Shared idiotypic determinants on B and T lymphocytes reactive against the same antigenic determinants. III. Physical fractionation of specific immunocompetent T lymphocytes by affinity chromatography using anti-idiotypic antibodies. Anti-idiotypic antibodies made against antigen-binding receptors on T lymphocytes with specificity for certain Ag-B locus antigens selectively react with T lymphocytes with potential immune reactivity against the very same Ag-B antigens. This was shown by affinity chromatography of normal Lewis T lymphocytes on anti-Ig columns after contact with the relevant anti-idiotypic antiserum. Here, it could be shown that incubation of the cells with an anti-(Lewis-anti-BN) antiserum caused subsequent selective retention of potential graft-vs.-host (GvH)-reactive cells against BN on the anti-Ig column, whereas Lewis T cells with reactivity against DA or August (Au) (carrying distinct Ag-B antigens in comparison to BN) passed through. The retained cells could be eluted and shown to display highly increased reactivity against BN with virtually no reactivity left against DA or Au antigens. Analogous results were obtained using an anti-(Lewis-anti-DA) antiserum. The anti-idiotypic antibodies can be used in fluorescent antibody tests to directly visualize the idiotype-positive cells. Using the separation design described above we analyzed selectively enriched or deleted T lymphocytes for presence of idiotypic cells as well as specific GvH reactivity. A highly significant positive correlation was found between percentage of a given idiotype in a population of T cells and the relevant GvH potential of the same T cells that can be visualized are indeed the very same T cells that express immune reactivity against the expected antigens. The present data would thus directly demonstrate the existence of a largely nonoverlapping population of immunocompetent T cells capable of reacting against the various Ag-B locus antigens in the rat. Highly purified, functionally intact immunocompetent T lymphocytes with restricted immune reactivity can thus be produced from normal lymphocyte populations for further analysis.


Enhancement of human interferon production by neutral red and chloroquine: analysis of inhibition of protein degradation and macromolecular synthesis. Two lysosomotrophic drugs, neutral red and chloroquine, enhance polyinosinic:polycytidylic acid-induced interferon production by a strain of diploid human fibroblasts (FS-4). Treatment of cells with neutral red or chloroquine between 2.5 and 3.5 h after induction increases interferon yields 16- to 64- and 4- to 16-fold, respectively, in the subsequent 20.5 h. The two drugs inhibit the rates of protein degradation and of RNA and protein synthesis. In addition, neutral red is a very potent inhibitor of uridine transport into cells. Normalized dose-effect curves show that interferon superinduction is correlated with the inhibition of macromolecular synthesis, but not with that of protein degradation. Treatment of cells with chloroquine at low concentration (25 mug/ml) for a prolonged period of time (24 h) caused approximately 40% reduction in the rate of protein degradation. The usual rapid shutoff of interferon production and the effectiveness of effectiveness of actinomycin D superinduction are not altered by this treatment. This strongly suggests that inhibition of intralysosomal protein degradation does not significantly contribute to interferon superinduction. Degradation of the rapidly and the slowly turning over proteins was unaffected by actinomycin D under conditions of treatment known to enhance interferon production. Treatment with cycloheximide (5 or 50 mug/ml for 5 h) inhibited the rate of degradation of the rapidly turning over component by 10% and the slow component by 30-40%, which suggests that the two components turn over by distinct cellular mechanisms.


Recognitive specificity of human cytotoxic T lymphocytes. I. Antigen-specific inhibition of human cell-mediated lympholysis. The specificity of antigen recognition by in vitro sensitized human cytotoxic T lymphocytes (CTLs) has been studied using a sensitive cell-mediated lympholysis (CML) assay. Frequently, high levels of cytotoxicity are observed on third-party targets unrelated to sensitizing or responding cells; however, no cytotoxicity differing significantly from zero has been observed on targets autologous to the responding CTLs. This "cross-killing" of third-party target cells has been observed when stimulating and third-party cells bear no cross-reacting serologically defined (SD) antigens, thought to be the target antigens recognized by CTLs. CML-blocking studies, using unlabeled normal human lymphocytes to inhibit 51Cr release from radiolabeled target cells, have shown that cross-killing, even in the absence of shared SD determinants, results from CTLs recognizing antigens shared by the third-party targets and the initial stimulating population. Furthermore, these antigens have been mapped to the major histocompatibility complex (MHC). The ability of human CTLs to specifically recognize MHC-controlled antigens not detected serologically suggests that SD antigens may be recognized differently by alloantisera and CTLs, or that MHC antigens other than SD may be the targets of CTLs in CML.


The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. Cytotoxic cells were generated by immunizing one strain of mouse with cells from an allogeneic strain which carries the same H-2 region. The effector cells assayed in a 4 h 51Cr release assay were shown to be T cells and indistinguishable, except in specificity, from cytotoxic T cells directed at H-2 alloantigens. Although the genetic differences between responder and stimulator cells responsible for the immunization did not code in H-2, the H-2 complex did restrict susceptibility of target cells. For example, BALB.B cytotoxic cells (H-2b) immunized against and capable of lysing C57BL/6 cells (H-2b) would not lyse B6.C/H-2d target cells. C57BL/6 and B6.C/H-2d are congenic and differ in the H-2 region. Two hypotheses are considered to explain the H-2 restriction of susceptibility to cytotoxic T cells generated by an H-2 identical alloimmunization. (a) The dual (self) recognition hypothesis states that the cytotoxic cell has two recognition units, one for H-2-coded structures and another clonally restricted receptor for the minor alloantigen. (b) The interaction antigen hypothesis states that all the surface alloantigenic determinants recognized by cytotoxic T cells are the result of interaction between H-2- and non-H-2-coded gene products. Two lines of evidence, one with F1 effector cells and the other a cold target competition experiment, are presented which argue strongly in favor of the interaction antigen hypothesis. The regions of H-2 required to be histocompatible were mapped to the D region and to the left of IC, probably the K region. These results, and recent work on the response to virus-infected and TNP-modified syngeneic cells, suggest that cytotoxic cells are restricted in specificity to preferentially recognizing alterations in structures that are coded in the major histocompatibility complex.


Regulatory mechanisms in cell-mediated immune responses. II. A genetically restricted suppressor of mixed lymphocyte reactions released by alloantigen-activated spleen cells. The mechanism of alloantigen-activated spleen cell suppression of mixed lymphocyte reaction (MLR) is explored in this report. Activated murine suppressor spleen cells elaborated a soluble noncytotoxic factor which suppressed MLR responses by 55-95%. Generation of suppressor factor required both in vivo alloantigen sensitization and specific in vitro restimulation. Suppressor factor was not produced by activated spleen cells which had been treated with anti-Thy-1.2 serum and complement. Antigenic specificity toward alloantigens of the stimulator cells was not demonstrable. In contrast, suppressor factor effectively inhibited MLR response only of responder cells of those strains that shared the D-end and the I-C subregion of the H-2 complex with the cells producing suppressor factor. Therefore, active suppression appears to require an MHC-directed homology relationship between regulating and responder cells in MLR.


Induction of cytotoxic T lymphocytes against I-region-coded determinants: in vitro evidence for a third histocompatibility locus in the mouse. Determinants controlled by the I region of the murine H-2 complex provoked the generation of cytotoxic T lymphocytes (CTL) in both a secondary and primary mixed lymphocyte culture. The stimulating determinants appeared to be controlled by loci within the I-A subregion. The target antigens of the CTL generated were present on both lipopolysaccharide- and concanavalin-induced blast lymphocytes, but were barely detectable on phytohemagglutinin-induced blast cells. The stimulating capacity for CTL induction of a complete H-2 complex incompatibility by far exceeded the sum of H-2D/K-region and I-region incompatibility, respectively.


Cell-mediated lympholysis of N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-beta-anaylglycylglycyl-modified autologous lymphocytes. Effector cell specificity to modified cell surface components controlled by the H-2K and H-2D serological regions of the murine major histocompatibility complex. Splenic lymphocytes from four C57BL/10 congenic mouse strains were sensitized in vitro to N(-3-nitro-4-hydroxy-5-iodophenylacetyl)-beta-alanylglycylglycyl-(N) modified autologous lymphocytes. The effector cells generated after 5 days of culture were assayed on a series of either N-modified phytohemagglutinin-stimulated spleen cells or N-modified tumor cells. The results indicated in all cases that both N modification of the targets and H-2 homology between the modified stimulating and target cells are required for lysis to occur. In each case the effector cells were found to lyse N-modified target cells only when there was homology at either or both ends of the major histocompatibility complex (MHC) between the stimulator and target cells. B10.BR lysed targets sharing alleles at K (or K plus I-A) and/or at D. B10.A effector cell specificity was mapped to K (or K plus I-A) and/or the D half of the MHC (D or D plus I-C and/or S). The two regions of specificity determined for B10.D2 effector cells were D (or D plus S plus I-C) and a region not including D of the MHC. C57BL/10 effector cells lysed N-modified targets only if there was target cell H-2 homology at K, I-A, and I-B or at the D serological region. As in the trinitrophenyl (TNP) system (6) B10.BR and B10.A effector cells lysed targets sharing K end H-2 serological regions greater than target cells sharing D-end serological regions. The C57BL/10 effector cells were shown to react to the K end greater than the D end, which differed from the equal reactivity seen in the TNP system for this strain. The data are consistent with the hypothesis that the antigen recognized by the effector cell includes an altered H-2 serological cell surface product. That the reaction is not "hapten specific" and the H-2 homology is required only for effector:target cell interaction was excluded by the use of two F1 combinations in which lysis of only N-modified target cells sharing the H-2 haplotype with the stimulating parental strain was obtained. Finally, it was demonstrated that N and TNP modification create distinct new antigenic determinants, since an effector cell sensitized to one modifying agent will lyse only H-2 matched target modified with that same modifying agent.


Expression of individual Ia specificities on T and B cells. I. Studies with mitogen-induced blast cells. Ia specificities 1-10 were detected on LPS-stimulated splenic lymphocytes and on Con A-stimulated spleen, lymph node, and thymus blasts by direct cytotoxic tests. Since Ia antigens are not readily detectable on resting thymocytes, our results suggest that T cells require some signal before they exhibit full expression of Ia specificities. Absorption-elution studies indicated that most of the Ia specificities detected on T and B cells may be identical. Ia antigens detected by homologous antisera gave much stronger reactions than those detected by cross-reacting antisera.


Hereditary asplenic-athymic mice: transplantation of human myelogenous leukemic cells. A new animal model characterized by hereditary athymia and asplenia was used as a recipient of chronic myelogenous leukemic (CML) cells with the Philadelphia (Ph1+) chromosome.  Transplanted CML cells form solid vascularized tumors containing cells similar to those seen in the patient in a long-term culture. Cells taken from the tumors were nearly triploid, retained all human chromosome markers, and had the same antigenic determinants(s) as cells in culture.


Relationships between membrane antigens of human leukemic cells and oncogenic RNA virus structural components. Leukemic cells from all human chronic granulocytic leukemia (CGL) and some acute myelomonocytic leukemia (AMML) donors are lysed by rabbit antisera to a purified glycoprotein of Friend murine leukemia virus (FLV gp71) in a microcytotoxicity assay. These antisera are not cytotoxic to cells from patients with acute myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or to peripheral blood lymphocytes from normal donors. A goat antiserum to gradient purified FLV in addition to reacting with cells from CGL and AMML donors also reacted with cells from AML patients and some ALL donors. However, this antiserum failed to react with cells from CLL patients. Peripheral blood and bone marrow leukocytes prepared from leukemic patients in clinical remission failed to react with antisera to FLV and FLV gp71. Absorption experiments demonstrated that the antigen on CGL cells which is reacting with the antiserum to FLV gp71 is also present on normal human platelets and neutrophils. Similar absorption studies showed that the antigen on AML cells detected by the FLV antiserum is not present on normal leukocytes and platelets and appears to be related to the major internal p30 antigens of mammalian RNA tumor viruses. Another antigenic relationship between oncornaviruses and membrane antigens of human leukemia cells was shown by the ability of FLV antigens to absorb the cytotoxic reactivity of nonhuman primate antisera detecting human leukemia-associated antigens. FLV and FLV gp71 antigens were able to absorb all cytotoxic activity of monkey and chimpanzee antisera to human myeloid leukemia antigens when these antisera were tested with CGL cells. These two approaches to an analysis of cross-reactivity indicate that the antigenic determinant(s) detected by the cytotoxic reactions of the FLV gp71 antiserum with human CGL cells is different from the determinant on FLV gp71 which is responsible for the inhibition of the reactivity of simian antisera with CGL cells. Since the goat and rabbit antisera to FLV and FLV gp71 are able to distinguish AML from CGL cells by direct cytotoxicity testing and absorption, they may be valuable reagents for the serological diagnosis of myeloid leukemia. In addition, since peripheral blood cells from AML and CGL patients in clinical remission were seronegative, the antisera may be valuable as management aids. The data in this report indicates that whatever the mechanism of leukemogenesis is in man, cells from CGL and AML patients possess certain membrane antigens which cross-react with FLV structural components such as p30 and gp71.


Phytoenzyme systems as models for an understanding of general metabolic pathways. A comparison is made between certain aspects of lipid metabolism in plant and animal tissues. While the general biochemical reactions are identical, a number of important variations are described and related to the general metabolic activities of the tissues.


Mitochondrial structure studied by high voltage electron microscopy of thick sections of Candida utilis. Mitochondrial structure in yeast cells under various physiological conditions has been studied by high voltage electron microscopy of sections that are 0-5 to 2-0 mum thick. Such thick sections of the yeast Candida utilis had a small number of long, branched tubular mitochondria per cell. The mitochondria extended into cell buds and unseparated daughter cells. It was apparent from parallel studies with thin sections that most of the rounded mitochondrial profiles viewed in thin sections should not be interpreted as being numerous small individual mitochondria. Attempts to study thick sections of the yeasts Saccharomyces cerevisiae and Schizossaccharomyces pombe were frustrated by poor contrast.


Congenital trigeminal neuropathy in oculoauriculovertebral dysplasia-hemifacial microsomia (Goldenhar-Gorlin syndrome). A 2 1/2 year old child with clinical features of Goldenhar-Gorlin syndrome showed diminished pinprick sensation over the right half of the face. After surgery for the cleft lip, the child died. Neuropathological investigations showed agenesis of the right trigeminal nerve and hypoplasia of the right trigeminal brain-stem nuclei. Nosological aspects of the Goldenhar-Gorlin syndrome and previously reported cases of congenital trigeminal anaesthesia in this disorder are discussed. It is suggested that the hypoplasia of the trigeminal nerve is responsible for the diminished facial sensation seen in some patients with this craniofacial syndrome.


Retrograde transport of horseradish peroxidase in transected axons. II. Relations between rate of transfer from the site of injury to the perikaryon and onset of chromatolysis. The sciatic nerves of 2--3 month-old mice, rats and rabbits were crushed and at the same time horseradish peroxidase (HRP) was applied around the crushed region at mid-thigh level. At varying time intervals thereafter, HRP was seen in neurons of the corresponding spinal ganglia and levels of the spinal cord. The rate of ascent of HRP appeared to be similar in the different animals and to be independent of the length of the nerve. The accumulation of HRP was more conspicuous in small than large neurons in the ganglia at early stages after the nerve crush. The arrival of HRP in the perikarya preceded the onset of early morphological changes in the neurons (chromatolysis). The rate of ascent of the signal for chromatolysis appeared to be within the same range as that of the retrograde transport of HRP in the crushed axons. The possibility therefore exists that these two phenomena are in some way interrelated.


Tumor imaging after administration of 99mTc-labeled bleomycin. Bleomycin, an anticancer drug, was labeled with 99mTc using stannous chloride and ascorbic acid and specific activities of 1-3 mCi/mg-eq with labeling efficiencies of 50-75% were achieved. Very rapid excretion of 99mTc-bleomycin through the kidney and concomitant rapid decrease of radioactivity in blood, various tissues and organs, and whole body were observed after intravenous administration of the radiopharmaceutical into tumor-bearing mice. In such animals, approximately 1% of the label was found in a transplanted fibrosarcoma within 30 min while 0.58% was recovered in such lesions even after 24 hr. In patients positive tumor images were obtained by scintigraphy as early as 1 hr after intravenous administration of 3-5 mCi of 99mTc-bleomycin. A total of 142 cases were examined by scintigraphy after administration of 99mIc-bleomycin and/or 67Ga-citrate. In 93 cases with various malignant tumors, tumor was detected in 80% using 99mTc-bleomycin and in 63% using 67Ga-citrate. Technetium-99m-bleomycin scintigraphy successfully detected tumors of the thyroid, lung, face, breast, extremity, and digestive tract and was also useful in finding metastatic lesions and brain tumors. However, 67Ga scintigraphy gave superior results in detecting lesions in patients with malignant lymphomas. In patients with inflammatory diseases, accumulation in lesions was detected in 13% using 99mTc-bleomycin and in 48% using 67Ga-citrate. The further use of 99mTc-bleomycin scintigraphy for tumor detection in patients appears to be warranted.


Technetium-99m labeling by means of stannous pyrophosphate: application to bleomycin and red blood cells. A new technique of technetium labeling using stannous pyrophosphate instead of stannous chloride as reducing agent for pertechnetate has been applied to red blood cells and bleomycin. Results are so encouraging that this technique could be extended to other compounds capable of forming stable complexes with reduced technetium. No saline washes of red cells are necessary before or after the addition of pertechnetate. No purification step is performed after labeling of bleomycin.


Prefatal cardiac arrhythmias.

Prefatal cardiac arrhythmias. Monitoring of the patient's heart rate and rhythm is becoming standard procedure for oral surgeons. Abnormal rhythms can develop suddenly in patients who have no history either of a diseased heart or of other systemic disease. Recognition of different types of abnormalities of the heart and a knowledge of how to handle them may prevent the occurrence of fatal arrhythmias.


A correlation between the effects of anti-mitotic drugs on microtubule assembly in vitro and the inhibition of axonal transport in noradrenergic neurones. 1. Podophyllotoxin, colchicine and griseofulvin inhibit the intra-axonal movement of noradrenaline storage vesicles in cat hypogastric nerve/inferior mesenteric ganglion preparations maintained in vitro, cause the disappearance of axonal microtubules and inhibit the assembly of microtubules from tubulin in vitro. The order of potency of the three effects is podophyllotoxin greater than colchicine greater than griseofulvin. 2. Lumicolchicine is without effect on the three parameters and does not interfere with the binding of tritiated colchicine to tubulin. 3. Podophyllotoxin causes a more rapid loss of microtubules from axons than the same concentration of colchicine. 4. The experiments provide strong evidence that microtubules are components of the system responsible for the intra-axonal migration of noradrenaline storage vesicles.


An effect of Tamoxifen (I.C.I. 46,474) on the surface coat of the late preimplantation mouse blastocyst. The oral adminitration of Tamoxifen on Days 2,3 and 4 after mating, or on Day 2 only, was found to prevent the oestrogen-dependent surface-coat change of the late preimplantation blastocyst in the mouse. It is suggested that his is an antioestrogenic manifestation and that ist is, at least in part, responsible for the drug's known antifertility effect.


Repeatability of the duration of oestrus and breed differences in the relationship between druation of oestrus and ovulation rate of sheep. The duration of oestrus and the time interval from removal of progestagen-impregnated pessaries to the onset and end of oestrus were examined in Texel, Finnish Landrace, Galway and Fingalway (Finnish Landrace X Galway) ewes. The differences among the breeds in the relationship between these variables and ovulation rate at the controlled oestrus were also investigated. Breed differences were significant for all traits except the interval from pessary withdrawal to the onset of oestrus. The relationship between ovulation rate and both the interval from pessary withdrawal to the onset of oestrus and the duration of oestrus differed significantly among the breeds. The repeatability of the duration of oestrus was significant for Texel and Rambouillet ewes (mean = 0.5) and for pooled data from ewe lambs of various breeds. It was concluded that, in view of the breed differences in the relationship between ovulation rate and duration of oestrus and other traits, generalizations should not be made from among-breed to within-breed relationships. The high repeatability for the duration of oestrus may mean substantial heritabilities for the physiological determinants of oestrus duration.


The estimation of the proportion of motile bull spermatozoa in various diluents and a comparison with the proportion eosinophilic. The proportion of motile spermatozoa in bull semen diluted with phosphate-buffered saline, citrate or milk has been estimated both photographically and with an image-analysing computer. The two methods produced similar estimates. The proportion of noneosihophilic spermatozoa was higher than the proportion of immotile spermatozoa, particularly when fluoride or formaldehyde was added to the diluents. The proportion of non-eosinophilic spermatozoa in diluents containing formaldehyde was the same as in the original semen.


Preservation of differential staining of spermatozoa by formol citrate. Semen from boar, bull, ram, rabbit, reindeer and stallion was diluted in formol citrate or formol saline and stained with eosinnigrosin. The proportion of eosinophilic spermatozoa did not differ from that in fresh semen after storage for 48 hr in the formol diluent at temperatures ranging from 4 degrees C to 40 degrees C. Some samples were kept for periods up to 3 weeks with very little increase in the proportion of eosinophilic spermatozoa.


Field ion microscopy of biomolecules.

Field ion microscopy of biomolecules. A new type of image, existing only at field strengths below the denaturation field strengths of molecules, has been discorvered. This type of image has structure, is not symmetrical and thus differs from previously reported low field strength images. The possibility that macromolecules adsorbed on tip surfaces produce such structured images has been exhaustively investigated. The result is that no observation has been found which disproves this hypothesis and many tests conducted in such attempts yielded correlations consistent with this hypothesis. It is therefore concluded that it is highly probable that biomolecules produce structured images and that it is highly improbable that these correlations represent a chance event. On the other hand, these correlations may be due to some cause unknown to the authors; but we consider this possibility to be unlikely. Some micrographs have been obtained which provide a reasonable basis for the hope that tertiary structure information may be defrived from low field strength imaging of partially embedded biomolecules or of biomolecules that are resistant to field denaturation during imaging. Information may presently be obtained from analysis of low field strength ion micrographs about the size and shape of some biomolecules.


The 'through focus plate' : a simple method for obtaining images through focus on a single photographic plate in the electron microscope using a tilting stage. Tilting the specimen in an electron -icroscope by a relatively small angle can provide a continuous through focal series on a single plate, as the displacement of the object at the edge of the field can be adjusted to be of the same order of magnitude as the alteration of focal point by the fine lens controls. This simple rapid manoeuvre could have applicaitons in the microscopy of uniform preparations, particularly if the specimen is subject to beam damage, and in assessing microscope performance rapidly.


A transmission electron microscope study of the effects of ion etching on cells. The effects of ion etching on blood cells have previously been studied by scanning electron microscopy. This present study by transmission electron microscopy was undertaken to evaluate the effects of the etching process on the cells. Critical point dried preparations were made, etched and subsequently processed and embedded in Araldite. Examination of thin sections of erythrocytes revealed disintegration of the plasma membrane; the residual membrane destruction products formed the tips of cones produced by long etching times. The effect of etching varied in erythrocytes in the same preparation. Nucleated cells showed a similar disintegration of the plasma membrane, but membranes of mitochondria,  granules, vesicles and vacuoles did not exhibit effects of etching comparable to those of the plasma membranes. After treatment with a number of different fixatives, erythrocytes on carbon-coated copper grids were also etched and examined directly in a high voltage electron microscope at 1 MV. The effects were comparable to those seen in thin sections. To study the etch rates of biological materials, the resonant frequencies of quartz crystals were measured after application of thin films of albumen and cholesterol and again after these had been etched. the ratio of the frequency changes indicated that the etch rate of albumen was approximately 2-5 times that of cholesterol. The results are discussed in the light of theories of the mechanisms involved in ion etching.


Immunological comparison of azurins of known amino acid sequence. Dependence of cross-reactivity upon sequence resemblance. To examine further the dependence of immunological cross-reactivity on sequence resemblance among proteins, we carried out micro-complement fixation studies with rabbit antisera to bacterial azurins of known amino acid sequence. There is a strong correlation (r = 0.9) between number of amino acid substitutions and degree of antigenic difference (immunological distance) among these azurins. The antigenic effects of amino acid substitutions are thus approximately equal and approximately additive. Similar observations and inferences were made before with a series of bird lysozymes. Indeed, the same approximate relationship between immunological distance (y) and percent difference in amino acid sequence (x) holds for both azurins and lysozymes, namely y congruent to 5x. An explanation is given for the dependence of immunological cross-reactivity on sequence resemblance among proteins. This entails reviewing evidence regarding the nature and number of antigenic sites on globular protein antigens as well as evidence for the existence of evolutionary biases against substitutions that are internal or cause large conformational changes. The explanation we give may apply only to those naturally occurring, globular, monomeric, isofunctional proteins whose sequences differ substantially from that of any rabbit protein.


Role of carbohydrate in determining the immunochemical properties of the major glycoprotein (gp71) of Friend murine leukemia virus. Treatment of Friend leukemia virus gp71 with protease-free glycosidase enzymes results in removal of the major portion of the carbohydrate without affecting the amount of protein present. The digested material migrates as protein of about 60,000 to 65,000 molecular weight on sodium dodecyl sulfatepolyacrylamide gel electrophoresis. Analyses of the serological properties of gp71 after enzyme treatment indicated that the type, group, and interspecies determinants were not destroyed. In contrast, treatment with proteolytic enzymes led to the complete destruction of the gp71 molecule, including the total elimination of its serological reactivity as measured by direct and competition radioimmunoassay and by a serum cytotoxicity assay. We conclude that the carbohydrate portion of gp71 is not of major significance in defining the antigenic determinants of this viral glycoprotein.


Thermolabile reverse transcriptase of a mammalian leukemia virus mutant temperature sensitive in its replication and sarcoma virus helper functions. Three temperature-sensitive mutants of the Rauscher strain of murine leukemia virus are defective in early post-penetration functions required both for leukemia virus infection and for initiation of transformation of cells by their pseudotypes of murine sarcoma virus. In the present study, the reverse transcriptase of one of these mutants (ts 29) is shown to be thermolabile compared with the enzymes of the wild-type virus and several other temperature-sensitive mutants. These findings provide evidence that the reverse transcriptase is required both for leukemia virus infection and for initition of transformation by the replication-defective murine sarcoma virus genome.


Transcription of 70S RNA by DNA polymerases from mammalian RNA viruses. DNA polymerases purified by the same procedure from four mammalian RNA viruses, simian sarcoma virus type 1, gibbon ape lymphoma virus, Mason-Pfizer monkey virus, and Rauscher murine leukemia virus are capable of transcribing heteropolymeric regions of viral 70S RNA without any other primer. In this reconstituted system the enzymes from simian sarcoma virus type 1, Mason-Pfizer monkey virus, and Rauscher murine leukemia virus transcribe viral 70S RNA almost as efficiently as the DNA polymerase from the avian myeloblastosis virus, but gibbon ape lymphoma virus DNA polymerase is approximately three-to fivefold less efficient. Although there is a substantial difference among the sizes of these DNA polymerases (160,000 daltons for the avian myeloblastosis virus enzyme, 110,000 daltons for the Mason-Pfizer monkey virus enzyme, and 70,000 daltons for the mammalian type C viral polymerases), the ability to transcribe viral 70S RNA is a characteristic common to these enzymes.


[Distribution of bleomycin in sesame oil suspension in organs of rat with mammary carcinoma induced by 7,12-dimethylbenz (a) anthracene and its effect on the tumors (author's transl)]. Distribution of the bleomycin A2 suspended in sesame oil (Oil Bleo Suspension) in rat organs and tumors after the intramuscular administration was investigated by bioassay, the effect of intratumor administration of the suspension on the growth of rat mammary carcinoma induced by 7, 12-dimethylbenz (a) anthracene was also studied. The oil suspension showed a protracted concentration in either tumor or organ tissues, but showed similar inhibitory effects on rat mammary carcinoma to those by regular bleomycin solution. Further studies should be performed on the effect of bleomycin A, in sesami oil on mammary carcinoma.


[Certain pathogenetic mechanisms of development of atherosclerosis in dogs, induced without the use of cholesterol]. Chronic investigations (up to 3 years) conducted in dogs have evidenced that periodic disturbances of vascular permeability produced by using dicoumarin with a long-term blocking of the thyroid function greatly aggravate pathological manifestations induced by the action of 6-methylthiouracil. They result in the development in the animals of endogenous hypercholesterinemia, elevated content in the blood of beta-lipoproteins and in a periodic rise of the arterial pressure. These changes were particularly spectacular at the final stage of the experiment in animals with marked manifestations of atherosclerosis and were accompanied by reduced stand-by potentialities of the adrenal gland, disruption of metabolic processes in the myocardium along with the slowed down resorption of NaI131 from the heart muscle. The sensitivity of the heart to adrenalin was down too.


Comparative ultrastructural cytochemistry of juxtaglomerular cell granules and renal tubular cell lysosomes. Because of certain similarities in morphology and function between juxtaglomerular cell granules and renal tubular cell lysosomes, the cytochemistry of both of these structures was compared. Juxtaglomerular cell granules and renal tubular cell lysosomes were found to be argentaphobic when ultrathin sections of Araldite-embedded kidneys were stained according to the periodic acid-thiocarbohydrazide-silver proteinate technique of Thiéry (Thiéry, J. P. J. Microsc. (Paris) 6: 987, 1967 and J. Microsc. (Paris) 8: 689, 1969). The rim of both structures was moderately positive when ultrathin sections of glutaraldehyde-fixed, glycol methacrylate-embedded kidneys were stained with phosphotungstic acid at a low pH. A reaction was also shown by the cell coats, residual bodies and, in proximal convoluted tubules, by the Golgi complex. In ultrathin sections of either glycol methacrylate- or Vestopal-embedded renal cortex stained by various methods with colloidal iron, juxtaglomerular cell granules were negative whereas renal tublar cell lysosomes were intesely positive. Colloidal iron also stained the cell coats of both justaglomerular and tubular cells. These results indicate that both juxtaglomerular cell granules and renal tubular cell lysosomes contain glycoproteins which are not acidic in the former and are acidic in the latter.


[Antigens of the human placenta (author's transl)]. The immunologic relations between mother, foetus and placenta are discussed and those antigens of the human placenta already characterized by their physico-chemical and immunochemical properties described. In diagnostics the detection and determination of placental proteins is used in pregnancy tests, for the evaluation of placental functions and the detection of malignant diseases. Antibodies to placental antigens have an abortive effect; immunization against placental specific proteins may have implications as an immunologic contraceptive method and for the immunotherapy of choriocarcinoma.


Studies of cellular recovery from injury. I. Recovery from anoxia in Ehrlich ascites tumor cells. The reversibility of changes in ultrastructure, K+, and ATP content was studied in experimental injury of Ehrlich ascites tumor cells. Different grades of injury resulted from incubations in N2 atmosphere and omitting substrate after which air and glucose were reinstated. The changes observed in cells after 1 hour of anoxia such as dilations of endoplasmic reticulum, complex invaginations of plasma membrane, and slight condensation of mitochondria, as well as a drop of K+ and ATP content to a level approximating 40 per cent of the paired controls, were entirely reversible. After 2 hours of anoxia approximately 50 per cent of the cells recovered, but after 3 and 4 hour of anoxia most of the cells were irreversibly damaged showing markedly swollen mitochondria with flocculent densities.


Use of a symmetry condition to compute the conformation of gramicidin S1. Using an improved method for computing conformations of closed rings with symmetry, in conjunction with an improved empirical energy function, the conformational space of Gramicidin S is reexamined. The search for minimum energy conformations is confined to the subspace containing closed symmetric rings. A large number of initial conformations selected from that subspace is subjected to energy minimization or is eliminated in a sequence of steps designed to locate the global minimum-energy conformation. One conformation having distinctly low energy is found and is judged to be the global minimum-energy conformation. This conformation is of the beta-pleated sheet type and is in complete agreement with experimental data. Similar structures with beta-pleated sheet-type conformations have been proposed previously on the basis of less extensive examiniations of the conformational space; the condition of exact ring closure, and the extensive examination of conformational space, used here, establish this structure on a firm basis.


Coronary heart-attacks in East London.

Coronary heart-attacks in East London. All cases of cardiac infarction, acute coronary insufficiency and sudden death occurring in residents of the London Borough of Tower Hamlets below age 65 were registered over nearly three years, and survivors were followed up for one year. The attack-rate in men aged 45-64 years was 1 per 100 per annum but the recurrence-rate in survivors was 1 per 100 per month. Immigrants from Asia had more than the average, and those from the Carribean one tenth of the average attack-rate. Although it was unusual for general practitioners to manage cases at home by choice, nonetheless two-thirds of the deaths happened outside hospital and half of these were not witnessed. Half of those suffering coronary heart-attacks had a previous history of coronary disease and a sizable minority were already unfit for work. Approximately half of those attacked were alive at one year.


Clinical and serological analysis of transfusion-associated hepatitis. Of 108 prospectively followed, multiply transfused, open-heart-surgery patients, 12 (11%) developed hepatitis. Patients received only volunteer donor blood tested for hepatitis-B surface antigen (HBsAg) prior to transfusion by counterelectrophoresis (C.E.P.). 4 of the 12 patients developed hepatitis-B-virus infection. Subsequent testing of donor serums by solid-phase radioimmunoassay (R.I.A.) revealed that an R.I.A.-positive, C.E.P.-negative blood unit was transfused to 3 of the 4 type-B hepatitis cases, but to none of the remaining 104 patients; 3 hepatitis-B cases could probably have been prevented by prescreening of donors by solid-phase R.I.A. 8 hepatitis cases were serologically unrelated to the hepatitis-B virus, the hepatitis-A virus, the cytomegalovirus, or the Epstein-Barr virus. Had R.I.A.-positive donors been excluded, 8 of the 9 residual hepatitis cases (89%) would have represented "non-A, non-B" hepatitis. The existence of previously unrecognised human hepatitis virus(es) is probable.


Controlled trial of bromocriptine, quinoestrol, and placebo in suppression of puerperal lactation. 2-bromo-alpha-ergocryptine (bromocriptine) in a dosage of 2-5 mg twice daily caused a rapid fall in plasma prolactin. It was more effective than either a single dose of 4 mg quinoestrol or a placebo in suppressing puerperal lactation, as judged by milk flow and the relief of breast pain and congestion. Patients who received quinoestrol were more comfortable than those who received placebo.


Triiodothyronine and thyroid-stimulating hormone in protein-calorie malnutrition in infants. Protein-calorie malnutrition (P.C.M.) in a group of 43 Senegalese children aged eighteen to thirty months was characterised by a sharp fall in serum-triiodothyronine (T3) concentration to 25-3% of the mean value in healthy age-matched controls. This decrease in T3 was significantly (P less than 0-001) more pronounced in kwashiorkor of recent onset than in long-term P.C.M., a finding which suggests that impaired thyroxine (T4) monodeiodination in the liver was responsible for the fall in serum-T3 concentration rather than a reduction in the secretion of T3 by the thyroid. Serum-T3 concentrations became normal in both malnourished groups after two weeks of appropriate nutrition. Serum-T3 concentrations in healthy, euthyroid, Senegalese children were higher than in White children. In frank kwashiorkor in Senegalese children, serum-thyroid-stimulating-hormone (T.S.H.) concentrations were within the normal range throughout the entire course of dietary therapy, indicating that the children remained euthyroid. In contrast, protracted P.C.M. led to impairment of the T.S.H./T3 feedback mechanism and to a condition resembling hypophysectomy, which required two weeks' dietary therapy for its correction.


Interrelation of the common congenital malformations: some aetiological implications. Analysis of congenital defects in a population of 90 921 singleton births revealed a strong interrelation between malformations: for example, 84% of lung defects, 70% of kidney defects, 34% of eye defects, 19% of cleft palate, and 15% of spina bifida coexisted with other defects which could not be designated as subsequently derived structural changes. The strength and intimacy of these interrelations casts doubt on the notion that multiple external factors are involved in the causation of human malformations.


Successful fetal liver transplantation in a child with severe combined immunodeficiency. Following transplantation with allogeneic fetal liver, a boy with a severe combined immunodeficiency and adenosine-deaminase (A.D.A.) deficiency developed immunocompetent T and B cells in an orderly manner. Engraftment was indicated by appearance of A.D.A. activity and donor-lymphocyte and red-cell antigens. The child remained free of major infections until one year later when he developed an ultimately fatal nephrotic syndrome associated with immune-complex glomerulonephritis.


A continuing common-source outbreak of botulism in a family. In December, 1974, three cases of botulism occurred in a family; two were fatal. The first patient died after a 10-day illness without botulism being suspected. 4 days later, after a 2-day illness, the second patient was diagnosed as having botulism after a cardiorespiratory arrest; she died 3 days later. In the third patient, the only symptom was dysphagia. Clostridium botulinum type B was found in stool specimens from all three patients. Home-canned (bottled) mushrooms, which were found to contain C. botulinum type B and its toxin, were believed to be responsible for the outbreak; mushrooms were found at necropsy in the gastrointestinal tracts of both patients who died. Heat treatment of the mushrooms during canning had been inadequate.


Upper-gastrointestinal endoscopy in perspective. Three and a half years' experience of an upper-gastrointestinal endoscopy service in a district general hospital is reviewed. It is concluded that the necessity for this investigation is considerably reduced when a positive contribution towards patient management is the main criterion for its use, when there is effective interdisciplinary cooperation, and when a double-contrast barium-meal technique is routinely employed.


Effect of group-A meningococcal vaccine in army recruits in Finland. During an epidemic caused by group-A, sulphonamide-resistant meningococci in Finland, group-A polysaccharide vaccine was administered in 1974 to 16 458 recruits of the Armed Forces, leaving 20 748 as controls. Specific antibody response was good, and after vaccination only 1% of the men were without anti-meningococcal group-A antibodies. Pharyngeal carriage of the epidemic strain was low, about 1-5%, in the men when entering service. Group-A meningococcal disease occurred during the nine months' mean observation period in 1 of the vaccinated men (an annual incidence of 11 per 100 000) and in 8 of those not vaccinated (71 per 100 000), indicating 89% protective effect of the vaccine. Furthermore, the total number of cases of group-A meningococcal disease was reduced to non-epidemic levels at a time when 36% of the men in service were vaccinated, and has remained low for the next twelve months even though the epidemic in the general population continued.


Chronic liver disease developing after outbreak of HBsAG-negative hepatitis in haemodialysis unit. Chronic liver disease developing after acute hepatitis type B is well documented, but is not thought to occur after acute hepatitis due to other viruses. However, follow-up of 29 patients in a haemodialysis unit who contracted HBsAg-negative acute hepatitis during 1968-70 revealed 8 cases with raised serum-aminotransferase levels dating from that time. Liver biopsy in 7 of these disclosed chronic aggressive hepatitis in 3, of whom 2 had already progressed to advanced cirrhosis. Chronic persistent hepatitis was present in 2 others, and the remaining 2 had non-specific hepatitis in association with massive iron overload. Immunological studies demonstrated a higher frequency of cellular immunity to HBsAg in those who had previously had acute hepatitis than in those who had not, although the prevalence of humoral antibody was similar in the two groups. One possible explanation for these findings is the presence of immunological cross-reaction at a cellular level between the hepatitis B virus and that responsible for the initial outbreak.


Chronic lymphocytic leukaemia of T-cell origin. Immunological and clinical evaluation in eleven patients. Eleven patients with chronic lymphocytic leukaemia of T-cell origin are reported. The identification of the leukaemic cells was performed with seven different membrane markers for either T or B lymphocytes. The reactivity of the leukaemic T cells with three different heteroantisera to T cells differed from patient to patient but was homogeneous in individual cases. This finding suggests that the leukaemic lymphocytes belonged to a single subset of T cells. These lymphocytes responded to allogeneic cells in some of these patients. In contrast, stimulation by non-specific mitogens was poor in most patients. Two patients were affected with the prolymphocytic type of chronic lymphocytic leukaemia, but a characteristic clinical and haematological pattern was found in nine patients. The blood and marrow infiltration was moderate and the proliferating T lymphocytes had a high content of lysosomal enymes in all patients and cytoplasmic granules in six cases. Other unusual features included massive splenomegaly (five patients), skin lesions (four patients), and major neutropenia (four patients).


Haemophilus influenzae type B resistant to tetracycline isolated from children with meningitis. During a three-year-period, 1971-73 inclusive, haemophili isolated from 96 children with severe infections, of whom 73 had meningitis and 19 acute epiglottitis, were serotyped and tested for sensitivity to antibacterial drugs. All strains were identified as Haemophilus influezae type b, and were sensitive to ampicillin, chloramphenicol, and trimethoprim. However, 3 isolates--from a boy aged 11 months and a girl aged 1 year with meningitis, and a girl aged 2 years with epiglottitis--were highly resistant to tetracycline, with a median minimal inhibitory concentration of 50 mug tetracycline hydrochloride per ml (resistance ratio greater than or equal to 50). Resistance was also demonstrated to doxycycline, oxytetracycline, and rolitetracycline and, in one strain, to minocycline. No evidence was obtained that the resistant organisms were capable of inactivating tetracyclines.


Early syphilitic hepatitis.

Early syphilitic hepatitis. 17 out of 175 cases of early syphilis had clinical, biochemical, and immunological evidence of liver damage. Before penicillin therapy the histological appearance of the liver was abnormal in 14 of the 15 patients from whom biopsy specimens were obtained. In 7 cases, treponemes were seen in the liver. After two months' penicillin therapy the extent and severity of the histological abnormality was reduced. In the repeat liver-biopsy specimens obtained after penicillin treatment no treponemes could be demonstrated. It is suggested that the hepatitis found in these 17 cases of early syphilis was produced by treponemes.


Formation of virosomes from influenza subunits and liposomes. The surface haemagglutinin and neuraminidase projections of influenza virus were removed from the viral envelope, purified, and relocated on the surface of unilamellar liposomes. The resulting structures were examined in the electron microscope and found to resemble the original virus. Units of both the viral haemagglutinin and viral neuraminidase could be discerned. The name virosome is proposed for these new bodies.


Transfer factor in Hodgkin's disease.

Transfer factor in Hodgkin's disease. In a controlled studiy, six patients with stage-IV Hodgkin's disease were given transfer factor (T.F.) prepared from patients with Hodgkin's disease in long remission. There was an apparent increase in cell-mediated immune responses as evidenced by a significant increase in the recipients' lymphocyte responses to phytohaemagglutinin stimulation. Three out of six patients converted to positive delayed-hypersensitivity tests. These three all had the nodular sclerosing type of Hodgkin's disease. These results warrant the further investigation of the use of Hodgkin's disease-specific T.F. as a therapeutic agent in this condition.


Inhibition of the plasma-aldosterone response to frusemide by bromocriptine. The administration of the long-acting dopaminergic agonist bromocriptine to five healthy volunteers inhibited the rise in plasma-aldosterone that normally follows the administration of frusemide. This inhibition was not due to a lowering of plasma-renin activity. It is suggested that dopamine may modulate the normal secretion of aldosterone either directly, or indirectly, possible by inhibition of prolactin secretion.


Energy density of food, gastric emptying, and obesity. An investigation of gastric emptying suggested that people choosing an energy-dense mixture of dood and drink have an empty stomach sooner--and might, therefore, eat more--than people who take their energy in more dilute form. Support for the notion that energy density (kcal divided by volume of food and drink) might be related to relative body-weight comes from a study in healthy males. A proportion, albeit a small one, of the variance in relative body-weight (Quetelet) could be ascribed to energy density, and the relationship was stronger among the more obese men.


Selective screening for breast cancer in Guildford. A preliminary survey has been carried out to test the feasibility of screening a high-risk group of women for breast cancer, using clinical examination and low-dose mammography, before the establishment of a two-tier screening system of basic well-woman clinics for the over-25s, and breast screening clinics for those over-35s considered to have a higher than average expectation of developing the disease. 7 breast cancers and 1 case of Hodgkin's disease were detected in 618 women (breast cancers 11-3/1000, malignancies 12-9/1000). Though numbers are small they suggest that the women themselves do not suspect the presence of those breast cancers which carry the best prognosis, though being aware of the larger cancers and of many of those benign localised breast lesions requiring surgical treatment.


Efficacy of hepatitis B immune serum globulin after accidental exposure. Preliminary report of the Veterans Administration Cooperative Study. A randomised, double-blind, controlled trial has been undertaken to compare the efficacy of hepatitis B immune globulin (H.B.I.G.) with that of immune serum globulin (I.S.G.) for the prophylaxis of viral hepatitis. Participants in the trial were individuals exposed accidentally to material infectious for hepatitis (primarily viral B hepatitis). Preliminary evaluation of the first 302 of the 561 individuals entered into the study indicates that H.B.I.G. significantly reduced the frequencies of both clinical and subclinical hepatitis during the first 3--4 months after the injection. Less than 10% of H.B.I.G. recipients had detectable anti-HBs at the sixth month after the injection, suggesting that H.B.I.G. might need to be given every 3--4 months to continually exposed individuals. Further long-term evaluation is required in order to define more clearly those most likely to benefit from H.B.I.G.


Treatment of radiation-induced gastrointestinal distress with acetylsalicylate. Highly buffered acetylsalicylate was used to treat diarrhoea and other gastrointestinal side-effects of radiotherapy in 28 women who were receiving treatment for uterine cancer. In a double-blind, balanced, and randomised trial, acetylsalicylate significantly reduced the number of bowel motions and relieved abdominal pain and flatulence.


Urinary and serum octopamine in patients with portal-systemic encephalopathy. Urinary excretion and serum concentrations of octopamine were studied in seventeen controls, thirty-three patients with portal-systemic encephalopathy, and thirteen patients with liver disease without encephalopathy. No differences were detected between control subjects and patients without encephalopathy. Urinary excretion and serum concentrations of octopamine were significantly higher in patients with encephalopathy compared with those without encephalopathy. The presence and grade of portal-systemic encephalopathy seemed to correlate more closely with the serum-octopamine concentrations than with urinary octopamine excretion. It is postulated that octopamine may be involved in the pathogenesis of portal-systemic encephalopathy.


Mucosal adherence of human enteropathogenic Escherichia coli. An in-vitro assay system has been developed to measure bacterial adhesion to the mucosa of human fetal small intestine. Two strains of Escherichia coli that are proven human enteropathogens (E.P.E.C.) have been shown to adhere in large numbers, compared with control organisms. The attachment mechanism is species specific and is not caused by common fimbriae. Mucosal adhesion may be as important as enterotoxin production or invasiveness in determining the virulence of some strains of human E.P.E.C.


Treatment of diabetes insipidus with carbamazepine. Oral carbamazepine has been shown to have antidiuretic activity in seven out of nine patients with neurohypophyseal diabetes insipidus. At the doses used side-effects were not a major problem. In the eighth patient a carbamazepine and clofibrate combination was effective but in the ninth carbamazepine was without effect. It is suggested that carbamazepine should be used initially in neurohypophyseal diabetes insipidus if oral therapy is indicated, but the mode of its antidiuretic action is as yet unclear.


Diagnosis of Hirschsprung's disease by quantitative biochemical assay of acetylcholinesterase in rectal tissue. Acetylcholinesterase activity was measured in rectal-biopsy specimens obtained from nineteen children. Seven children in whom the diagnosis of Hirschsprung's disease was established were found to have a significantly higher enzyme activity than the twelve in whom this diagnosis was excluded. The estimation may prove to be of value in the diagnosis of Hirschsprung's disease.


Coronavirus propagated from patient with non-bacterial gastroenteritis. A faecal suspension from a patient with gastroenteritis, which contained large numbers of coronavirus particles when examined by electron microscopy, was inoculated into human embryo intestinal-organ cultures and primary human embryo-kidney monolayers. In the organ cultures, the villous epithelium became detached and large numbers of coronavirus particles were seen by electron microscopy both in the medium and in thin sections of the intestinal epithelial cells, where the virus appeared to be multiplying. In organ cultures and in human embryo-kidney cells, intracytoplasmic virus was demonstrated by indirect immunofluorescence with convalescent serum from the patient.


Clinical sign of obstructed axoplasmic transport. Orthograde and retrograde axoplasmic transport in retinal ganglion-cell axons can be interrupted by axonal ischaemia. This report is believed to be the first to illustrate how this phenomenon can be obserbed clinically in man in cases of retinal vascular disease. The intense retinal "whiteness" of small cottonwool spots and at the periphery of larger areas of retinal ischaemia represents gross localised axonal distension secondary to the cessation axoplasmic flow.


Coeliac disease: a cause of various associated diseases? Deposition in other organs of immune complexes originating from the small-intestinal musosa is suggested as a possible reason, in some patients, for the described association between coeliac disease and a range of "autoimmune" diseases.


A clinical service for prenatal diagnosis. A centralised clinical prenatal diagnostic service has been established and the results of amniocentesis in 174 patients are discussed. Termination of pregnancy was performed in 3 patients on the basis of cytogenetic abnormalities (47,XXY, 47,XXX, 47,XY 21+): in 2 patients with anencephalic fetuses on the basis of alpha-fetoprotein and ultrasound investigations, and 1 patient with fetal Hurler's syndrome. One mother, aged 45, refused amniocentesis and gave birth to a child with Down syndrome. Amniocentesis was followed by fetal death and abortion in 3 patients, all of whom had repeat amniocentesis. Cytogenetic results were not obtained from cell-culture in 9 out of 155 patients, but it was possible to explain all but 2 of the failures. An unexplained error in fetal sex determination occurred once.


Variation in annual incidence of primary acute pancreatitis in Nottingham, 1969-74. A review of the 202 patients admitted to Nottingham hospitals with primary acute pancreatitis during the six years 1969-74 has been undertaken. The City of Nottingham and the four adjacent former urban districts had a population of 469 720 in 1971, and an attempt was made to obtain details of all patients from within this defined population area. 134 of the 202 patients came from this area. The annual incidence varied by 4-fold throughout the six years of the survey from a peak incidence of 83-0 per million population in 1974 to a low incidence of 21-2 per million in 1970. There was no detectable pattern behind this variation and consideration of the individual figures did not suggest that any particular predisposing factor accounted for the variation. Spatial variation analysis is now being undertaken to see if population and environmental subgroups can be identified.


Mass screening for hypertension in Copenhagen supermarkets. During its "heart week" in February, 1975, the Danish Heart Foundation drew the attention of the public to the problem of heart-disease with special reference to high blood-pressure; and 24 377 people attending supermarkets in Copenhagen took advantage of an offer to have their blood-pressure checked. There was a small charge for measurement, but the supermarket owners usually paid the fee on behalf of their customers. This unconventional approach to blood-pressure screening proved to be cheap, straightforward, and acceptable to the public. 23% of people measured were referred to their general practitioners for further evaluation.


General professional training in medicine. A programme of general professional training in medicine based on the Royal Commission report has been in operation at the Western Infirmary, Glasgow, and associated hospitals since 1969. It involves a two-year rotation through general medicine, dermatology, psychiatry, paediatrics, geriatrics, and a variety of medical specialties. A third year is spent as far as possible in one unit of the doctor's choice. The scheme has been popular with trainees and senior staff. A high pass-rate has been achieved in the M.R.C.P.--23 out of 26 being successful within the three-year period. The trainees have subsequently taken up a wide variety of hospital posts within the broad division of medicine or entered general practice. The concept of a broadly based three-year period of general professional training in medicine has proved both practical and useful.


Decreased serum cholesterol-binding reserve in premature myocardial infarction. Incubation of human serum with crystalline cholesterol which had been pulverised by sonication resulted in a measurable uptake of cholesterol by the serum. This uptake was designated "serum cholesterol-binding reserve" (S.C.B.R.). Among more than 200 men and women examined, S.C.B.R. values varied from less than 10 to over 200 mg/dl, while the values from repeated determinations on two individuals over several months varied within 24 mg/dl. S.C.B.R. could be attributed to two serum-lipoprotein subfractions--S.F.V. separated from very-low-density lipoprotein and S.F.H. from high-density lipoprotein, by gel filtration. Without further purification, S.F.V. solubilised 4-5 mg and S.F.H. solubilised 0-36 mg of additional cholesterol/mg of protein, while the remaining bulk of the lipoproteins lacked this property. It is proposed that S.F.V. and S.F.H. have physiological roles in retarding atherogenesis by removing cholesterol from the arterial intima and carrying it back to the circulating serum. Accordingly, individuals who have low S.C.B.R. values, being deficient in S.F.V. and  S.F.H., are at higher risk for the development of atherosclerosis and coronary heart-disease. This hypothesis was tested by comparing S.C.B.R. values of patients with premature myocardial infarction with values of controls. The results indicated a trend of increasing S.C.B.R. values with increasing levels of serum cholesterol and triglycerides among the controls, but this trend was virtually lost among the patients. The S.C.B.R. values also were lower among patients than controls, and the difference was statistically significant between patients and controls with serum-cholesterol above 250 mg/dl or fasting serum-triglycerides above 160 mg/dl. These results are consistent with the proposed hypothesis.


Pericarditis in acute myocardial infarction. In a prospective study of 300 consecutive patients who survived the first 24 h of acute myocardial infarction, pericarditis was present in 44 patients (14-7%). The only factors independently associated with pericarditis were transmural myocardial infarction, extent of myocardial damage, atrial fibrillation, and longer duration of fever. Pericarditis did not affect immediate prognosis or incidence of cardiac rupture. These findings and the high incidence of atrial fibrillation suggest that anticoagulant therapy should not be discontinued in patients with pericarditis complicating acute myocardial infarction.


Bird-fancier's lung and jejunal villous atrophy. Sixteen patients with bird-fancier's lung were screened for evidence of coeliac disease by assessing their clinical features, red-bloodcell or serum folate levels, and serum for reticulin antibodies. Five of nine patients selected for jejunal biopsy showed villous atrophy, and in some this seemed to be a true gluten-sensitive enteropathy.


Value of routine serum-triiodothyronine estimation in diagnosis of thyrotoxicosis. Thyroid-stimulating hormone (T.S.H.), triiodothyronine (T3), and thyroxine (T4) concentrations were estimated on 432 blood specimens from patients with a provisional diagnosis of thyrotoxicosis. 59 patients had a raised serum T3 concentration with T.S.H. and T4 levels in the normal range. Further information was obtained in 41 of these patients, and T3 toxicosis was diagnosed in 17 cases, thus providing a projected total of 24 patients with T3 toxicosis. In addition, there were 56 patients, with more common biochemical features of thyrotoxicosis, having both a raised serum T3 and T4 concentration. Therefore 30% of the patients considered thyrotoxic in this retrospective survey were only diagnosed with the aid of a serum-T3 estimation.


Immunoglobulin E in rectal mucosa of patients with proctitis. Rectal-biopsy specimens were obtained from a group of patients with proctitis in different stages of activity. Large numbers of brightly fluorescent IgE-producing cells were demonstrated in rectal-biopsy specimens taken from these patients during disease activity and clinical remission. An immediate hypersensitivity reaction is suggested as one of the mechanisms involved in the pathogenesis of proctitis.


Levels of alpha-fetoprotein in maternal blood as a screening test for fetal neural-tube defect. A range has been established for maternal plasma-alpha-fetoprotein (A.F.P.) levels in normal pregnancies (930 women). A.F.P. levels between 10 and 40 weeks gestation were examined in 51 pregnancies associated with fetal neural-tube defect. In 96% of cases (20 anencephalus, 6 spina bifida) examined between 16 and 26 weeks of gestation A.F.P. levels were above the 95th centile of the normal range. It is suggested that measurement of A.F.P. in maternal blood should become a screening test in all pregnancies, and a scheme for the futher investigation of patients with abnormal results is described.


Pancreatic-islet fibrosis in young infants of diabetic mothers. Pancreatic-islet fibrosis was found at necropsy in six out of ten infants (aged 11-142 days) born to diabetic mothers. Fibrosis covered an islet area of 5-10% in three cases, 10-20% in two cases, and more than 20% in one case. The three infants with the most pronounced islet fibrosis were heavier than normal at birth, and at least two of them were of "diabetic appearance" at birth. Five of the six cases with islet fibrosis had major malformations.


Identification of cholecystokinin-secreting cells. Cholecystokinin (C.C.K.)-producing cells were identified in the mucosa of the upper small intestine in man and other mammals by immunocytochemical techniques and electron microscopy on semi-thin and serial thin sections. Ultrastructural studies suggested that the C.C.K.-producing cells resemble I cells of the modified Wiesbaden classification. The combination of these techniques provides a simple and reliable method of identifying C.C.K. cells in human biopsy material and will be useful in the investigation and diagnosis of gut endocrine dysfunctions.


Validity of clinical examination and mammography as screening tests for breast cancer. This study is aiming to determine the validity and observer variability of clinical examination and mammography as screening tests for breast cancer. Women over the age of forty are given two independent clinical examinations of the breasts, and mammograms are taken and read independently by two radiologists. This paper presents the results of screening the first 1215 women to be enrolled in the study. At their first screening attendance, 231 women (19%) were referred for surgical opinion, 119 (9-8%) underwent biopsy, and cancer was diagnosed in 17 (1-4%). 2 further cancers were diagnosed in the ensuing six months among women who had been negative on initial screening, representing a false-negative rate of 2 out of 19 (11%). Clinical examination resulted in 189 referrals (15-6%), 90 biopsies (7-4%), and detected 11 cancers; corresponding figures for mammography were 76 referrals (6-3%), 55 biopsies ((4-5%), and 14 cancers. Observer variability was greater for clinical examination than for mammography. These early results suggest that as a screening test mammography compares favourably with clinical examination, but both tests are necessary if many false negatives are to be avoided.


Inhalational analgesia in labour: facemask or mouthpiece. A mouthpiece offered as an alternative to a facemask increased the acceptance of inhalational analgesia during labour from 76% to 96% of 50 patients. 92% of those patients offered a choice of a mask or mouthpiece would use the same device in another labour compared with only 64% of those offered only a facemask.


Cumulative effect of concussion.

Cumulative effect of concussion. Twenty young adults were studied after a second concussion. The rate at which they were able to process information was reduced more than in controls who had been concussed only once, and they took longer to recover than the controls. The effects of concussion seem to be cumulative, and this has important implications for sports where concussion injury is common.


Prophylactic oral antimicrobial agents in elective colonic surgery. A controlled trial. A controlled trial has been carried out in 50 patients undergoing elective colonic surgery to assess the efficacy of prophylactic oral metronidazole specifically directed against anaerobic colonic microflora in combination with kanamycin to reduce the aerobic flora. A control group received dietary and mechanical preparation alone. A significant reduction of both aerobic and anaerobic colonic microflora was achieved in the group receiving prophylactic antimicrobial agents, and this was reflected in a significant reduction in postoperative wound infections. 1 control patient died from Bacteroides septicaemia. No toxic or other side-effects from this prophylactic regimen occurred in this trial.


Plasma 25-hydroxyvitamin-D-levels during pregnancy in Caucasians and in vegetarian and non-vegetarian Asians. Plasma 25-hydroxyvitamin-D(25-O.H.D.), Ca, P, and alkaline-phosphatase levels were determined in three separate periods during pregnancy in 14 Caucasian mothers, 23 vegetarian Asians, and 16 non-vegetarian Asians. Non-pregnant women from the same group were used as controls. The expected steady rise in alkaline phosphate during pregnancy due to increase in the placental isoenzyme, and the fall in total Ca due to haemodilution, were noted. No appreciable changes in 25-O.H.D. levels occurred, but throughout pregnancy the levels in the vegetarian Asians were lower than in the other two groups. The same analyses were made in maternal and cordplasmas in some of these patients. The babies' 25-O.H.D. levels averaged 87% of their mothers'. There was no clear evidence that pregnancy as such led to increased vitamin-D requirement in any case of these groups.


Intestinal biopsy in the diagnosis of cow's milk protein intolerance without acute symptoms. 4 infants, suspected of cow's milk protein intolerance, were placed on an elimination diet and then challenged with cow's milk. None reacted clinically, yet in 2 of the 4 patients jejunal biopsy revealed clear histological, ultrastructural, and immunological changes. It is suggested that these changes are the objective criteria on which the diagnosis of cow's milk intolerance should be based, and that the clinical evidence derived from milk challenge after an elimination diet may be unreliable.


Depressed monocyte chemotaxis during acute influenza infection. The chemotactic responsiveness of monocytes from patients with serologically proven influenza infection has been quantified in vitro. Individuals with acute influenza had a significant (P less than 0-001) depression of monocyte chemotaxis. The depression ranged from 40% to 72% during acute infection but rose to normal by three weeks after recovery. When isolated mononuclear leucocytes from the recovered patients were incubated with the infecting strain of virus (Port Chalmers), a 49-54% inhibition of chemotaxis was obtained. These findings support the hypothesis that the altered immune responsiveness and increased predisposition to superinfections found frequently in patients with influenza can be due to the ability of the virus to depress monocyte function.


Coagulation changes during second-trimester abortion induced by intra-amniotic prostaglandin E2 and hypertonic solutions. The coagulation system was studied in twenty-seven patients undergoing second-trimester abortion induced by intra-amniotic prostaglandin (P.G.) E2 alone and in combination with a hypertonic solution of urea or glucose. Changes consistent with intravascular coagulation, namely a rise in fibrin degradation products and a fall in plasma-fibrinogen and platelet-count, were observed in those patients treated using P.G.E2 with hypertonic urea. Similar but less pronounced changes were found in the group treated using P.G.E2 with hypertonic glucose. In patients treated with P.G.E2 alone no changes suggestive of intravascular coagulation were detected. One patient treated using P.G.E2 with hypertonic urea who did not abort for 26 hours demonstrated changes indicative of a pronounced degree of disseminated intravascular coagulation. These findings show that when abortion is induced using P.G.E2 and a hypertonic solution, particularly hypertonic urea, disseminated intravascular coagulation can occur as a result of a hypertonic agent being used.


24-hour control of intragastric acidity by cimetidine in duodenal-ulcer patients. The effects of two dose regimens of cimetidine on 24 h intragastric acidity were investigated in six patients with duodenal ulcer. They received placebo capsules on the first day and cimetidine on the second day. Cimetidine 0-8 g/day decreased 24 h mean H+ activity by 55% but 1-6 g/day decreased it by 67%, the difference being due to a greater nocturnal decrease in the high-dose group. Intragastric pH remained below 2-0 for much of the treatment day but similar values were found in four post-vagotomy patients. Cimetidine 0-8-1-6 g/day results in a decrease of intragastric acidity that is compatible with successful medical treatment of duodenal ulceration.


Effect of cimetidine on gastric potential difference in man. The effect of the histamine H-2 receptor antagonist cimetidine on gastric potential difference (P.D.) has been studied in five healthy volunteers. P.D. was recorded continuously, and basal P.D. (mean +/- S.E.) was -48+/- 1-0 mV. Cimetidine, 300 mg orally, increased P.D. to -64+/- 2-4 mV. Cimetidine also significantly decreased basal acidity from pH 2 to pH 7 within an hour. The effect on both P.D. and pH persisted throughout each 3h study. P.D. has been shown to correlate with changes in the human gastric mucosal barrier. Cimetidine, therefore, may have a protective effect on the gastric mucosal barrier in addition to its suppression of acid secretion.


Unsaturated monohydroxy bile acids as a cause of idiopathic obstructive cholangiopathy. It is proposed that some cases of biliary atresia and neonatal hepatitis may be initiated by an adverse effect of unsaturated monohydroxy bile acids on the fetal and infantile hepatobiliary system. The hypothesis is founded on morphological observations in patients with biliary atresia and on the toxic effects of monohydroxy bile acids on the hepatobiliary system.


Infantile gastroenteritis: a clinical study of reovirus-like agent infection. In a clinical study of 32 infants with symptoms from infections with the human reovirus-like agent (R.I.A.) identified by electron microscopy (E.M.) of faecal extracts, a fairly consistent clinical pattern was found in 30 who had a gastroenteritis-like illness. The disease was usually mild, affecting mainly infants less than 2 years and males more commonly than females. The incubation period appeared to be 48-72 hours; and the onset was sudden, often with vomiting in the first 1-2 days of the illness. Loose yellow-green offensive stools without blood or mucus developed after a variable time, and there was often accompanying fever. Severe dehydration and electrolyte inbalance were uncommon; and with standard treatment the illness was uncomplicated, usually lasting 5-8 days. These features resemble those of previously reported winter epidemics of infantile non-bacterial gastroenteritis, and it is suggested that these epidemics were due to R.L.A. 2 infants in whom R.L.A. was identified in the stool did not have a gastroenteritis-like illness although both had protracted diarrhoea.


Controlled trial of intermittent regimens of rifampicin plus isoniazid for pulmonary tuberculosis in Singapore. A total of 481 adult Chinese, Malays, and Indians in Singapore with newly diagnosed smear-positive pulmonary tuberculosis were allocated at random to four regimens of intermittent rifampicin plus isoniazid. All patients received an initial 2 weeks of daily streptomycin plus isoniazid plus rifampicin. This was followed either by twice-weekly isoniazid 15 mg/kg plus rifampicin 900 mg (HR2 regimen) or 600 mg (LR2 regimen), or by once-weekly isoniazid 15 mg/kg plus rifampicin 900 mg (HR1 regimen) or 600 mg (LR1 regimen). In addition, all patients received a daily capsule containing, at random, either rifampicin 25 mg or a matched placebo to see if the rifampicin supplement would reduce the incidence of adverse reactions to the drug. At 12 months, all the patients on the two twice-weekly regimens (HR2, LR2) had a favourable bacteriological status as had 97% of 102 HR1 and 93% of 112 LR1 patients. The therapeutic response was significantly better on the twice-weekly than on the once-weekly regimens (P = 0-0005), but the dose size of rifampicin did not have a statistically significant effect. Adverse reactions to intermittent rifampicin occurred in 25% of the HR1 patients but on the other three regimens their incidence was low. The incidence of rifampicin-dependent antibodies was higher, ranging from 48% (HR1) to 24% (LR2). The effect of dose size on the incidence of the "flu" syndrome (the commonest reaction) and of antibodies was statistically significant (P less than 0-01 and less than 0-001, respectively). The interval between doses affected the incidence of the "flu" syndrome (P less than 0-001), but not of antibodies (P greater than 0-25). The rifampicin 25 mg supplement had no effect therapeutically or on the incidence of adverse reactions or of antibodies.


Photocoagulation in treatment of diabetic maculopathy. Interim report of a multicentre controlled study. A multicentre randomised controlled trial of xenon-arc photocoagulation for diabetic maculopathy is reported. This interim account reports the visual-acuity results of those who were followed up for up to three years. 76 patients were seen after one year, 44 after two years, and 25 after three years. Initially each patient had two similarly affected eyes of which one was treated. The treated eyes retained significantly better visual acuity than the untreated ones. Treated eyes deteriorated by 1 or 2 Snellen lines significantly less often than did untreated eyes. 8 treated and 18 untreated eyes became blind. Prognosis was best in those with initial visual acuity of 6/24 or better.


Role of heat-labile toxigenic Escherichia coli and Reovirus-like agent in diarrhoea in Boston children. 61 Boston children aged five years or less with acute diarrhoea were studied for evidence of infection with Escherichia coli strains that produce heat-labile enterotoxin (L.T.) or with a reovirus-like agent associated with childhood gastroenteritis. This represented the first evaluation of the prevalence of disease produced by these two agents in the same population. E. coli, isolated from acute-phase stool specimens, were tested in adrenal-cell tissue-culture and adult-rabbit ileal-loop assays for L.T. Acute and convalescent phase sera, collected from 31 children, were tested by the adrenal-cell assay for anti-L.T. activity. None of the 61 children demonstrated evidence of infection with L.T.-positive E. coli. Paired sera from 31 of the children studied were also tested for evidence of recent infection with the reovirus-like agent by determining titres of immunofluorescent-staining antibody to the serologically related Nebraska calf diarrhoea virus. 11 of the children (35%) had evidence of recent infection. These results suggest that an important proportion of endemic acute diarrhoea of young children in Boston is caused by the reovirus-like agent, and that disease caused by L.T.-producing E. coli is uncommon.


Enterotoxigenic Escherichia coli and idiopathic diarrhoea in Bangladesh. Faecal Escherichia coli from Bangalee patients with idiopathic diarrhoea were tested in the Chinese hamster ovary cell (C.H.O.) assay to detect production of thermolabile enterotoxin (L.T.). C.H.O-positive E. coli produce both L.T. and a thermostable toxin (S.T.). C.H.O.-positive strains were found in 19.2% of all cases and in 70% of the most severely ill patients with non-vibrio cholera. E. coli which produce S.T. alone were identified in a third of the C.H.O.-negative cases. Enterotoxigenic E. coli were found in 55% of inpatients with idiopathic diarrhoea and, if an aetiological role is confirmed, may be one of the commonest causes of tropical diarrhoea.


Breast cancer in patients with Hashimoto's thyroiditis. The case records of four groups of women over thirty on the books of a thyroid clinic were used to explore a possible association between breast cancer and Hashimoto's thyroiditis. The index group consisted of 1810 women (10 160 person-years of observation) with Hashimoto's thyroiditis, and the three control groups, matched by sex, age, marital status, and residency, were selected from patients with myxoedema (essential hypothyroidism), benign nodular goitre, or hyperthyroidism. The incidence of breast cancer for the index group, though not for control groups, was significantly higher than that expected from data for the general population, suggesting that patients with Hashimoto's thyroiditis are one high-risk population for breast cancer.


Gastric function in chronic renal failure. Effects of maintenance haemodialysis. 40 patients with chronic renal failure have been studied in order to determine why some patients with azotaemia have previously been reported to secrete abnormally large amounts of acid and some to secrete very little. 15 of the 40 patients were undergoing regular haemodialysis, while the remaining 25 patients had not been so treated. 10 of the 25 non-dialysed patients had much-impaired capacity to secrete acid. The impaired gastric secretory capacity was corrected and became abnormally great after some months of regular haemodialysis in 4 patients. Regular haemodialysis, by removing factors responsible for the gastric mucosal damage, permits manifestations of an underlying gastric hypersecretory state.


Gallstone dissolution in man using cholic acid and lecithin. Seven patients with radiolucent  stones in the gallbladder and two patients with radiolucent stones in the biliary tree were treated with oral cholic acid and purified soya-bean lecithin for 6 months. In two patients the stones disappeared and in one patient the stones were reduced in size. In five patients fasting bile samples were obtained before and during treatment and assayed for cholesterol, bile acid, and phospholipid. In all five patients the lithogenic index of bile was reduced during treatment. The biliary deoxycholic acid concentration was increased and chenodeoxycholic acid concentration decreased during treatment.


Stimulation of luteinising hormone (L.H.) release after oral administration of an analogue of L.H. releasing hormone. An analogue of luteinising-hormone-releasing hormone ([D-Leu-6, desGly-NH2-10]-L.H.R.H.-ethylamide) was administered by mouth to thirteen healthy men. In eight men 10 mg of this superactive L.H.R.H. analogue significantly increased mean plasma-L.H. within 45 minutes of administration. This increase was sustained for more than 5 hours. 2 mg of the analogue did not significantly increase plasma-gonadotrophin concentrations in the five men to whom this smaller dose was given. Oral administration of some L.H.R.H. analogues would seem to be effective in releasing L.H. in man.


Immunity to intra-erythrocytic protoza.

Immunity to intra-erythrocytic protoza. Intra-erythrocytic inclusion bodies were seen in Giemsa-stained smears of peripheral blood from mice infected with Babesia microti. These bodies, which were probably the pyknotic remnants of dead protozoa, increased as parasitaemia fell and the animal recovered. It is suggested that a soluble mediator liberated by cells of the host during infection penetrates the red blood-cell and leads to degeneration of the parasite.


How barefoot? Next steps for the medical auxiliary. The arguments for and against medical auxiliaries are over and interest must now shift to ways of maximising their effectiveness. An important issue is to what extent the findings of high-technology medicine can be successfully combined with the barefoot concept of delivery. An important question for the future is to what extent they can be applied by the individual to himself.


Presenting features and diagnosis of rabies. The early clinical features important in the establishment of a diagnosis of rabies are described from experience of 23 fatal cases in Sri Lanka. The importance of the "fan test" as a diagnostic sign is stressed. The earliest features of the disease may suggest hysteria if a history of a bite from a rabid animal is not obtained. In a district in which there is an outbreak of rabies cases of rabies hysteria may also develop.


Treatment of inoperable carcinoma of bronchus. A randomised prospective trial comparing "no immediate treatment" with single and multiple agent chemotherapy in 188 patients with inoperable carcinoma of the bronchus is reported. No immediate treatment proved a significantly better policy both for patients' survival and for quality of remaining life.


Bromocriptine therapy in acromegaly.

Bromocriptine therapy in acromegaly. Bromocriptine (CB-154, Sandoz) has been given to 21 acromegalic patients (11 female, 10 male) for a period of 6-10 months. The mean serum growth-hormone (G.H.) levels ranged from 10 mug/1 to 512 mug/1 before therapy. Bromocriptine suppressed G.H. values to 5 mug/1 or less in 4 patients and to less than 10 mug/1 in a further 8 patients, but in 2 patients G.H. levels did not show any significant reduction. Bromocriptine did not block stress-induced G.H. secretion. It did not distrub pituitary function other than secretion of prolactin and had negligible side-effects. Its effect on tumour size is uncertain and it is therefore unsuitable for patients with suprasellar extension of the tumour. Otherwise it seems reasonable to offer a trial of bromocriptine to all patients with acromegaly where therapy is deemed necessary. In those who show a full response of G.H. levels with a dose of 20-40 mg of bromocriptine per day, external radiation to the pituitary can be used to prevent tumour expansion and bromocriptine withdrawn at intervals to assess the effect of the radiation. In patients with a partial response to bromocriptine, the decision to offer alternative therapy depends on the extent of the response and on the age and medical condition of the patient. In patients who fail to respond to bromocriptine, particularly those younger patients with active disease, more definitive local treatment (e.g., trans-sphenoidal removal of the tumour or yttrium-90 implantation) would be indicated. Bromocriptine may also be used with benefit in the large number of patients who have shown a partial response to other forms of therapy.


Treatment of osteoporosis of ageing with 1alpha-hydroxycholecalciferol. Seven patients with osteoporosis of ageing were treated with synthetic 1alpha-hydroxycholecalciferol (1alpha-H.C.C.) for 3-4 months. The compound was given at a daily oral dose of 2 mug together with an oral supplement of 1 g of calcium. Clinically there was a striking improvement in the patients' physical fitness. Increased bone formation and mineralisation were seen on iliac-crest bone biopsy, and this was supported by an increased osteoblastic activity demonstrated by histochemical measurement of alkaline-phosphatase activity. Bone histology furthermore showed a reduced bone resorption, which was supported by a reduced urinary excretion of total hydroxyproline. Photon absorptiometry of the forearm accorded with the histological findings, showing a significant increase in the bone mineral content. Serum-calcium rose in all patients, one developing a severe transitory hypercalcaemia. The urinary excretion of calcium and magnesium increased significantly. The serum concentrations of 25-hydroxycholecalciferol and parathyroid hormone were not significantly affected by the treatment. It is concluded that 1alpha-H.C.C. is an effective tool in the treatment of senile osteoporosis.


Incidence and clinical significance of e antigen and antibody in acute and chronic liver disease. "e" is a serum antigen associated with type-B hepatitis. It is found only in hepatitis B surface antigen (HBsAg) positive sera, but is antigenically distinct from HBsAg. e antigen was not detected in the serum of any of 99 cases of acute type-B hepatitis who recovered normally. Its antibody, anti-e, was found in 14 (14%). The antibody usually appeared before clearance of HBsAg and before appearance of HBsAb. Serum e was not detected in any of 29 symptom-free carriers of HBsAg, but 21 (73%) showed anti-e. Serum e was found in chronic active hepatitis (44%) and chronic persistent hepatitis (31%). The antibody, however, was detected in only 2 of 79 patients with chronic active hepatitis but in 7 (44%) of chronic persistent hepatitis. Serum e was not found in 5 patients with primary liver-cell carcinoma or 5 with inactive HBsAg-positive cirrhosis. The antibody was, however, found in all 5 of those with inactive cirrhosis and in 4 of the 5 with primary cancer. These results suggest that the presence of e antigen is associated with active and usually continuing liver disease. Anti-e, however, is associated with inactive liver disease and asymptomatic carriage of HBsAg, and its presence must be regarded as a valuable sign in predicting those who will escape progressive chronic liver disease.


e antigen and anti-e in HBsAg carriers.

e antigen and anti-e in HBsAg carriers. A new antigen/antibody system, "e" and anti-e, was described in 1972. In order to assess the clinical significance of e antigen and anti-e, their presence was correlated with the clinical status, S.G.P.T. levels and liver biopsies of HBsAg carriers. 31 of the carriers had liver biopsies, 32 of 70 carriers had anti-e and 2 had e antigen. 28 of 55 carriers with normal S.G.P.T. and 4 of 15 patients with raised S.G.P.T. had anti-e. This difference is not statistically significant. 2 patients with e had raised S.G.P.T. All patients with normal histology, 45% of patients with mild, and 23% of patients with striking histological changes in the liver had anti-e. This association of anti-e with a normal or mildly abnormal liver was statistically significant. The 2 patients with e antigen had the most severe abnormalities in liver function and liver histology.


Controlled trial of prophylactic antibiotics in minor wounds requiring suture. Minor wounds presenting in the accident department requiring suture were randomly allocated to one of three treatment groups: an intramuscular injection of 1-25 megaunits of penicillin as a long-acting depot preparation, local wound irrigation with 100mg of tetracycline in solution, or no antibiotics. All wounds had a standard surgical toilet and were closed under aseptic conditions. Wound infections were noted five to seven days after suture, and in the two groups receiving antibiotics 23% of the wounds were infected whilst in the control group the frequency was 7%. The wisdom of using routine antibiotic prophylaxis in minor wounds is questioned.


R factors in gentamicin-resistant organisms causing hospital infection. An abrupt increase in gentamicin-resistant isolates was noted in the Manhattan Veterans Administration Hospital in 1973 and 1974. Bacteraemic infection occurred in 17 patients, 9 of whom died. R factors mediating gentamicin resistance were demonstrated in 34 of 36 strains. Organisms from 9 of 11 patients transferred a resistance pattern common to all other isolates from that patient, suggesting in-vivo interbacterial spread of the R factor.


Immunological observations on patients with Lesch-Nyhan syndrome, and on the role of de-novo purine synthesis in lymphocyte transformation. Three patients with the Lesch-Nyhan syndrome were found to have normal delayed hypersensitivity, peripheral-blood T-lymphocyte counts, lymphocyte responses to P.H.A., and serum IgM, IgA, and IgE levels. However, the percentages of B-lymphocytes, IgG levels, serum-isohaemagglutinin titres, and lymphocyte responses to pokeweed mitogen (P.W.M.) were subnormal. These observations suggest that activity of the salvage pathway of purine synthesis catalysed by hypoxanthine-guanine phosphoribosyl transferase (H.G.P.R.T.) is not required for the responses of T-lymphocytes to mitogenic or antigenic stimulation, but may contribute to the proliferation and function of B lymphocytes. The major role of the de-novo pathway of purine synthesis in human lymphocyte responses to mitogenic or antigenic stimulation is shown by the effects of inhibitors of this pathway, including immunosuppressive agents, and by the effects of congenital deficiency or inhibition of adenosine deaminase.


Mechanisms of reflex cardiac arrest in tetraplegic patients. Four patients with physiologically complete high cervical spinal-cord lesions, sustained within the previous 6 weeks, were observed. All needed intermittent positive-pressure ventilation. In the stage of spinal shock, stimuli to the trachea induced bradycardia, and in two patients cardiac arrest resulted. The bradycardia occurred when the patients were hypoxic, and seemed to be due to a vaso-vagal reflex. Normally this reflex is opposed by sympathetic activity, and during hypoxia by increased pulmonary (inflation) vagal reflex activity due to increased breathing. In these patients, however, compensatory sympathetic activity was prevented by the cervical cord lesion, and increased pulmonary vagal reflex activity by the fact that the breathing was artificial and therefore did not increase with hypoxia. Treatment in emergency includes the administration of atropine. Adequate oxygenation and, if this cannot be achieved, maintenance atropin should prevent the bradycardia and cardiac arrest associated with stimulation of the trachea in artificially ventilated tetraplegic patients.


Interaction of maternal and neonatal cells in mixed-lymphocyte cultures. One-way and two-way mixed-lymphocyte cultures of cells from male newborn infants and their parents were studied. The tests between the lymphocytes of the parental pairs in the one-way system, in which one population stimulates and the other responds, indicated that maternal lymphocytic response was not generally depressed. However, there was some evidence that the response of the maternal cells was depressed when the cells of the newborn infant were stimulatory. When both maternal and neonatal lymphocytes were viable and the origin of the dividing cells was monitored by using sex chromosomes as markers, it was clearly shown that the division of maternal cells was inhibited, most of the metaphases being XY. The mechanism of this inhibition may depend on contact between viable cells or on the liberation of inhibitory factors by the neonatal cells.


Incongruous referrals.

Incongruous referrals. A survey of 1344 patients registered at a new health centre in Glasgow assessed the prevalence of symptoms and referrals together with subjective, gradings of medical symptoms in terms of pain, disability, and perceived seriousness, and of social symptoms in terms of worry or inconvenience. These grading scales were used to define referral behaviour which appeared to be incongruous in the light of the respondents' own perceptions of their symptoms. In this way incongruous referrals indicated the size of the medical and social symptom "iceberg" and "trivia". For both medical and social symptoms the "icebergs" were larger than the "trivia"; the medical-symptom "iceberg" was two to three times greater than the medical-symptom "trivia".


Mortality study of workers in a polyvinyl-chloride production plant. Age-standardised mortality-rates for a population of 2100 male workers exposed to vinyl chloride for periods of up to 27 years do not show any excess of total or cause-specific mortality. 1 case of angiosarcoma of the liver was identified just outside the study period. There was no suggestion of an increased frequency of deaths from the more common malignant diseases.