of cells from a suppressed animal. However, the possibility of active suppression by hyperimmune suppressed cells was not ruled out. On the basis of the present data, the simplest interpretation is that cells with anti-Ar receptors from immune, suppressed animals, being present in larger numbers, compete successfully for antigen with nonimmune cells and thus prevent the expression of the idiotype. The system may provide a basis for quantitative studies of competition among cells for a limited supply of antigen, particularly if B cell populations are utilized.


Reaginic antibody formation in the mouse. V. Adoptive antihapten IgE antibody response of dinitrophenyl-keyhole limpet hemocyanin-primed spleen cells cultured with dinitrophenyl heterologous carrier conjugates. DBA/1 mice were primed with dinitrophenyl-keyhole lympet hemocyanin (DNP-KLH) included in aluminum hydroxide gel, and the adoptive anti-DNP IgE antibody response of their spleen cells was studied by transfer into irradiated syngeneic mice. As expected, depletion of T cells by anti-theta antiserum and complement abolished the response of the spleen cells to homologous antigen. If the same T-depleted spleen cells were cultured with DNP-KLH for 24 hr and then transferred into irradiated mice, anti-DNP IgE antibody response was obtained. It was also found that DNP-KLH-primed spleen cells were triggered for  IgE antibody response if they were cultured for 24 to 48 hr with DNP heterologous carrier conjugate, such as DNP-bovine gamma-globulin or a copolymer of D-tyrosine, glutamine, and lysine. Transfer of the cells cultured with the antigen into irradiated recipients resulted in the formation of anti-DNP IgE antibody. The DNP-KLH-primed cells cultured for 24 hr in the absence of antigen and then treated with DNP-BGG at 0 degrees C, also gave an adoptive  IgE antibody response. If the same DNP-KLH-primed cells were treated with the DNP heterologous carrier conjugate at 0 degrees C or injected into irradiated recipients together with the antigen, no IgE antibody response was obtained. The results indicated that T cell dependency of the IgE antibody response is diminished by culture of DNP-KLH-primed cell for 24 to 48 hr.


Allotypic suppression in rabbits: competition for target cell receptors between isologous and heterologous antibody and between native antibody and antibody fragments. Neonatal injection with various foreign proteins (normal goat serum, human Cohn fraction II, human albumin) caused a stimulation of immunoglobulin synthesis. This effect was not antigen-specific and did not constitute a conventional antibody response directed against the injected substance. When this stimulatory effect of foreign protein was minimized, the heterologous (goat) anti-rabbit allotype antibody and rabbit antibody F(ab') 2 fragments not only failed to induce suppression but also competed with the suppression-inducing native rabbit antibody. Allotypic suppression in a rabbit can thus only be induced by an antibody molecule possessing an intact Fc portion of isologous, rabbit origin. Antibody to Ae14, an allotypic specificity located on the Fc portion, failed to induce suppression or stimulation of immunoglobulin synthesis. This was attributed to the position of Ae14 in the cell membrane which reduced its accessibility to antibody.


Neural antigens and induction of myelination inhibition factor. Rabbits were sensitized or immunized with a variety of central nervous system antigens, including bovine spinal cord, bovine, monkey, human, guinea pig, rabbit and rat S myelin basic proteins, and a polypeptide derived from guinea pig basic protein. The animals were observed for development of experimental allergic encephalomyelitis, and their sera were collected at varying intervals after inoculation and evaluated for presence of precipitating anti-basic protein antibody and for their ability to inhibit myelin formation in cerebellar tissue cultures. The resulting complete dissociation between development of experimental allergic encephalomyelitis, the presence of anti-basic protein antibody and the occurrence of myelination inhibition factor suggests that myelination inhibition factor is not involved in the pathogenesis of experimental allergic encephalomyelitis, and argues against a role for anti-basic protein antibody as an antimyelin factor in vitro.


Broad antigenic relationships among rhinovirus serotypes revealed by cross-immunization of rabbits with different serotypes. The rhinoviruses are a large group of at least 89 serotypes and extensive cross-relationships have been demonstrated among these serotypes using both rabbit and human antisera. The extent of these cross-relationships was further investigated by sequential intravenous immunization of rabbits with different virus serotypes, known to be both related and unrelated. In all cases in which a relationship had previously been demonstrated with monovalent antiserum, after heterotypic stimulation with the related virus, the antibody titer to the virus used as primary immunogen showed an anamnestic response, whereas the antibody response to the secondary immunogen was good, but resembled a primary response. In some instances when immunized rabbits were injected with an unrelated antigen, previously unsuspected relationships were revealed. A number of clusters of related rhinoviruses were demonstrated: 5, 17, 42; 3, 4, 6, 14; 9, 32, 67; and 13, 14, 41. Heterotypic immunization proved to be a powerful biologic probe for detecting relationships among the rhinoviruses, and together with newly available epidemiologic data it offers a possible approach for design of a vaccine for the common cold.


In vitro response of mouse spleen cells to the solid phase immunogen DNP-O-Bio-Gel. The in virto immunogenicity of the solid-phase hapten, dinitrophenyl-ornithine-Bio-Gel (DNP-O-Bio-Gel), was investigated in cultures of mouse spleen cells. Appropriate combinations of cells and immobilized hapten were determined. Large numbers of direct anti-hapten plaque-forming cells (PFC) were generated when 1 times 10-7 C57BL/6 or C57BL/10 spleen cells were cultured with 4 times 10-3 DNP-O-Bio-Gel beads. Specificity studies of the responses of cultured spleen cells to DNP-O-Bio-Gel yielded the following results: soluble DNP-ornithine or DNP-bovine gamma-globulin inhibited the induction of anti-hapten PFC by DNP-O-Bio-Gel; neither dinitrophenyl-Bio-gel (DNP-Bio-gel) nor ornithine-Bio-Gel (O-Bio-Gel) induced anti-hapten responsiveness; furthermore, neither DNP-Bio-Gel nor O-Bio-Gel inhibited the induction of PFC by DNP-O-Bio-Gel. It was concluded, from the results of these specificity experiments, that a spacer, ornithine, is required for immunogenicity of immobilized DNP; and that the Bio-Gel bead, itself, acts solely as a physical carrier for the hapten.


Fractionation of functional lymphocytes sensitized to basic encephalitogen on derivatized collagen and gelatin gels. The lymph node cells of basic encephalitogen (BE)-sensitized guinea pigs were fractionated on derivatized collagen and gelatin gels. The population of cells specifically reactive to this antigen can be isolated from derivatized gelatin gels and retain their viability and functionality as assayed in vitro. The specific binding of BE-sensitized cells to BE-derivatized gels comprised between 1 and 2% of the cells applied per plate. The ratio of sensitized cells bound to non-sensitized cells bound ranged between 4 and 6. The viability and functionality of adherent cells detached from collagen gels after enzymatic degradation were impaired. In contrast, the responses obtained with the adherent cell population released from the gelatin gels, by melting at 37 degrees C, were equal or greater than those of the original unfractionated lymph node cell cultures. Furthermore, it was possible to obtain a nonadherent cell population which was virtually completely depleted of the capacity to respond to the sensitizing antigen.


Modulation of cyclic AMP in purified rat mast cells. I. Responses to pharmacologic, metabolic, and physical stimuli. The cyclic adenosine 3', 5'-monophosphate (cAMP) content of isolated unstimulated mast cells and the changes induced by a variety of pharmacologic, metabolic, and physical stimuli were studied. A modified bovine serum albumin density gradient purification method consistently provided mast cell preparations which were 95% or more pure, without apparent damage, and a 73% recovery of the mast cells applied to the gradients. The measured cAMP in unstimulated mast cells was high, a mean of 16 picomoles per million cells. Moderate agitation or contact with glass increased cAMP content about 2-fold. When calcium was omitted from the medium mast cell cAMP was markedly elevated; incremental increases in added calcium ion concentration from 1 muM to 1 mM caused a linear decrease in cAMP content. Theophylline (3 to 20 mM) caused a dose-related increase in mast cell cAMP content, approximately 2-fold at 20 mM theophylline. Epinephrine (0.01 to 1 mM) caused a modest, dose-related increase in cAMP. In the presence of theophylline, epinephrine increased cAMP levels equal to or greater than the sum of the effects of the agents used individually. The increase in cAMP induced by epinephrine was completely inhibited by 100 muM propranolol and partially inhibited by 10 muM propranolol, thus suggesting that a beta adrenergic receptor is involved. Prostaglandin E1 (PGE1) and histamine (in the presence of theophylline) also raised cAMP. Carbamylcholine (1 nM) lowered cAMP 38%; Atropine (0.1 mM) inhibited the decrease in cAMP induced by 1 nM carbamylcholine by 83% indicating that a muscarinic receptor is involved. In these homogeneous single cell suspensions, therefore, cholinergic and beta adrenergic agents have opposing effects on cAMP levels. Diazoxide (10 muM) and adenine (1 muM) caused 37 and 32% decreases in cAMP, respectively. The availability of highly purified mast cells and the identification of agents which either decrease or increase cAMP content allows a direct examination of the role of cAMP in histamine release.


Modulation of cyclic AMP in purified rat mast cells. II. Studies on the relationship between intracellular cyclic AMP concentrations and histamine release. Changes in intracellular and extracellular rat mast cell adenosine 3':5' monophosphate (cAMP) concentrations during stimulation of histamine release by 48/80 were studied. There was a rapid and progressive fall in intracellular cAMP beginning within 10 sec after the addition of 48/80. The lowest cAMP values were obtained at 10 min, with return to control levels by 30 min. The fall in cAMP was dose-related with progressive decreases in 10-min cAMP measurements as the 48/80 concentration was increased from 0.25 to 1.00 mug/ml. There was a graded increase in histamine release over the same concentration range. Attempts to demonstrate significant amounts of cAMP in the medium during 48/80 stimulation were unsuccessful, indicating that the changes in cAMP intracellularly are not due to altered cellular permeability. There was a general correlation between the ability of pharmacologic agents to sustain high intracellular levels of cAMP in the presence of 48/80, and inhibition of histamine release. Theophylline (20 mM) which increased cAMP levels 2- 3-fold prevented a detectable decrease in cAMP after 1 mug/ml 48/80 (measured at 10 min) and almost completely inhibited histamine release. Prostaglandin E1 (27 muM) also raised cAMP levels, decreased the 48/80-induced fall in cAMP (by 42%). Epinephrine increased mast cell cAMP levels, but did not prevent the subsequent 48/80-induced decrease in cAMP and did not inhibit histamine release. Carbamylcholine (1 nM), adenine (1 muM), and diazoxide (10 muM) lowered mast cell cAMP and potentiated 48/80 induced release. In view of previous studies from this laboratory indicating that 48/80 stimulates mast cell phosphodiesterase, it seems likely that the 48/80-induced fall in cAMP is due, at least in part, to increased cAMP destruction. Since agents which prevent the fall in cAMP inhibit histamine release, it is apparent that cAMP is an important part of the control mechanism of histamine secretion. On the other hand, it cannot be concluded that a decrease in cAMP alone is sufficient to produce a response since carbamylcholine, diazoxide, and adenine which lower cAMP do not alter histamine release unless 48/80 is also present.


Compound d+y+ particles of Australia antigen. Australia antigen (HB8 Ag) particles vary in their antigenic structure. They are generally found to carry either determinant d or determinant y, but not both. This report describes seven sera which contain Australia antigen carrying both d and y on the same particle.


Experimental autoimmune encephalomyelitis in mice: immunologic response to mouse spinal cord and myelin basic proteins. It was confirmed that experimental autoimmune encephalomyelitis EAE, could be induced in SJL/J mice with mouse spinal cord homogenate. It was shown that induction of EAE in mice was critically dependent on the concentration of pertussis vaccine. The encephalitogen present in mouse brain was the basic protein of myelin. The smaller form of the mouse and rat basic proteins induced EAE; thus the mouse like the rat responds to determinants other than the "tryptophan region," which induced EAE in guinea-pigs. Mice with EAE developed a cell-mediated immune response to myelin basic protein, as judged by inhibition of peritoneal cell migration. However, levels of antibody to mouse basic protein were low, as judged by radioimmunoassay. The establishment of this autoimmune disease model in the mouse will allow the application of well established techniques for the analysis of the immunologic mechanisms leading to disease manifestation.


Structural studies on induced antibodies with defined idiotypic specificities. I. The heavy chains of anti-p-azophenylarsonate antibodies from A/J mice bearing a cross-reactive idiotype. Amino acid sequence analysis has been performed on three groups of heavy (H) chains of A/J mice. H chains derived from unimmunized animals were compared to anti-p-azophenylarsonate (anti-Ar) antibodies which were further subdivided into those possessing and those depleted of a cross-reacting idiotype (CRI). It was found that anti-Ar antibodies bearing the CRI are homogeneous through the first hypervariable region of the H chain. The same sequence was obtained for pooled antibody isolated from the ascites fluid of 18 A/J mice or from a single mouse. The H chains appear to belong to a minor V-H subgroup. In the first 30 positions Anti-Ar antibodies depleted of the CRI had the same sequence as those containing the CRI (with small amounts of heterogeneity at some positions), but contained a mixture of sequences in the first hypervariable region of the H chain. These studies indicate that antibodies with similar specificity and with identical framework sequences, but which differ in their hypervariable regions, contain different idiotypic determinants, and support the concept that the idiotypic determinants reside primarily within hypervariable regions.


Induction of histamine release and desensitization in human leukocytes. Effect of anaphylatoxin. Hog anaphylatoxin (AT) in concentrations from 0.5 to 5 mug/ml gives a dose-dependent histamine release from human leukocytes. Concentration of 100 mug/ml AT give the same high histamine release as 5 mug/ml. This is in contrast to the histamine release obtained with anti-IgE or allergen, which give low histamine release with high doses. The histamine release obtained with AT is completed in 20 sec and the reaction is temperature- and calcium-dependent. Treatment of cells with AT in the presence or absence of calcium makes them insensitive to another challenge with AT. Such treated cells are fully responsive, however, to challenge with anti-IgE if the pretreatment has been performed in the absence of calcium. This, together with the calcium- and temperature-dependence indicates that the AT-induced histamine release is nontoxic. Treatment of cells with AT in the presence of calcium induces, besides histamine release, decrease in sensitivity to anti-IgE, indicating that both AT and anti-IgE release histamine from the same cells. We discuss to what extent AT and cell-bound Ig share intracellular mechanisms for induction of histamine release.


A hemolytic plaque assay for the detection of direct and indirect antibody-forming cells to keyhole limpet hemocyanin. A procedure is described for the in vitro enumeration of individual lymphoid cells producing antibody against Keyhole Limpet Hemocyanin (KLH) by a modification of the hemolytic plaque technique. Optimal conditions for the coupling of KLH to sheep erythrocytes by chromic chloride are described. Plaque-forming cells are detected in a liquid monolayer slide chamber assay system. The kinetics of the in vivo primary and secondary PFC responses of both rabbit popliteal lymph node cells and mouse spleen cells are described. Both direct (IgM) and indirect (IgG) plaque-forming cells can be enumerated. The method can also be used to detect an in vitro anamnestic response in dispersed rabbit lymph node cell suspensions. The method is simple, extremely sensitive and the results correlate with those previously obtained in which newly synthesized antibody was detected in similar systems using the coprecipitation assay.


A comparison of the Farr technique with equilibrium dialysis for measurement of antibody concentration and affinity. The Farr technique has been compared with equilibrium dialysis in regard to its ability to measure antibody concentration and affinity. An excellent qualitative agreement between the two techniques was obtained. Quantitatively, the Farr technique tended to underestimate antibody concentration and overestimate antibody affinity. It is likely that these observations are due to the failure of some low affinity antibodies to bind hapten under the conditions of the Farr assay.


Enzymoimmunoassay of human alpha-fetoprotein. A non-competitive method for the determination of human alpha-fetoprotein (AFP) in serum, using a pure specific antibody linked to glucose oxidase is described. When applied to human AFP, this method gives reproducible results in the range 0.7 to 15 ng/ml, in a relatively short time (6 hr). AFP sera levels of healthy human adults, pregnant women and adults with liver diseases, were tested both by enzymoimmunoassay and radioimmunoassay. In all cases, good agreement was noted between the two methods.


Immunologic studies in hypersensitivity pneumonitis--quantitative precipitins and complement-fixing antibodies in symptomatic and asymptomatic pigeon breeders. Quantitative precipitation and complement fixation tests were performed on sera from a group of patients with hypersensitivity pneumonitis (pigeon breeders' disease). Their antibody levels were compared to a selected group of similarly exposed but asymptomatic subjects. The quantity of precipitating antibodies was generally greater in serum from symptomatic breeders, although quantities in the serum from some of the asymptomatic subjects were greater than that seen in ill breeders. Complement-fixing antibodies were detected in the serum of both groups. Here again, complement-fixing activity was generally greater in the serum of ill breeders. However, one asymptomatic breeder showed complement-fixing activity greater than most of the symptomatic breeder group. These findings indicate that the presence of complement-fixing antibodies per se in serum to pigeon gamma-globulin is not sufficient to cause the symptoms of pigeon breeders' disease. We suggest that other factor(s) may be involved, such as lgE- or cell-mediated hypersensitivity.


Antigenicity and cross-reactivity of denatured fibril proteins of primary, secondary, and myeloma associated amyloids. Antisera have been produced against amyloid fibril preparations of primary, secondary, and myeloma origins. These have revealed the presence of both idiotypic and shared antigenic determinants. A high degree of cross-reactivity among the 3 types of amyloid has been found irrespective of classification. One antiserum to a secondary amyloid fibril preparation proved to be directed against A protein (the major nonimmunoglobulin constituent of secondary amyloid fibrils). This antiserum detected A protein in several of the secondary amyloids as well as in two primary amyloid fibril preparations which were degraded with alkali; These finding indicate that amyloid fibrils of various origins have similarities in composition and, therefore, may have common factors involved in fibrillogenesis.


Upper-respiratory tract complaint protocol for physician-extenders. A protocol for upper-respiratory tract complaints was administered to 226 patients in a walk-in clinic. The protocol, for use by a physician-extender in conjunction with a physician, specified the collection of data necessary for management. A decision-making algorithm separated the major causes of upper respiratory infection (URI) complaints and led to one of four plans: a physician referral, a culture only, antibiotic treatment, or symptomatic treatment only. Each patient was seen by a physician following the health assistant's interview. Of 226 patients, 96 (42 percent) would have been sent home by the protocol without seeing the physician. None of these had a complication of URI. Sixteen (seven percent) of the 226 had serious complications - all would have been referred to the physician. The protocol proved to be safe and efficient, acceptable to patients, and a reliable approach to physician-extender management of URI.


Oxime derivatives of erythromycin: inhibitors of Rous sarcoma virus reverse transcriptase activity and focus formation. 9-O-methyloximd erythromycin A and its analogue inhibited reverse transcriptase and blocked focus formation of Rous sarcoma virus. These chemicals inhibited neither DNA-dependent DNA polymerase nor DNA-dependent RNA polymerase from bacterial sources. However, they inhibited reverse transcriptase with an apparently differnt mechanism than that by rifamycin ABDP.


Purification and electron microscopy of lactic dehydrogenase virus of mice. Lactic dehydrogenase virus (LDV) was purified from infectious ascites fluid of mice bearing Ehrlich tumours using Sepharose gel filtration and rate zonal and isopycnic sedimentation. In glycerol gradients, a sedimentation coefficient of about 200S and a buoyant density of 1-14 g/ml was determined for the virus particle. Spherical particles with diam. between 62 and 80 nm, depending on the method of fixation and staining, have been identified electron microscopically. The virus particle consists of a spherical nucleocapsid wrapped into a double-layered envelope. The nucleocapsids, isolated by treatment with NP40 and purified by centrifuging on sucrose gradients had a sedimentation coefficient of 176S. Electron micrographs show spherical particles with a diam of 35 plus or minus nm. Classification of LDV as a member of the togaviridae family is discussed.


Abundant nuclear rods in adult-onset rod disease. Abundant, highly organized, rod-shaped particles have been found in skeletal-muscle nuclei of two patients with adult-onset rod disease. They were usually single in affected nuclei. Like myofibrillar rods, the nuclear rods consisted of bundles of long, parallel, apparently cross-linked filaments. On longitudinal section the rods had an axial periodicity and in transverse section a wire-mesh appearance. Average periodicities were 189A (nuclear) and 178A (myofibrillar) axially, 180A (both) transversely between the longitudinal rod-filaments on longitudinal-section and cross-section of the rods. Minor differences were that the nuclear rods were slightly lighter stained after osmium-uranyl acetate-lead citrate, lacked thin filaments protruding from their ends, and often were broader. It is proposed that nuclear rods may have a contractile-protein composition and pathokinesis similar to that of myofibrillar rods. Their formation may reflect an epitomization of a newly recognized general biological capability of exogenous, or perhaps endogeneous, nuclear protein alteration.


Cardiac histamine-ouabain interaction: potentiation by ouabain of the arrhythmogenic effects of histamine. Cardiac effects of histamine include stimulation of sinus rate and ventricular contractile force, impairment of atrioventricular conduction and increase in ventricular automaticity. Atrioventricular block and increase in ventricular automaticity are common features of digitalis toxicity. The purpose of the present investigation was to study the influence of low concentrations of ouabain on the cardiac effects of immunologically released and administered histamine. Hearts excised from guinea pigs passively sensitized to penicillin antigens responded to antigen with sinus tachycardia, atrioventricular conduction block, increase in ventricular automaticity, decrease in coronary flow rate and histamine release. During anaphylaxis in the presence of ouabain, 10-9 and 3 times 10-9 M, the duration of conduction arrhythmia and the incidence of ventricular automaticity were greatly increased. Dose-response studies for the cardiac effects of exogenous histamine were conducted in vitro in the presence of ouabain 10-9 and 3 times 10-9 M. Ouabain, in a concentration-dependent fashion, potentiated histamine-induced prolongation of the P-R interval, but not the increases in sinus rate and in ventricular contractile force. Oution block and idioventricular also greatly increased the incidence of histamine-induced atrioventricular conduction block and idioventricular rhythms. Our results clearly identify a histamine-Ouabain interaction leading to severe disruption of atrioventricular conduction and to increased ventricular automaticity.


The uptake of a substituted acridone by rat mast cells in relationship to histamine release: a possible indicator of exocytosis-induced expansion of the plasma membrane. A substituted acridone, 10-(2-dimethylaminopropyl)-9-acridone HCl (M-129), was taken up by isolated rat peritoneal and pleural mast cells in direct relationship to the degree of selective histamine release induced by compound 48/80. Other selective releasing agents, i.e., polymyxin B and anti-rat mast cell serum, also augmented uptake of M-129. Augmented uptake of M-129 was inhibited by measures that inhibited selective histamine release, i.e., cold, brief heating of the mast cells, N-ethylmaleimide and ninhydrin. 48/80 did not agument uptake of M-129 in rat erythrocytes or in rat serous fluid cells from which mast cells had been removed. M-129 taken up by mast cells was readily removed by two to three washes. Augmented uptake induced by 48/80 was specific for M-129 and acridone itself. Related compounds, i.e., a quaternary acridone derivative [10-(2-triethylaminoethyl)-9-acridone iodide] (M-231), acridine and acridan did not show augmented uptake. There was no relationship between heptane-water partition coefficients and uptake. It is postulated, based on estimates of cell membrane area, that M-129 is loosely bound to plasma membrane and that the augmented uptake associated with selective histamine release from rat mast cells is due to expanded plasma membrane that results from irreversible or slowly reversible exocytosis.


The cyclical variation in the percentage of ciliated cells in the normal human endometrium. The percentage of ciliated cells in the luminal and glandular epithelia of endometrial samples from sixty-eight normal women has been studied. Although the concentration of ciliated cells found in the luminal epithelium tended to lag behind and below those found in the glandular epithelium, no significant difference was found between the absolute percentages of ciliated cells in each site. The number of ciliated cells increased during the proliferative phase to reach a maximum of around 20%. This was maintained during the ovulatory phase, and then declined. The hormonal basis of this variation is discussed.


A simple method for the preparation of luminal epithelial and stromal cells from rat uterus. An apparatus and procedure is described permitting the ready separation of luminal epithelial and stromal cells (together with the glands) from the rat uterus.


Prenatal diagnosis of a neural tube defect: Meckel syndrome. A severe neural tube defect diagnosed in a 191/2-week-old "at risk" fetus on the evidence of a markedly elevated alpha-fetoprotein level in the amniotic fluid, turned out to be an occipital myelocoele. However, the fetus also had polycystic kidneys and postaxial hexadactyly on all extremities. The karyotype was normal. These are the features of the rare Meckel syndrome, caused by a pleiotropic, autosomal, recessive gene, and one and possibly two other sibs were also affected.


A case of hyalinosis cutis et mucosae (lipoid proteinosis of Urbach and Wiethe) with common ancestors in four remote generations. We report a case of hyalinosis cutis et mucosae, a rare disorder of hyalin deposition in skin and mucous membranes, in a 27-year-old male, whose coefficient of inbreeding was 0-0106 due to seven common ancestors, including an aunt of an early American president, in the eight preceding generations.


Giemsa banding of chromosome 1gh+ and linkage analysis. A four-generation transmission of 1qh+ chromosome was ascertained by routine chromosome analysis of a mildly dysmorphic and retarded 61/2-year-old female. Concordance between synophrys and the 1qh+ marker was the only consistent phenotypic relationship. The variant chromosome did not appear uncoiled, and Giemsa centromeric staining (C-bands) revealed an increased width of the heterochromatin commensurate with the increased length of the long arm. Giemsa banding of the entire chromosome (G-bands) revealed two heterochromatin bands, identical in appearance, in the centromeric region with the remainder of the chromosome showing normal banding. The distribution of Duffy blood groups in the pedigree was consistent with the locus being on chromosome No. 1.


Deletion of the short arm of chromosome No. 10. A newborn male infant, whose karyotype was 46,XY,del(10)(p13) is presented. The clinical features included cleft lip and palate, preauricular pits, low set malpositioned auricles, antimongoloid slant of the eyes, microcephaly, micrognathia, congenital heart disease, hypertrophic pyloric stenosis, cryptorchidism, and abnormal dermatoglyphics. The child died at the age of 3 months in overwhelming urinary infection with septicemic complications. It is suggested that the features described here may represent a new, clinically recognizable chromosomal syndrome.


Correlation analysis of electrical noise in lipid bilayer membranes: kinetics of gramicidin A channels. If a membrane contains ion-conducting channels which form and disappear in a random fashion, an electric current which is passed through the membrane under constant voltage shows statistical fluctuations. Information on the kinetics of channel formation and on the conductance of the single channel may be obtained by analyzing the electrical noise generated in a membrane containing a great number of channels. For this purpose the autocorrelation function of the current noise is measured at different concentrations of the channel-forming substance. As a test system for the application of this technique we have used lipid bilayer membranes doped with gramicidin A. From the correlation time of the current noise generated by the membrane, the rate constants of formation (k-R) and dissociation (k-D) of the channels could be determined. In addition, the mean square of the current fluctuations yielded the single-channel conductance lambda. The values of k-R, k-D, and lambda obtained from the noise analysis agreed closely with the values determined by relaxation measurments and single-channel experiments.


Biochemical properties of a hamster syncytium-forming ("foamy") virus. A hamster syncytium-forming ("foamy") virus (HFV) was characterized. The HFV sedimented in isopyknic sucrose density gradients at 1.16-1.165 g/ml. It had RNA but no DNA, its replication was inhibited by actinomycin D, and it contained virion-associated, RNA-dependent DNA polymerase. Analysis of the RNA from purified virus showed several species: 62S, 40S, 28-30S, 18-20S, and 4-7S.


Development of hepatocellular carcinomas in rats treated with benzene hexachloride. The effects of prolonged oral administration of the alpha-, beta-, and gamma-isomers of benzene hexachloride (BHC) on rat liver were examined histologically. Well-differentiated hepatocellular carcinomas were observed in the liver of rats fed a basal diet containing 1,500 or 1,000 parts per million (ppm) of alpha-BHC for 72 weeks. Many typical nodular hyperplasias developed in all groups given 1,500 or 1,000 ppm alpha-BHC. In non-neoplastic areas, slight oval cell infiltration and bile duct proliferation were seen. No neoplastic changes or other abnormal findings, such as oval cell infiltration, fatty changes, fibrosis, or bile duct proliferation of the liver, were observed in groups receiving 500 ppm alpha-, beta-, gamma-, or gamma-BHC.


Subsequent neoplasia in chronic lymphocytic leukemia. We performed a retrospective analysis of all 102 cases of chronic lymphocytic leukemia (CLL) treated by the Hematology Service of the University of Manitoba from Jan 1, 1955, to April 1, 1974. The incidence of secondary cancer was compared with that in the Cancer Registry population of Manitoba of the same age and sex distribution. The risk of all cancers developing in patients with CLL was threefold that for the age- and sex-matched population, eightfold for skin cancers, and twofold for all cancers excluding skin cancer.


Acute viral hepatitis in adults. Comparison of the radioimmunoassay and counterimmunoelectrophoresis methods of detecting HbsAg. We compared the radioimmunoassay (RIA) and counterimmunoelectrophoretic (CIE) methods in detecting hepatitis B antigen (HBsAG) in 407 acute and 336 convalescent sera of adults with viral hepatitis. The CIE method demonstrated that 41% of acute and 28% of 14-to 17-day serum specimens were HBsAg-positive. The RIA method demonstrated seropositivity in 60% of acute and 56% of convalescent specimens (P less than .001). Eighty-four percent of coded specimens initially positive for HBsAg by RIA were found to have subtype antigenic determinants d or y; 92% of the HBsAg-negative controls were negative for subtype antigens, confirming the specificity of the RIA test. RIA subtyping data corroborated earlier work with immunodiffusion techniques.


Palliative irradiation for liver metastases. Eleven patients underwent palliative irradiation for symptomatic liver metastases. The whole liver is included in the radiation field. The treatment is given with a cobalt teletherapy unit. Daily doses are 150 rads calculated in the midliver plane. The total dose employed is 2,500 rads given in a three-week period. Eight patients had good response, two moderate response, and one patient failed to respond to treatment. Liver function studies and liver scans also reflected the treatment response. All patients tolerated the treatment and no deaths were attributed to liver irradiation. The impression is that radiation therapy is valuable for the treatment of symptomatic liver metastases in the young patient who does not have a terminal condition.


Studies on the pathogenesis of rheumatic heart disease. An immunological relationship between the polysaccharide of group A streptococcus and the glycoprotein of heart valve. The immunization of rabbits with bovine heart valve homogenates induced the formation of antibody which reacted with CTC soluble extracts and also proteolytic enzyme treated fractions. Analysis by fractionation of materials revealed 2 peaks and both peaks contain monosaccharides. The first peak was more antigenic to anti-valvular sera. The cross-reactivity between the valvular glycoprotein and group A streptococcal polysaccharides was confirmed by the immunological inhibition tests. Widespread deposits of gamma globin were observed in valve of patients with recurrent rheumatic valvulitis who has valve replacement. This work was performed under scientific-grants-in-aid from the Ministry of Education. Portions of this study were presented at the 38th annual meeting of the Japanese Circulation Society, Yamaguchi, April, 1974.


Studies on myocarditis in childhood, with special reference to the possible role of immunological process and the thymus in the chronicity of the disease. Twenty-one cases of idiopathic myocarditis were studied. Fulminant form 1 case, acute fatal form 2 cases, acute benign form 4 cases, recurrent form 1 case. Chronic dilated form 2 cases progressive hypertrophy form 2 cases and asymptomatic and sudden death form was 10 cases. Clinical signs and symptoms of these cases were manifold. Also laboratory findings were nonspecific. Ten cases of latent myocarditis which showed sudden death syndrome were found among 47 cases, progressive hypertrophy form 2 cases and children. Early detection of latent myocarditis is considered to be necessary for preventing sudden death syndrome in school children. The relationship between cardiomyopathy and idiopathic myocarditis was discussed. Two cases of idiopathic myocarditis simulating cardiomyopathy were presented. The pathogenesis of chronicity in idiopathic myocarditis was discussed. Bound gammaglobulin in heart muscle was detected in a case showing progressive hypertrophy of the ventricles. Autopsy results showed a previously undescribed finding that the cases having normal thymus/body weight ratio tended to have markedly increased heart weight but the cases having increased thymus/body weight ratio tended to have near normal heart weight. These results are considered to suggest the possible role of immunity in the chronicity of idiopathic myocarditis.


[The single child (author's transl)].

[The single child (author's transl)]. Single children are in a special situation which tends to disturbances of behavior and psychosomatic reactions. They are often symbiotic children with mainly anxiety symptoms. A narcissistic link between mother and single child renders the necessary detachment and achievement of identity more difficult. Psychodiagnosis provides important clues. The doctor has duties of advice and education for mother and child which have already been pointed out by v. Czerny. Success of psychotherapy achieving maturation of such children is often likely only if both mother and child are treated simultaneously.


[The diagnostic value of cytology of the CSF (author's transl)]. Cytological examination of cerebrospinal fluid needs special techniques of cell collecting and staining. On condition of realizing the methodical requirements cytology of the cerebrospinal fluid brings more advancement in diagnostics than other laboratory examinations. The advantages of this procedure are: 1. Meningitis, meningoencephalitis, and subarachnoidal hemorrhage can be immediately diagnosed by cytological examination of the cerebrospinal fluid. In cases of encephalitis cytological findings depend on the extend of the inflammatory process and its distance from the cerebrospinal fluid compartement. Absence of tumor cells in preparations of cerebrospinal fluid cannot exclude primary or secundary brain tumors. 2. Cytological examination enables a better insight into the dynamics of cellular reactions proceeding in the cerebrospinal fluid as well as in its enlining tissues.


[The lymphocyte cytotoxicity test in tumor immunology (author's transl)]. The cytotoxic action of lymphocytes on cancer cells in vitro indicates sensitization of the patient against his own tumor. The technical difficulities of this test and possibilities of standardization and simplifying the procedure are discussed. Critical steps are isolation of lymphocytes and culturing target cells without loosing their specific antigenic structure. The need for specificity controls both for lymphocytes and tumor cells is emphasized. Labelling tumor cells with isotopes represents a major improvement in evaluating the result. The role of thymus- and bone marrow-dependent lymphocytes as well as blocking factors in the serum of tumor patients can be analyzed in the cytotoxic assay. A better understanding of these mechanisms may facilitate a therapeutic approach by manipulating the interaction of tumor cells and host.


Light-microscopical demonstration of different cell membrane structures of human peripheral blood lymphocytes (PBI). Labelling of membrane structures in human peripheral blood lymphocytes is achieved by a Fe-(III)-hydroxide-glycane-complex. According to the distribution of labelled structures, coarse-granular clustered (about 80%) and fine-granular diffuse marked peripheral blood lymphocytes can be distinguished. Each of these populations seems to have morphologically discernible subpopulations.


Blood and Urinary nicotine in non-smokers. Of 39 urban non-smokers about half had measurable quantities of nicotine in their plasma (range 0 to 5times5 ng. per ml.) and almost all had nicotine in their urine during the early afternoon. The average concentration of urinary nicotine in non-smokers under natural conditions was 10times7 ng. per ml., but after deliberate exposure to tobacco smoke (mean duration seventy-eight minutes) in an unventilated room (38 p.p.m. of carbon monoxide) the average urinary nicotine level (80 ng. per ml.) was significantly higher than in non-smokers who had not been deliberately exposed to smoke (P less than 0times 001). Under natural conditions there was no overlap between the urine levels of non-smokers and the far higher levels of 18 smokers (mean 1236 ng. per ml.), suggesting that urinary nicotine may provide a more accurate assessment of an individual's smoking-status than blood-carboxyhaemoglobin. It is concluded that, as a result of passive smoking, most urban non-smokers have measurable amounts of nicotine in their bodyfluids for most of their lives.


Rubella-specific serum and nasopharygeal immunoglobulin responses following naturally acquired and vaccine-induced infection. Prolonged persistence of virus-specific IgM. Rubella-specific immunoglobulin responses in sera and nasopharyngeal secretions were compared in groups of adult females who had experienced naturally acquired rubella or infection induced by Cendehill, HPV77.DE-5, RA27/3 (subcutaneously and intranasally), and To-336 vaccines. Serum IgG and IgA and nasopharyngeal IgA responses after vaccination by RA27/3 intranasally most closely resembled those induced by naturally acquired infection. However, the other vaccines failed to induce a persistent local IgA response. Levels of local antibody induced by HPV77.DE-5 were especially poor. Virus-specific IgM was detected for prolonged periods. The highest levels and the most persistent response followed vaccination by HPV77.DE-5, four of five volunteers still having rubella-specific IgM at 1 year. Virus-specific IgM persisted for 6 months in seventeen of twenty-five (68%) and for a year in nine of twenty-four (38%) vaccinees. It was still present in four of nine (44%) naturally infected patients at a year.


Persistence of specific IgM after natural infection with rubella virus. Levels of specific IgM antibody in thirteen cases of rubella were determined at intervals during the year after the illness. Persistence of IgM varied; in one patient it was no longer detectable at 23 days, but in two it was still detectable more than 10 months after the acute infection. Thus the mere finding of rubella-specific IgMin the blood does not indicate the timing of the acute episode any more accurately than some time within the previous 10-12 months.


Neglected coeliac disease.

Neglected coeliac disease. A review has been carried out of patients diagnosed as having coeliac disease some years previously and subsequently lost to follow-up. Most were unaware of the need for continuing treatment and had returned to a normal diet. The resulting morbidity was slight, although one patient had died of a small-bowel lymphoma. If untreated coeliac disease is indeed a pre-malignant condition, then it is suggested that there must be a large population at risk, with no motivation to return to treatment other than the risk of malignancy itself.


Severe viral hepatitis type B in infancy;. Fourteen infants aged from 2 to 5 months were admitted to hospital with acute viral hepatitis. Their clinical presentation ranged from severe disease to fulminant hepatitis. In all patients the prothrombin-time was 10% or less of normal and serum glutamic pyruvic transaminase and bilirubin were increased. In eight cases liver-biopsy specimens were obtained during liver failure and showed a widespread necrosis without inflammatory cells. Hepatitis-B-surface antigen (HBSAg) and antibody (HBSAb) were sought by several techniques, including passive haemagglutination and radioimmunoassay. Hepatitis was associated with hepatitis-B  virus in eleven out of fourteen patients as judged by the detection of HBSAg and/or a secondary rise in HBSAb. In eight cases, the infants had received blood-derivatives in the neonatal period. The mothers of five of the remaining cases were found to be chronic carriers of HBSAg. Despite intensive supportive therapy, including repeated exchange transfusions and administration of anti-HBS gamma-globulins (six cases), eight patients died. These cases demonstrate that severe or fulminant type-B hepatitis can develop in infants, who are capable of completely eliminating the hepatitis-B virus. They also suggest that severe hepatitis can result from maternal contamination.


Surgical and economic advantages of polyglycolic-acid suture material in skin closure. A prospective, randomised trial compared polygycolic-acid subcuticular skin closure with interrupted silk skin closure in 152 patients. There was no significant difference in the incidence of wound infection. The use of polyglycolic acid was associated with economic advantages.


Common variable immunodeficiency, Hodgkin's disease, and other malignancies in a Newfoundland family. A large inbred family is described in which there were seven cases of Hodgkin's disease, three of lymphosarcoma, two of thymoma, two of common variable immunodeficiency, and single cases of retinoblastoma, neuroblastoma, and rhabdomyosarcoma. There have been no other lymphoma cases in the community during the past decade. Further study of this family may help to define the genetic basis for development of Hodgkin's disease and other disorders.


Selective planned induction in conditions of civil strife. Selective planned induction may be defined as the initiation of labour by artificial means for reasons not strictly medical. Where the indications are merely social or for conveniencewhether patient's, hospital's, or doctor'sīt is doubtful that the procedure is acceptable until we have more detailed knowledge of its effects on the mother and fetus. However, the civil strife that occurred in Belfast in 1972 provided conditions in which the present study of the technique seemed justified. The results suggest that, provided the selection criteria are sufficiently rigorous and meticulously applied, there are no serious maternal risks. The main fetal risk is of unexpected prematurity; this can be avoided, but the precautions applied in this preliminary study reduced significantly the number of patients for whom the method could be used. A second series, with controls and using less rigorous selection criteria, is at present being studied.


Slow encephalopathies, inflammatory responses and arachis oil. There is much interest in the possibility that diets rich in some plant oils may be of prophylactic and curative value in certain clinical conditions. This is generally attributed to the immunosuppressive effects of polyunsaturated fatty acids. Arachis (peanut) oil injections can increase the incubation period of experimental scrapie in mice. In the late 1950s several workers showed that arachis and some other oils contained very potent anti-inflammatory components quite apart from the polyunsaturated fatty acids. This suggests that the supposed efficacy of these acids in some clinical situations could be due to trace substances rather than the lipid itself and that the apparent ability of scrapie agents to use the host's lymphoreticular system as a Trojan horse may involve elements of the inflammatory system rather than the B/T cell immune system.


Polymyositis and myasthenia gravis: immunodeficiency disorders involving skeletal muscle. Human polymyositis and aspects of myasthenia gravis may be consequences of subtle immunodeficiency states. Autoimmune processes leading to inflammatory muscle disease and the presence of associated tumours may reflect the partial loss of antibody-mediated homoeostatic mechanisms.


Mortality committee as an educational and administrative tool. The establishment of a mortality committee as an educational exercise in a general hospital in rural Kenya was found to have widespread implications. Its findings led to an expansion of the community health services based on the hospital. Within the hospital it resulted in extensive alterations in routine procedures, plant, equipment, and a redeployment of staff.


Future prospects for British graduates and the health service. What are the prospects, in the National Health Service, for the increasing output of British medical schools? A comparison of the numbers of training and career posts likely to be available in N.H.S. hospitals with the probable requirements of British graduates seeking training suggests that the supply of senior-house-officer and registrar posts will far exceed the demand, so that dependence on overseas doctors is likely to continue. The number of senior-registrar posts should ensure that the present percentage of graduates become consultants, but available consultant posts seem likely to exceed the output of qualified applicants. The only grade for which demand looks likely to exceed supply is the compulsory preregistration grade: in three years' time medical-school output could be greater than the number of approved posts.


Medicine and health: What connection?

Medicine and health: What connection? In most countries resources for the health services are allocated, increasingly and often overwhelmingly, to hosptial-oriented medical care and drug-dependent therapy. The assumption that community health will thereby be improved remains questionable even in developed countries, and is insupportable in developing countries. Technical advances and specialisation in medical sciences are now counterproductive by pre-empting limited resources and obscuring basic needs. To re-establish proportionality, priority should be accorded to: (a) application of proven preventive procedures for hazards of high prevalence, including excessive population growth; (b) improvements in housing and sanitation; and (c) extension of primary care by medical and other staff specially trained in the early recognition and management of personal complaints and of family and community problems.


Neuropsychological dysfunction in children with chronic low-level lead absorption. To investigate the relation between low-level absorption and neuropsychological function, blind evaluations were under-taken in forty-six symptom-free children aged 3-15 years with blood-lead concentrations of 40-68 mug. per 100 ml. (mean 48 mug. per 100 ml.) and in seventy-eight ethnically and socioeconomically similar controls with levels greater than mug. per 100 ml. (mean 27 mug. per (100 ml). All children lived within 6-6 km. of a large, lead-emitting smelter, and in many cases residence there had been lifelong. Mean age in the lead group was 8-3 years and in the controls 9-3. Testing with Wechsler intelligence scales for schoolchildren and preschool children (W.I.S.C. and W.P.P.S.I.) showed age-adjusted performance I.Q. to be significantly decreased in the group with higher lead levels (mean scores, W.I.S.C. plus W.P.P.S.I., 95 v. 103). Children in all ages in the lead group also had significant slowing in a finger-wrist tapping test. Full-scale I.Q., verbal I.Q., BEHAVIOUR, AND HYPERACTIVITY RATINGS DID NOT DIFFER.


Relation of thyroid-stimulating immunoglobulins to thyroid function and effects of surgery, radioiodine, and antithyroid drugs. Thyroid-stimulating immunoglobulins (T.S.I.) have been detected in the serum of all patients with untreated Graves' disease, and in these patients the levels of T.S.I. correlated significantly with the early uptake of 131I by the thyroid. The frequency of T.S.I. in patients treated solely by antithyroid drugs, by radioiodine, or by partial thyroidectomy was 53 per cent, 50 per cent, and 17 per cent, respectively. The reduced frequency of T.S.I. in the serum of patients treated by drugs or radioiodine was probably due to spontaneous remission, but in the case of partial thyroidectomy the operation itself clearly had a dramatic effect on the serum-T.S;I. These results accorded well with the reported frequency of thyroid autonomy in similar groups of patients and suggested that thyroid-stimulating immunoglobulins were responsible for hyperthyroidism in Graves' disease.


Ampicillin-resistant Haemophilus influenzae type B possessing a TEM-type beta-lactamase but little permeability barrier to ampicillin. Ampicillin-resistant Haemophilus influenzae type B have been reported only during the past year. Five clinical isolates from the U.S. and Germany all had the TEM-type beta-lactamase which is known to be transferred widely among other gram-negative bacilli. Unlike those bacilli, however, the H. influenzae cell had very little barrier to entry of penicillins. This greater permeability of the H. influenzae cell to penicillins appeared to reduce the protective effect of its beta-lactamase, in that acquisition of the TEM-type beta-lactamase increased levels of resistance to penicillins much less for individual cells of H. influenzae than for those of Escherichia coli. Large inocula of either species appeared highly resistant. The unusually low level of resistance of individual cells of H. influenzae containing the TEM-type beta-lactamase may have delayed their emergence or recognition, and has unresolved clinical implications.


Treatment of osteolytic myelomatosis with mithramycin. The treatment of rapidly progressive skeletal demineralisation in myelomatosis has been studied with the help of metabolic calcium balance in two patients; In one, osteoporosis accelerated during treatment with melphalan and prednisolone, although he remained normocalcaemic throughout, suggesting that osteoporosis was aggravated by corticosteroid therapy. In the other patient, who was initially hypercalcaemic, conventional treatment produced clinical remission before eventual relapse with more hypercalcaemia and skeletal dissolution. Both patients were then treated with mithramycin alone, and, although neither obtained haematological remission, bone pain was relieved, hypercalciuria and hypercalcaemia were abolished, and calcium balances proved that mithramycin was effective in restoring calcium equilibrium. The results indicate that mithramycin may abolish excessive bone resorption in myelomatosis and that severe bone dissolution may occur in the absence of hypercalcaemia. Regular determination of 24-hour urinary calcium excretion as well as of plasma-calcium is important in monitoring process. Mithramycin should be considered in the early treatment not only of hypercalcaemia but also of severe hypercalciuria, if these complications do not rapidly remit during the first course of conventional myeloma therapy, with or without steroids. Finally, these results add to evidence that a humoral factor may be responsible for osteoclast stimulation in myelomatosis.


Insulin, plasma aminoacid imbalance, and hepatic coma. It is proposed that severe impairment of liver function in cirrhosis or portacaval shunt results in unrestricted entry of insulin into the peripheral circulation. The ensuing high level of insulin promotes excessive removal of the branched-chain aminoacids by muscle, thereby lowering the plasma levels of these aminoacids. In consequence, the competitive action of the branched-chain aminoacids on the entry of tryptophan into the brain is reduced, more tryptophan enters the brain, and serotonin is synthesised in excess, thus facilitating hepatic coma.


The role of lipid in the pathogenesis of atherosclerosis. An experimental model of atherosclerosis sheep veins identical to the human disease indicates (i) that ingestion of an atherogenic diet is not a prerequistie in atherosclerosis and (ii) that haemodynamic stress must be the dominant aetiological factor in atherosclerosis. Ultrastructural studies reveal that the early lipid deposition in spontaneous human atherosclerosis and in haemodynamically induced atherosclerosis is related to the trasnformation of extracellular vesicular debris into closely packed membranous profiles with electron-translucent centres. It is postulated that the vesicular dtsintegration of mural cells is due to the same haemodynamic stresses which induce degenerative changes in the vascular connective tissues, and that the lipid accumulation within the vesicular disintegration of mural cells is due to the same haemodynamic stresses which induce degenerative changes in the vascular connective tissues, and that the lipid accumulation within the vesicular debris is a cellular debris which have not undergone resolution or phagocytosis.


Needle biopsy for muscle chemistry.

Needle biopsy for muscle chemistry. Needle biopsy can readily provide samples of human skeletal muscle for biochemical analysis. Muscle metabolites are measured by enzymic microanalytical techniques and electrolytes by neutron-activation analysis. This paper summarises the methods of analysis, gives the normal ranges for muscle contents of metabolites and electrolytes, and reviews the reported changes in a number of neuromuscular and metabolic disorders. Muscle is a fairly homogeneous tissue in health, but replacement with fat and fibrous tissue in myopathies causes error in analyses unless metabolites are referred to a reliable standard. It is recommended that needle-biopsy samples to be freeze-dried and dissected to remove connective tissue before analysis. Total creatine (phosphorylcreatine+free creatine) total adenosine+inosine nucleotides, and potassium and phosphorus separtely correlated very highly with sample dry weight after dissection, suggesting that these may be used as standards. When assessing whether a given metabolite is present in an abnormal amount, it is probaby advisable to check the content with reference to more than one standard, since one or more of these may be changed in disease.


Association of foot lesions with retinopathy in patients with newly diagnosed diabetes. A proportion of newly diagnosed diabetic patients have features so characteristic that they form a distinct syndrome. The patients are predominantly male and present with a foot lesion which is often long established. They are subsequently found to have diabetes mellitus and diabetic retinopathy. In addition, many of them manifest a striking indifference towards their illness. 47 such patients have been seen between the years 1960-1969 at a diabetic clinic in Birmingham which saw a total of 6451 newly diagnosed patients in the same period. 26 of the 45 patients in whom follow-up was complete have died. The present state of health of the 19 surviving patients indicated that the prognosis is poor for patients who have retinopathy and foot lesions when diabetes is diagnosed.


Islet-cell antibodies in juvenile diabetes mellitus of recent onset. Antibodies reacting with human pancreatic islet cells were found by immunofluorescence in the sera of 51 of 105 children with diabetes mellitus of recent onset. These antibodies were of IgG class, and several of them fixed complement and reacted with pancreatic islets of other species. Thyroid microsomal and/or gastric-parietal-cell antibodies were found in only 10 of the patients with islet-cell antibodies, and none of them had adrenal antibodies. These findings contrast with previous reports which have stressed the rarity of islet-cell antibodies in adult diabetics and their occurrence only in patients with other evidence of autoimmune disease.


Increased incidence of malignancy during chronic renal failure. The incidence of cancer in 646 dialysis/transplant patients before uraemia developed, during the period of progressive uraemia, and post-transplantation was compared. 10 tumours (3 breast, 2 kidney, 1 leukaemia, 1 lung, 1 insulinoma, 1 thyroid, 1 cervix in situ) developed in 9 patients during the period of progressive uraemia, a significant increase over the expected number in the age-matched general population. 6 of these patients have received transplants and have no evidence of recurrent disease 6 months to 4 years post-transplantation. 11 de-novo tumours have developed in 530 transplant recipients (4 cervix in situ, 2 skin, 2 reticulum-cell sarcoma, 1 lip, 1 dysgerminoma, 1 colon)--a significant increase over the age-matched general population. The cancers in the uraemic patients are relatively common types of mesenchymal tumours while the cancers in the transplant recipients are epithelial and lymphoproliferative. This difference may reflect the presence of the graft in the transplant patient or may be due to different patterns of immunosuppression in these two populations.


Direct inhibition of gastric acid by growth-hormone release-inhibiting hormone in dogs. To find out if growth-hormone release-inhibiting hormone (G.H.-R.I.H.) had any direct action on gastric acid production independent of its effect on gastrin release, cyclic G.H.-R.I.H. was infused at a rate of 20 mug. per kg. per hour into dogs with gastric fistulae. Gastric acid output fell sharply in response to three stimuli acid production--a meal and pentagastrin and histamine infusions. The fact that acid output was inhibited during pentagastrin administration suggests that G.H.-R.I.H. has a direct action on the gastric parietal cell.


Direct inhibition of gastric acid and pepsin secretion by growth-hormone release-inhibiting hormone in cats. Growth-hormone release-inhibiting hormone (G.H.-R.I.H.) inhibited gastric acid and pepsin secretion in response to pentagastrin and food stimulation in cats. This effect is mediated by a direct action on the parietal and peptic cells. No evidence of a post-inhibitory acid or pepsin secretory rebound was obtained. Thus a compound of hypothalamic origin can exert a direct effect on exocrine secretion. In view of its widespread actions and its presence in relatively high concentrations in various organs apart from the hypothalamus, G.H.-R.I.H. might also be regarded as a factor responsible for local coordination of endocrine and exocrine secretion.


Narcotic analgesics and delayed gastric emptying during labour. The rate of gastric emptying in women during labour was estimated indirectly from the kinetics of absorption of orally administered paracetamol (acetaminophen). Gastric emptying was normal in patients who had not received a narcotic analgesic but was markedly delayed in women given pethidine, diamorphine, or pentazocine. The inhibitory effect of diamorphine and pethidine on gastric emptying was not reversed by metoclopramide.


Effect on cytotoxicity antibodies in potential transplant recipients of leucocyte-poor blood-transfusion. In a controlled clinical trail, 40 uraemic patients received only leucocyte-poor blood (L.P.B.) while 30 uraemic controls received whole blood and ordinary packed red blood-cells (R.B.C.). Alloimmunisation by HL-A antibodies was found in 15% of the study group and 52% of the control group. Thus, L.P.B. was significantly less likely to produce alloimmunisation than ordinary whole blood or R.B.C. transfusion. Frozen R.B.C may produce even less alloimmunisation, but the advantages of L.P.B. include lower cost, prolonged storage, and ready availability in emergencies.


Cell-mediated immunity to gliadin within the small-intestinal mucosa in coeliac disease. In an attempt to demonstrate local cell-mediated immunity (C.M.I.) to gliadin in patients with coeliac disease, fragments of jejunal-biopsy specimens were cultured in the presence and absence of alpha-gliadin and the culture-medium was assayed for its capacity to inhibit migration of normal human peripheral-blood leucocytes (i.e., for a migration-inhibition factor [M.I.F.]). No M.I.F. activity was detected in the culture-medium when biopsy specimens from patients with coeliac disease or controls were cultured without added antigen. However, an M.I.F. was secreted into the culture-medium when biopsy specimens from patients with coeliac disease were cultured with alpha-gliadin. These findings suggest that there is a population of lymphocytes which are sensitised to gliadin in the intestinal mucosa of patients with untreated coeliac disease. They support the theory that a local C.M.I. reaction to gliadin may be the cause of villous atrophy and crypt hyperplasia in coeliac disease.


Prostaglandins and obesity.

Prostaglandins and obesity. In metabolic obesity energy in triglyceride stores is not readily accessible, and lipolysis to free fatty acid and glycerol seems to be somehow restrained. In the normal situation, there is a balance between a forward reaction via cyclic A.M.P. ending in lipolysis and a negative-feedback mechanism in which prostaglandins participate. In metabolic obesity there may be a biochemical error leading to overproduction of prostaglandins; as a result the forward reaction is overwhelmed and lipolysis does not take place. Since prostaglandin antagonists and inhibitors of prostaglandin synthesis are known, this hypothesis is not without therapeutic interest.


Potential effect on coronary-heart-disease morbidity of lowering the blood-cholesterol. As a practical aid to physicians and patients facing the decision whether or not to embark upon a life-long lipid-lowering regimen in the hope of preventing coronary heart-disease, estimates have been made of the potential benefits to be gained from lowering the plasma-cholesterol over a period of 20 years. The estimates have been derived from analyses of experiences in the Framingham population study. The results suggest that if 100 men who are non-smokers, with normal blood-pressure and electrocardiogram, lower their plasma-cholesterol from 310 to 260 mg. per 100 ml. starting at 35 years of age, 6 could potentially benefit by avoiding a coronary incident, 94 would be likely to follow the regimen without apparent benefit, and 8 of these would have an attack within 20 years despite adherence to the regimen. The potential benefit is less for women and for those who start the regimen at an older age. It is greater if cholesterol is lowered further and if other risk factors are present: for instance, 29 of 100 men starting at age 35 who are ciagrette smokers with moderate hypertension and left-ventricular hypertrophy and who reduce their plasma-cholesterol concentration from 310 to 210 mg. per 100 ml. would benefit.


Outpatient surgery in a developing country. 233 outpatient operations were performed under general anaesthesia on Nigerian patients whose selection was not influenced by adverse social circumstances. The complication-rate was similar to that found in comparable series from the United Kingdom. The incidence of wound infection was related to the age and social circumstances of the patient and was not affected by the type of hospital in which the operation was performed.


Diagnosis of carcinoma of the larynx: a review of current methods. There is a need to establish the diagnosis of cancer of the larynx as early as possible. Delay in making the diagnosis should occur rarely if all of the available methods are fully utilized. Having established the presence of a carcinoma it should be possible to define the site and extent of the tumor; only with this additional information can the best treatment be selected. The use of a fiber-optic laryngoscope or a telescopic laryngoscope (Gould) has made examination of the "difficult larynx" more satisfactory. X-ray examination, with or without contrast material, has provided useful information regarding extent of the tumor, particularly with regard to its relation to the glottis. Microscopic laryngoscopy has proven to be a most reliable way to identifying "the early lesion" and of establishing the extent of an established tumor, especially if supravital staining is applied and the microsurgical laryngeal mirror and laryngeal caliper are used. The most difficult diagnosis to make at the present time is the presence of residual tumor after radiation, when the tumor does not present on the surface. The solution to this problem will not be found easily.


[20 min 99mTc thyroid uptake (author's transl)]. The 20 min 99mTc thyroid uptake compares favourably with the more time consuming 24 h 131J uptake because it results in a lower radiation dose to the thyroid gland. The reliability of both methods is nearly the same. In all conditions in which the 131J uptake is altered, a similar deviation of the 99mTc uptake has been found. A single exception are patients treated with antithyroid drugs (together with thyroid hormones), who show frequently an elevated 99mTc uptake (in contrast to the 131J uptake). Prognostic conclusions have been drawn by other autors from the 99mTc uptake in similar cases.


Flavin mononucleotide reductase of luminous bacteria. NAD(P)H: FMN oxidoreductase (flavin reductase) couples in vitro to bacterial luciferase. This reductase, which is also postulated to supply reduced flavin mononucleotide in vivo as a substrate for the bioluminescent reaction, has been partially purified and characterized from two species of luminous bacterial. From Photobacterium fischeri the enzyme has a M. W. determined by Sephadex gel filtration, of 43,000 and may have a subunit structure. The turnover number at 20 degrees C, based on a purity estimate of 20 percent, is 1.7 times 10-4 moles of NADH oxidized per min per mole of reductase. The reductase isolated from Beneckea harveyi has an apparent molecular weight of 23,000; its purity was too low to permit estimation of specific activity. Using a spectrophotometric assay at 340 nm with the P. fischeri reductase, both NADH (Km, 8 times 10-5 M) and NADPH (Km, 4 times 10-4 M) were enzymatically oxidized, the Vmax with NADH being approximately twice that of NADPH. Of the flavins tested in this assay, only FMN (Km, 7.3 times 10-5 M) and FAD (Km, 1.4 times 10-4 M) were effective, FMN having a Vmax three times that of FAD. In the coupled assay, i.e., measuring the bioluminescence intensity of the reaction with added luciferase, the optimum FMN concentration was nearly 100 times less than in the spectrophotometric assay. The studies reported suggest the existence of a functional reductase-luciferase complex.


[Surgical treatment of carcinoma of the stomach (author's transl)]. Patients with carcinoma of the stomach are seen too late for surgical treatment. 130 out of the 1641 patients treated at the Erlangen hospital between 1956 and 1973, survived for a period of five years. Related to the curatively resected cases and irrespective of the surgical lethality, the rate of 5-year-survival is 34%. The proportion of prognostically favorable early carcinomas, which is 15.5% in our own patients, should be increased by early endoscopic exploration. In the patients surviving for more than five years, the rate of mortality is similar to that of the normal population. The surgical approach to carcinoma of the stomach depends on the location. Among the palliative operations, only resection results in an improvement of morbidity and mortality.


[Our experience with phase-contrast microscopy in clinical practice (author's transl)]. It is shown in a series of cases that phase-contrast microscopy is particularly suitable for intra-operative diagnosis in almost all gynecological operations. Also in smaller diagnostic measures (e. g. punch biopsy from the urinary bladder and rectum as well as curettage), phase-contrast assessment of the extracted tissue is possible with astonishing reliability.


The human leukocyte test system. III. Premature chromosome condensation from chemically and x-ray induced micronuclei. Premature chromosome condensation (PCC) was induced in human leukocytes in vitro by a bifunctional alkylating agent 2,5-bis-(methoxyethoxy)-3,6-bis-ethylene-imino-p-benzoquinone (A 139), bleomycin and X-rays. Analysis shows that PCC originates from micronuclei that have been slowed down in their cell cycles in respect to the main nuclei. The mitosing chromatin of the main nuclei induced PCC in the associated micronuclei. Morphologically the PCC was mostly of the S-phase type with the chromatin exhibiting a more or less pulverized appearance; in some experiments this was verified by incorporation of (3H) thymidine (TdR). In a few cases the PCC looked like G2-phase PCC with ladder-like chromosomes. GI-phase PCC was not found. PCC of the type described in this work may be used as an indicator of induced lagging of chromatin that can be the result of chromosomal aberrations or of nondisjunction.


Immediate hypersensitivity to hog trypsin resulting from industrial exposure. Clinical, immunologic and psysiologic studies were undertaken to establish the role of hog trypsin dust in four cases of occupational asthma and to define the mechanism of this respiratory disease. Objective evidence was obtained that these patients, but not their asymptomatic co-workers, were allergic to trypsin, and that this fact accounted for their respiratory symptoms. Direct skin testing, passive transfer of IgE antibodies, antigen-mediated histamine release from peripheral blood leukocytes and airway obstruction in response to inhalation challenge indicated IgE-mediated, Type I hypersensitivity. These effects were induced by inactivated trypsin and were therefore independent of tryptic enzymatic activity. The data suggested that periodic skin testing for immediate sensitivity to organic dust would be an inexpensive and convenient screening procedure for early detection and prevention of some types of occupational asthma.


Form and function of cat retinal ganglion cells. Recent explorations of the morphology of retinal neurones, combined with neurophysiological recordings have made it possible to link specific anatomical types with particular physiological classes. At the same time, the relatively complete anatomical mapping of the retina has revealed some bias in the sampling of neurones by electrophysiological techniques.


[Influenza. Study of recent acquisitions. Prevention and therapy]. Experience in the field of influenza (vaccination, chemical prevention, clinical pictures, treatment) during the period 1964-1974 is briefly described. The possibility that certain gastroenteric syndromes may suitably be labelled as"influenza" is examined. The usefulness of EAI antibody determination in "a posteriori" differential diagnosis of certain clinical forms, the assessment of the value of vaccination, and for mediocolegal purposes is asserted. It is suggested, in the light of personal experience, that vaccination with virus strains involved at the outset of an epidemic will only be useful where the antibody response to such strains is equal to more than 1:80. The chemical prevention of the disease is briefly examined,though the view that it is only effective in special cases is maintained.


Significance of proliferative epithelial lesions of the uterine tube. Proliferative epithelial lesions of the oviduct have been called adenomatous hyperplasia or carcinoma in situ. In order to assess the incidence and significance of these lesions, we sectioned entire oviducts from 124 nonselected hysterectomies. We found 23 cases (18.5%) with lesions corresponding to those described in the literature. We have found no justification for diagnosing and treating these lesions as carcinoma in situ. There appears to be an association with salpingitis.


Arteriography and infusional chemotherapy in localized trophoblastic disease. Despite recent advances in the systemic chemotherapy of patients with malignant trophoblastic disease, there remains a small group of patients who fail to achieve remission with this type of treatment. The present study presents 19 patients with malignant trophoblastic disease who underwent a total of 25 arteriographic studies for localization of persistent malignant lesions and 8 patients who underwent arterial infusional chemotherapy after they had failed to achieve remission by standard administration of systemic methotrexate or actinomycin D. Patients underwent pelvic, pulmonary, carotid, and multiple abdominal selective arteriograms with a high correlation of positive findings and the later documented presence of persistent malignant disease. Findings include prominent uterine arteries, arteriovenous shunts, hypervascularity, irregular vessels, and tumor staining within the tumor. Arterially infused chemotherapy with methotrexate or actinomycin D was used in 8 patients whose disease was resistant to systemic chemotherapy. Technics of arterial infusion are discussed.


Ovulation induction: ovarian response to human gonadotropins and synthetic gonadotropin-releasing hormone. Human ovarian responses to FSH- and LH-releasing hormone (FSH/LH-RH) were observed at laparotomy and studies by histologic and histochemical examination of ovarian biopsy specimens. The responses were compared to those induced by human menopausal gonadotropin (HMG) and human chorionic gonadotropin (HCG) singly and together. The subjects were healthy, fertile, young women rendered anovulatory by injections of depomedroxyprogesterone acetate (DMPA) or depochlormadinone acetate (CA). Supplementary studies included measurement of urinary pregnanediol, examination of the cervix and vagina for estrogenic and progestational responses, and endometrial biopsy, Both HMG and HCG induced follicular growth and proliferation of granulosa and theca cells, but neither, when given alone, induced ovulation or corpus luteum formation. When given in conjunction they induced single or multiple ovulations and corpora lutea in 11 of 18 women treated. FSH/LH-RH CONSISTENTLY STIMULATED FOLLICULAR DEVELOPMENT AND INDUCED OVULATION IN 2 OF 16 WOMEN TREATED. Preovulatory mature follicles were found in 3 more. FSH/LH-RH may prove to be useful in the treatment of some cases of anovulatory sterility of hypothalamic origin.


Cancer of the colon and rectum. A review. Colonic cancer remains a major cause of death because diagnosis is usually delayed. Improved methods for earlier detection will maximize the patient's chances for survival. At present, surgery offers the greatest possibility of cure, but even in those instances where less than definitive resection is possible, there is much in the way of adjunctive and palliative therapy to offer the patient.


Induction of endogenous murine C-type virus in spleen cell cultures treated with mitogens and 5-bromo-2'-deoxyuridine. In short-term cultures of BALB/c spleen cells, treatment with a combination of 5-bromo-2'-deoxyuridine (BrdU) and either lipopolysaccharide W. Escherichia coli or concanavalin A resulted in release of C-type virus into the medium. Only lipopolysaccharide induced virus release when given alone. This could be potentiated by a combined treatment with BrdU. In contrast, phytohemagglutinin at mitogenic concentration had no effect with or without BrdU, suggesting that inducibility may vary between various mitogen-responsive spleen cell populations. In AKR mice, spontaneous virus release was detectable in nonstimulated spleen cell cultures. This could be potentiated by lipopolysaccharide, whereas no further increase occurred upon additional BrdU treatment. The induced viruses had C-type characteristics in that they contained reverse transcriptase that could be distinguished from cellular enzymes by template-primer preference experiments. Furthermore, the enzyme activities were particle-associated, banding in isopycnic sucrose gradients at 1.15-1.17 g/cm-3. The presence of C-type viruses was confirmed by electron microscopy.


The structure and function of immunoglobulin domains: studies with beta-2-microglobulin on the role of the intrachain disulfide bond. Beta-Microglobulin, a low-molecular-weight protein structurally related to the homology regions of immunoglobulins, has been used to study the role of the intrachain disulfide bond in the unfolding of immunoglobulin domains. The intact protein could be reversibly unfolded in guanidine hydrochloride, as judged by circular dichroism and optical rotation. Similarly, reoxidation of the reduced protein, during transfer from high concentrations of guanidine to neutral aqueous buffer, yielded a product with spectral characteristics typical of the native protein. However, if the free SH groups were prevented from reoxidizing either by chemical modification or by holding them in the reduced state, the molecule appeared to be in the randomly coiled state even under conditions where the intact protein is in the native conformation, judged on the basis of chiroptical measurements. The complement-fixing activity exhibited by native beta-2-microglobulin was retained by the reduced and alkylated derivative, suggesting that the site may be formed from a linear array of amino acids. We suggest a model for the folding of beta-2-microglobulin (and immunoglobulin domains) in which one of the early folding events results in disulfide bond formation, the latter being an obligatory step for continued folding to the native state.


Effect of bilirubin on the distribution, elimination and anticoagulant action of dicumarol in Gunn rats-1-2 (38547). Jaundiced Gunn rats were found to have a significantly larger apparent volume of distribution and higher rate constant for elimination of dicumarol than their nonjaundiced littermates.  Anticoagulant effect-log plasma dicumarol concentration lines were parallel in the two groups of animals, with the line for the jaundiced rats shifted to a lower concentration range.  In vitro studies showed that bilirubin can displace dicumarol from serum protein binding sites. There are indications of a genetic influence on the distribution and anticoagulant effect of dicumarol in Gunn rats.


Immunochemical pattern of aspartate aminotransferase isozumes in servral rodents and in Ehrlich ascites cells (38549). Antisera against rat liver aspartate aminotransferase (EC 2.6.1.1) isozymes were used to study the activity and immunologic pattern of these isozymes in the livers of the rat, mouse, hamster, gerbil and in Ehrlich ascites cells. A double immunodiffusion precipitin test and immunoelectrophoresis showed that, except for the gerbil, there was a pattern of identity of AAT isozymes in the presence of either the antianionic or the anticationic antisera. Although gerbil AAT isozymes are immunochemically different from those of the other rodents studied, they were inactivated by the respective antiserum in a manner similar to that observed with the other species. This may suggest that antigenic determinants at the catalytic site of each of the liver aspartate aminotransferase isozymes are least likely to change throughout the evolutionary process.


Trabecular barriers (FRENULAE) of the extracapsular clefts (38563). Ferrocyanide was perfused through the vascular system of the isolated legs of 10 dogs.  Ferric ion was then injected intramuscularly (not intravascularly) into the leg.  The injected materials spread along the trabeculae of the tissues, rupturing the sheets of fibrous connective tissue (frenulae) inpeded the movement of materials in the trabeculae.  The barriers consist of sheets of connective tissue which insert on adjacent fibrous capsules.  The capsules enclose each cluster of muscle, glandular or other cells.  These barriers appear to function in conjunction with the lymphatic drainage system.


On the possible mechanism of cyanoacrylate histotoxicity. The loss of tissue fluid as a possible mechanism of cyanoacrylate histotoxicity was studied in vitro. There appears to be no statistical difference in the rates of fluid removal between methyl, isobutyl and N-octyl 2-cyanoacrylates, nor is there any correlation between fluid removed and the observed in vivo tissue damage. It is suggested that tissue fluids play a dual role in initiating polymerization and in polymer degradation; and that tissue damage depends upon the rate of polymer decomposition with the formation of toxic degradation products.