Mechanisms of clonal abortion tolerogenesis. I. Response of immature hapten-specific B lymphocytes. B lymphocytes with receptors specific for the hapten fluorescein (FLU) were prepared from the spleens of mice of various ages. For most experiments, a one-step fractionation procedure based on the adherence of FLU-specific cells to FLU-gelatin was used. For some experiments, a subset of higher FLU-binding capacity was prepared from the FLU-gelatin binding population through the use of the fluorescence-activated cell sorter (FACS). FLU-specific B cells were placed into microculture with either FLU(3.6)-human gamma globulin (FLU(3.6)HGG) or FLU(12)HGG usually for 24 h at 37 degrees C. The tolerogen was then removed and 0.1 mug/ml of a T-independent antigen, FLU-polymerized flagellin, was substituted. 3 days later, cells were harvested from the microcultures and assayed for FLU-specific plaque-forming cells to determine any reduction in clonable hapten-specific B cells which the tolerogenesis treatment might have induced. The results showed that with FLU(3.6)HGG, hapten-specific newborn B cells could be tolerized at 1,000-fold lower tolerogen concentrations than adult splenic B cells of equal antigen-binding capacity. The high-avidity subset was even more susceptible to tolerance induction. Tolerance could be induced within 8 but not within 2 h, and at lower tolerogen concentrations, longer periods of tolerogenesis were required for a given effect. Using a 24-h tolerogenesis phase, 50 percent reduction in clone frequency among newborn FLU-gelatin fractionated cells was achieved at 0.08 mug/ml of FLU(3.6)HGG. Tolerance induction in immature B cells was inhibited by the concomitant presence of a polyclonal B-cell activator, Escherichia coli lipopolysaccharide (LPS) but tolerance once induced, was stable to challenge with LPS. Tolerogenesis was hapten specific. The proportion of tolerizable cells in spleens decreased with increasing age, reaching 50 percent at around 9 days. FLUI(12)HGG proved a more powerful tolerogen than FLU(3.6)HGG. It had an effect on adult cells, 50 percent reduction in clone frequency being noted at around 1 mug/ml. However, and in contrast to results claimed for other T- independent systems, there still was a major difference between immature and mature B cells, the immature cells displaying much greater sensitivity to tolerogenesis.


A requirement of Pi for the transitory uncoupling of rat liver mitochondria by hydrazine, when beta-hydroxybutyrate is the substrate. We have recognized an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and, therefore, became interested in the mitochondrial target of hydrazine, which is not only a potential environmental hazard as a carcinogen but is also a likely metabolite of many drugs. Hydrazine induced a Pi dependent transitory uncoupling of rat liver mitochondria when beta-hydroxybutyrate was the substrate. Uncoupling was inhibited by rutamycin; accordingly, the mitochondrial target for nucleophilic hydrazine is an electrophilic site, presumably involving activated Pi. The protective action of ATP2, ADP, PPi and Mg++ was attributed to a conformational change of the phosphorylating enzyme which participated in oxidative phosphorylation. In a mitochondrial system which included ATP gramicidin potassium ion and sulfate, hydrazine, acting as a large cation but not as a nucleophile, blocked mitochondrial swelling and the increment in ATPase activity associated with potassium ion. These data in conjunction with our previous reports dealing with other carcinogens and certain of their derivatives also contribute to an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and are compatible with toxic effects of hydrazine on mitochondria observed previously by others.


The tumor-producing effect of automobile exhaust condensate and fractions thereof. Part I: chemical studies. The criteria of a biological detection system discriminating carcinogenic and non-carcinogenic fractions of a mixture are discussed. Automobile exhaust gas condensate (in total 545.5 g) produced by a passenger car during the Europa driving cycle was separated into fractions with and without polycyclic aromatic hydrocarbons (PAH) by liquid-liquid distribution between methanol + water / cyclohexane and cyclohexane + nitromethane, respectively. This fractionation was chosen because of the general experience that PAH are highly potent carcinogens. To prove whether other non-PAH contribute to the total carcinogenic effect, these had to be separated from the PAH-containing fraction. Carbazol and acridine derivatives as well as aromatic amines remain predominantly in the PAH-free methanolic phase.


Idiotypic cross-reactivity between antibodies of different specificities. Cross-idiotypic specificity has been demonstrated between antibody populations of different specificities using antibodies directed toward human sickle cell hemoglobin (HbS). A site-specific antibody directed toward the beta6-position of HbS, anti-Val, was used to elicit an anti-idiotypic response in rabbits. Using this anti-idiotypic serum, idiotypic cross-reactivity was demonstrated between antibody populations that bind to human adult hemoglobin (HbA). It was demonstrated that in the case of the goat antibodies, these idiotypically cross-reacting antibodies are directed towards the beta6-position of the hemoglobin molecule. However, they differ in their specificity, binding to this site on HbA, whereas anti-Val binds only to HbS. The sheep antibody populations directed toward HbS differ qualitatively from those of the goat. Using rabbit anti-idiotypic serum specific for sheep anti-Val, cross-reactivity could be demonstrated with antibodies directed toward the alpha-chain of the hemoglobin molecule, as well as the beta-chain. There was also a low level of cross-reactivity with antibodies from a goat immunized with HbA.


Mechanism of action of factor D of the alternative complement pathway. Factor D (C3 proactivator convertase) of human serum has been shown to be absolutely necessary for alternative pathway function, for activation of the C3/C5 convertase of that pathway and not to be a subunit of this enzyme. Factor D was found to be present in human plasma in active form only, at a concentration of 2 microgram/ml, and not to be controlled by plasma protease inhibitors or by spontaneous decay. Unlike trypsin, factor D cleaves and activates factor B only when it is in Mg++-dependent complex with C3b, has no esterolytic activity, and is unable to cleave the B chain of insulin. The alleged functional and antigenic relationship of factor D to alpha-thrombin could not be verified. The results of this study led to the description of the mechanism of action of factor D in terms of the cryptic site hypothesis.


Immunological dissection of human Ia molecules. The immunochemical analysis of Daudi Ia molecules by a variety of alloantisera led to the recognition of at least three molecular species carrying different antigenic determinants: DRw6, DC-1, and DC-2. Genetic as well as structural evidence indicates that DRw6 and DC-1 molecules are controlled by separate, HLA-linked loci, rather than by alleles at the same locus. The alloantigenic determinants appear to be expressed on the small Ia subunit. DC-1 and DC-2 determinants discussed had not been defined by serological analysis at the population level, but were demonstrated to be present by immunochemical analysis at the molecular level.


Involvement of H-2L gene products in virus-immune T-cell recognition. Evidence for an H-2L-restricted T-cell response. The H-2L locus is closely linked to H-2D and codes for antigenic specificities present on a 45,000 mol wt glycoprotein that is distinct from the molecule which bears the D region private specificity. It was found that BALB/c-H-2db mice, which lack detectable cell-surface H-2L gene products, were able to generate influenza- and vaccinia-immune cytotoxic T cells which lyse D region-compatible target cells, although they have been reported to be incapable of making a similar response to ectromelia virus (7). Thus, the lack of H-2L antigenic specificities does not produce a general loss of responsiveness for other viruses even when a highly cross-reactive pox virus (vaccinia) was studied. Antisera-blocking experiments utilizing sera specific for either L or D molecules indicated that BALB/c mice generate influenza virus-immune cytotoxic T-cell subsets which independently recognize H-2L and H-2D gene products in association with viral antigens. These results are the first indication that products of the H-2L locus can operate analogously to H-2K/D gene products in virus-immune T-cell recognition.


Myelin basic protein serum factor. An endogenous neuroantigen influencing development of experimental allergic encephalomyelitis in Lewis rats. Age-related concentrations of myelin basic protein serum factor (MBP-SF), an endogenous neuroantigen detected and quantitated by inhibition of binding of rat myelin basic protein (RMBP) antibody with 125I-RMBP reagent antigen and immunochemically indistinguishable from native RMBP in this respect, reach peak levels as high as 21 ng/microliter among 2-3-wk-old normal suckling Lewis rats. Levels then progressively decline to low, usually undetectable levels of less than or equal to 0.6 ng/microliter MBP-equivalents in adult animals by 7 wk of age. MBP-SF levels are inversely related to the age-related increasing capacity of maturing Lewis rats to develop experimental allergic encephalomyelitis (EAE) after sensitization to MBP of syngeneic, but not xenogeneic, origin. MBP-SF appears to be an endogenous neuroimmunoregulatory product of potential importance for immunologic tolerance to autologous RMBP in Lewis rats.


Selective stimulation and differentiation of early antigens in lymphoblastoid cell lines producing Epstein-Barr-like viruses. Comparisons of early antigens (EA) of EBV-related lymphotropic herpes virus of Old World primates have proved difficult to accomplish because antigen levels are low in infected cells and the ratio of virus capsid antigen to EA is generally high. To overcome these difficulties, we have developed a procedure which combines antigen stimulation with inhibition of late virus functions and results in the selective stimulation of EA. Using this procedure, we have examined the EA of EBV, herpesvirus papio, h. pongo, and h. pan. The results show that the EA of these viruses are composed of both R (restricted) and D (diffuse) components and that the EA, while related, are distinguishable.


Effect of trypsin treatment on the antigenic characteristics of plaque variants of type-O 1 and type Asia-1 foot-and-mouth disease viruses. Antigenic differences were demonstrated between the large and small plaque variants of both types O1 and Asia-1 foot-and-mouth disease viruses. Treatment of the large and small plaque variants of the viruses with trypsin essentially abolished the observed antigenic differences. Thus, these plaque variants have antigenically different trypsin-sensitive determinants that may influence their immunogenicity and infection capabilities.


Topographical distribution of sulfated glycosaminoglycans in the surface layers of the human temporomandibular joint. A histochemical study of an autopsy material. The right temporomandibular joint (TMJ) was removed at autopsy from 18 individuals and the articular surfaces were scored for macroscopic lesions. Soft tissue specimens were cut out of the medial, lateral and posterior parts of the temporal and condylar components and frozen. The sections were stained with toluidine blue (1-N HCl solution) and with alcian blue (CEC method) for sulfated glycosaminoglycans. The sections were examined for inter- and pericellular metachromasia and alcian blue staining. Macroscopic surface lesions were found in 14 of the joints. The highest score of interand pericellular metachromasia was found in the anterior parts of the joints and a negative correlation was found between the score of surface lesions and that of intercellular metachromasia. Pericellular metachromasia was found mainly in the mineralized cartilage and cartilage layers of the articular surface. Although the CEC values of pericellular staining commonly reached a level indicating the presence of keratan sulfate, the majority of the CEC values found corresponded to those of chondroitin-dermatan sulfate. It was concluded that sulfated GAG are localized mainly to the anterior part of the TMJ and that macroscopic TMJ surface lesions are associated with a reduction of sulfated glycosaminoglycans.


Ultrastructural study of adenomatoid odontogenic tumor. Two cases of adenomatoid odontogenic tumor were examined by light and electron microscopy. Morphologically the tumors could be divided into four layers. The ultrastructure of the tumor cells of each layer was revealed to be similar respectively to that of four layers seen in the enamel organ of a normal tooth germ. Duct-like structures and eosinophilic small areas were frequently present in compactly proliferating cell layers. Short columnar cells forming duct-like structures and eosinophilic small areas appeared similar ultrastructurally to ameloblasts during predentin formation. Therefore it seems reasonable to assume that this tumor originates from the enamel organ. The contents in the lumen of each eosinophilic small area varied, and seemed to be secreted into the stroma by circumscribing epithelial tumor cells. A fine filamentous layer was present in both of the duct-like structures and some of the eosinophilic small areas, and the former was different from the latter with respect to the alcian blue (pH 2.5) and toluidine blue (pH 4.4) staining reactions.


Lipopigment in odontogenic cysts.

Lipopigment in odontogenic cysts. A study of 105 odontogenic cysts revealed the presence of pigmented cells in the cyst wall in 38% of the cases. The frequency of pigmented cells was higher in the inflammatory odontogenic cysts than in the development cysts. Although isolated pigmented cells were seen within the epithelial lining and cyst cavity, the larger collections were closely associated with cholesterol crystals and hemosiderin deposits; they contained light brown cytoplasmic pigment which manifested sudanophilia, acid-fastness, silver reduction capacity, PAS positivity and yellow autofluorescence in ultraviolet light. The morphology, histochemical reactions and autofluorescence suggest that the pigmented cells are macrophages containing ceroids. It has been suggested that the hemosiderin which is found in the cyst wall serves as an oxidation catalyst for the locally liberated lipids, the end result of which is the formation of the ceroid pigment.


Corpora amylacea in mesothelioma of the atrioventricular node. Rounded or polyhedral, acellular, dense lamellated structures were seen within gland-like spaces in a case of atrioventricular mesothelioma. These structures exhibited many of the histochemical characteristics of amyloid, viz., pink colour with green birefringence and bright red fluorescence with alkaline Congo red; ortochromasia and red birefringence with standardised toluidine blue; positive DMAB-nitrite and diazotisation coupling reactions and spontaneous autofluorescence. It is suggested that these bodies are derived from spontaneous assembly or polymerisation of microfibrils of desquamated cells lining the cystic spaces of the tumour as occurs in prostatic corpora amylacea. The peculiar intramyofibre proliferation of tumour cells in the peripheral part of the tumour suggests that viable tumour cells can penetrate, survive and proliferate within atrial or nodal myofibres leaving an intact sarcolemmal sheath. The slow tumour cell growth and the successive degeneration of central tumour cells may explain the tubular and/or glandular pattern constantly seen in this tumour.


Ultrastructural study of bleomycin-induced pulmonary changes in mice. The pulmonary changes produced in mice given bleomycin intraperitoneally (twice weekly for 4 weeks, total dose 240 mg/kg) were examined by light and electron microscopy. Bleomycin damaged the pulmonary vessels and produced type I pneumocyte necrosis, resulting in non-uniform pulmonary fibrosis. The sequence of events leading to pulmonary fibrosis may be arbitrarily divided into three phases: firstly, a focal perivascular lesion consisting of interstitial oedema with plasma cell and lymphocyte infiltration; followed by the middle proliferative phase characterised by type I pneumocyte necrosis, intra-alveolar fibrin deposition, an increase in the numbers of type II pneumocytes and fibroblasts and an overall decrease in the alveolar diameter. The third phase consisted of organisation, with intra-alveolar and interstitial collagen formation and the synthesis of elastin. These phases, although occurring sequentially, did not bear a constant time relationship to the dosage schedule, for new early focal lesions continued to appear throughout the period of the experiment. These ultrastructural changes are not specific for bleomycin, but represent a general reaction of the lung to injury. The exact mechanism whereby bleomycin produces the lung damage has yet to be ascertained.


Axonal transport of acetylcholine, choline acetyltransferase and cholinesterase in regenerating peripheral nerve. 1. The axonal transport of acetylcholine (ACh), choline acetyltransferase (ChAc) and cholinesterase (ChE) was estimated in the peroneal nerves of rabbits by measuring the accumulation of each against a nerve crush over a period of 20 hr. 2. Estimates were made of the amounts of these substances that were transported in nerves that had been regenerating for up to 111 days after being crushed or up to 13 days after being cut. 3. The initial response was the same whether the injury was a crush or a cut; the amount of ACh transported was increased, while ChAc and ChE transport was reduced. 4. The amounts of ACh, ChAc and ChE transported tended to return to normal levels when the nerves were allowed to reinnervate the denervated muscles. ChAc transport also showed an early recovery in the cut nerves. 5. The ACh content of the central nerve stump did not alter throughout regeneration but ChAc and ChE contents were reduced at the times when the transport of the enzymes was reduced. 6. These results are discussed in relation to the time course of nerve regeneration.


Benzopyrones. 14. Synthesis and antiallergic properties of some N-tetrazolylcarboxamides and related compounds. A series of chromones containing an acidic group has been synthesized and screened for the ability to inhibit passive cutaneous anaphylaxis and the release of histamine from mast cells of the rat. Many of the chromones contain the N-(5-tetrazolyl)carboxamido group, a novel source of acidity. Others contain a carboxyl, C-(5-tetrazolyl), 5-(4H)-oxotetrazolinyl, or N-(5-tetrazolyl)sulfonamido function. The compounds were compared with cromolyn sodium (sodium cromoglycate) and many were found to be powerful inhibitors of anaphylaxis. The most potent was 7-methoxy-4-oxo-N-(5-tetrazolyl)-4H-1-benzopyran-2-carboxamide (15). Structure-activity relationships among the chromones and also some related compounds are discussed.


Studies on streptococci resembling Streptococcus milleri and on an associated surface-protein antigen. Ninety-nine strains of streptococci were isolated from 97 cases of pyogenic infections, most of which involved the teeth. Physiological and serological tests were performed on these streptococci and on 37 strains of streptococci from culture collections. The results were used for a numerical classification. Seventy-nine of the strains isolated from patients formed a cluster with Streptococcus milleri and group-F reference strains, and were therefore considered as streptococci resembling S. milleri. By the use of an antiserum prepared against strain Z3, protein antigens were demonstrated in acid extracts of 65% of the strains of S. milleri. These antigens were in only five strains not included in the S. milleri cluster.


Response of women with primary orgasmic dysfunction to audiovisual education. Of 17 women ages 19 to 38 with primary orgasmic dysfunction, 7 achieved orgasm within a week after viewing an audiovisual sex education program, a statistically significant change (p less than .02). No other intervention (educational, behavioral, psychotherapeutic) occurred between the audiovisual session and later inquiry about subsequent sexual response. These results suggest that explicit sex education can help remedy sexual dysfunction in a significant number of women and that further investigation is needed.


Carcinoma of the rectum and rectosigmoid colon: role of radiation therapy. Surgery is the modality of choice in curative treatment for cancer of the colon and rectum. Since a majority of the patients present advanced disease where the surgical outlook is poor, adjuvant therapy may be warranted. Clinical and experimental data demonstrate the benefits from preoperative radiation therapy and some clinical reports indicate the beneficial effects of postoperative radiotherapy. Two national studies are underway to determine the effectiveness of preoperative radiation therapy in moderate doses. A similar study is suggested to establish the effectiveness of postoperative radiation therapy.For patients who are poor surgical risks, or for a tumor which is considered to be inoperable, and in a selected group, radiation therapy can be used as a curative procedure. Advantages include eliminating the need for a permanent colostomy. In case of failure, electrocoagulation and abdominal perineal resection are still available alternatives.A modest amount of radiation therapy can afford maximum palliation with minimum discomfort to the patient. About 80-90 percent of patients with pain and bleeding and 50 percent of patients with symptomatic liver metastasis respond favorably.


Binding of tryptophanyl-tRNA to the reverse transcriptase of replication-defective avian sarcoma viruses. The ability of reverse transcriptase to bind to [3H]tryptophanyl-tRNA and to function as DNA polymerase was compared for five temperature-sensitive mutants of avian sarcoma virus. Both activities of the reverse transcriptase were found to be heat labile in LA 335 and LA 336 as compared with the wild-type parents. For the other mutant viruses, LA 338, LA 343, and LA 672, grown at the permissive temperature, the reverse transcriptase was nearly as heat stable as for the wild-type parents in terms of tRNA binding and DNA polymerase. LA 338, LA 343, and LA 672 showed characteristic defects in their reverse transcriptase when propagated at the nonpermissive temperature; namely, tryptophanyl-tRNA binding and DNA polymerase activities were coordinately decreased in these virions. The reduced enzymatic activities were not entirely due to an inactive reverse transcriptase present in the virions, however, but rather lower amounts of enzyme protein incorporated into the virions contributed to the effect, according to assays of reverse transcriptase antigen by radioimmune competition.


Acquisition of oncogenicity by endogenous mouse type C viruses: effects of variations in env and gag  genes. Several dual-tropic isolates derived from the thymuses of preleukemic or leukemic AKR mice and a more recrnt group of viruses generated by in vitro or in vivo passage of a poorly infectious endogenous virus of C3H mouse cells have been shown to be highly oncogenic. By analysis of the immunological properties of their gag gene-coded structural proteins, each of the AKR-derived isolates and two dual-tropic C3H-derived isolates were found to closely resemble AKR murine leukemia virus. In contrast, gag gene-coded proteins of two other leukemogenic isolates of C3H origin, including one ecotropic and one dual-tropic virus, were indistinguishable from those of Moloney murine leukemia virus. All of the oncogenic isolates, including those of AKR and C3H origin, were found to possess common envelope glycoprotein determinants of a unique class not shared by the nononcogenic ecotropic viruses from which they were derived. These findings support the possibility that oncogenic variants of endogenous ecotropic mouse type C viruses are derived by genetic recombination. This recombinational event appears to involve the acquisition, by different ecotropic viruses, of a common class of endogenous virus-coded envelope glycoprotein determinants which are presumably required, but not necessarily sufficient, for oncogenicity.


Inhibition of compound 48/80-mediated histamine release from isolated rat mast cells by oosponol-related compounds (4-acyl-isocoumarins). Oosponol (4-hydroxymethylketone-8-hydroxyisocoumarin) is a metabolic product isolated from Oospora astringens which originated from house dust in a room of an asthmatic patient. The compound and the structurally related isocoumarins were studied to determine the inhibition of histamine release induced by compound 48/80 from isolated rat peritoneal mast cells. The released histamine was assayed by fluorometry. The compounds tested were not observed to release histamine. Some of 4-acyl-isocoumarins inhibited the histamine release at doses less than 10 micrometers, whereas the 3-acyl- and the 4-alkyl-compounds were not effective at doses over 100 microns. The pretreatment of mast cell with the compound for 15 min before the application of compound 48/80 was more effective than the simultaneous administration. The mode of inhibitory action of KIT-302, 4-(4'-carboxy-benzoyl)-isocoumarin, was non-competitive antagonism to compound 48/80 on the mast cells.


Possible role of IgE-constituent carbohydrate in the mediation of histamine release. A possible role of IgE-constituent carbohydrate in the mediation of histamine release was pharmacologically studied in isolated peritoneal rat mast cells. Among polysaccharides obtained commercially, mannan and dextran induced histamine release, and the ED50 was 4 microgram/ml and 52 microgram/ml, respectively. At doses higher than 1 mg/ml,  Ficoll, hyaluronic acid and heparin induced the release, while agarose did not. The weak histamine releasing polysaccharides did not induce inhibition of the dextraninduced histamine release. Monosaccharides such as N-acetylglucosamine, mannose and N-acetylneuraminic acid induced marked inhibition of the mannan-induced histamine release, although other carbohydrate constituents of IgE fucose and galactose were weak inhibitors. The antagonism of the monosaccharides against polysaccharide-induced histamine release was found to be a competitive type. Also, antigen-induced histamine release from peritoneal mast cells actively immunized with egg albumin glucosamine. Hence it appears that IgE-constituent carbohydrate may play an important role in IgE-mediated histamine release.


Characterization of sialytransferase in noncancerous and neoplastic human liver tissue. When compared to uninvolved adjacent tissue, metastatic tumors in human liver appear to have significantly reduced sialytransferase activity. No significant kinetic differences (Michaelis constants, thermostability, and pH optima) between noncancerous and cancerous tissue sialytransferase were found. Mixing experiments between cancerous and noncancerous tissues indicated that inhibitors of sialytransferase activity were present in cancerous tissue. Subsequent experiments demonstrated increased levels of bound sialic acid in the tumor tissues. Inasmuch as futuin, a sialoglycoprotein, inhibits sialyltransferase activity, the increased levels of bound sialic acid in tumor tissue may be responsible for the reduced enzyme activity in these tissues.


Characterization of a new virus from Mus cervicolor immunologically related to the mouse mammary tumor virus. A virus, similar to the murine mammary tumor viruses (MuMTV) of the laboratory mouse Mus musculus, was identified in the milk of M. cervicolor popaeus mice. The virus was morphologically indistinguishable from the type-B MuMTV and was thus termed MC-MTV. Radioimmunoassays for the 52,000-dalton major envelope glycoprotein and the 28,000-dalton major internal protein of MuMTV demonstrated that MC-MTV shared some antigenic determinants with both of these MuMTV proteins. This reactivity was clearly different, however, from that observed with all MuMTV tested from M. musculus. MC-MTV had a density of 1.16 g/ml in sucrose and a virion-associated DNA polymerase with a divalent cation preference for Mg2+ over Mn2+. Radioimmunoassays clearly differentiated MC-MTV from the other viruses previously identified from M. cervicolor, i.e., M432, CERV-CI, and CERV-CII. These studies thus identified the first virus from another species that is immunologically related to the MuMTV of M. musculus. Particles similar to MC-MTV were also observed in a spontaneous M. cervicolor popaeus mammary tumor.


Selective decontamination of the digestive tract of Syrian hamsters. Conventional Syrian hamsters colonized with aerobic gram-negative bacteria such as Pasteurella pneumotropica and various Enterobacteriaceae species were successfully and permanently freed from these microorganisms by oral treatment for 4 weeks with dihydrostreptomycin and 'Orabase' premixed with appropriate antibiotics. Concomitant oral treatment with dimetridazol for the elimination of intestinal flagellates was unsuccessful. During treatment the animals were maintained under germ-free isolation conditions.


Existence of a common precursor to ACTH and endorphin in the anterior and intermediate lobes of the rat pituitary. Extracts of rat anterior and intermediate-posterior pituitary were fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for immunoactive ACTH and endorphin. In both lobes the major forms of immunoactive ACTH have apparent molecular weights of 31,000 (31K), 20--21K, 14K, and 4.5K, and the major forms of immunoactive endorphin have apparent molecular weights of 31K (coincident with the peak of immunoactive ACTH), 13K (a betaLPH-like peptide), and 3.5K (a beta-endorphin-like peptide). However, the quantitative distribution of immunoactivity among the various forms differs greatly between the lobes. Assays using an extreme COOH-terminal ACTH antiserum indicate that the 31K ACTH/endorphin molecule in rat anterior and intermediate pituitary is similar to the pro-ACTH/endorphin molecule from mouse pituitary tumor cells. A radioimmunoassay that is specific for the NH2-terminal non-ACTH, nonendorphin segment (referred to as 16K fragment) of the mouse pro-ACTH/endorphin molecule was used to assay extracts of rat pituitary. In addition to detecting material at 31K and 20--21K, the 16K fragment radioimmunoassay detects significant amounts of cross-reactive material with an apparent molecular weight of 16K in extracts of both lobes. This result also suggests that the structure and processing of the rat 31K ACTH/endorphin molecule is similar to that of mouse tumor cell pro-ACTH/endorphin. Cell suspensions were prepared from the anterior and intermediate lobes of the rat pituitary and maintained in culture for a 24-h period. The isolated cells from both lobes incorporate [3H] phenylalanine into immunoprecipitable ACTH- and endorphin-containing molecules. By sequential immunoprecipitation with ACTH and endorphin antisera, it is possible to demonstrate directly that a single molecule (31K ACTH/endorphin) has antigenic determinants for both ACTH and endorphin. Significant amounts of 31K ACTH/endorphin are released into the culture medium by isolated anterior lobe and intermediate lobe cells. The isolated intermediate lobe cells synthesize and secrete relatively large amounts of a beta-endorphin-like molecule; the isolated anterior lobe cells secrete significant amounts of both a betaLPH-like molecule and a beta-endorphin-like molecule. These same quantitative differences between anterior and intermediate lobe tissue were observed in immunoassays of extracts of the separated lobes and probably reflect differences in the processing of the common precursor. The isolated anterior lobe cells can be stimulated to release increased amounts of immunoprecipitable ACTH and endorphin by incubation with a cyclic AMP analog and a phosphodiesterase inhibitor.


[A clinical constelation in disuse: vitiligo, mastocytosis of the bone marrow, circulating heparinoid, chronic leg ulcer, hypoalbuminemia, ulcerative colitis and hepatic fibrosis]. We report an unusual case. Our patient had vitiligo, ulcerative colitis, hepatic fibrosis, hypoalbuminemia, bone marrow mastocytosis, a circulating heparinoid and chronic leg ulcers. The relationship between some of the components of this constellation seems logical. This is the case with bone marrow mastocytosis and circulating heparinoid. Also, between hypoalbuminemia and colitis and liver disfunction. On the other hand, the relationship between other features does not seem clear in the light of current knowledge.


Very long-term treatment of peptic ulcer with cimetidine. In an open trial, 96 patients with endoscopically proven peptic ulcers were randomly allocated to treatment with cimetidine (1 g/day) for periods of 3, 6, 9, or 12 months. After their courses of treatment, the patients were followed up for at least 6 months. In 92% the ulcers had healed after treatment for 1 month, and in a further 5% the ulcers healed during the next 2 months. Ulcers recurred during treatment in 24% of patients and within 6 months of withdrawal of treatment in a further 43%. In nearly a third of patients the recurrences were asymptomatic and were discovered only through routine endoscopic studies. Continuous treatment with full doses of cimetidine for a year seems to prevent relapse of the majority of ulcers which have healed during treatment; but it does not cure the ulcer disease, since relapse generally occurs quite rapidly when treatment is discontinued.


Toxic-shock syndrome associated with phage-group-I Staphylococci. Seven children (aged 8--17 years) presented with a high fever, headache, confusion, conjunctival hyperaemia, a scarlatiniform rash, subcutaneous oedema, vomiting, watery diarrhoea, oliguria, and a propensity to acute renal failure, hepatic abnormalities, disseminated intravascular coagulation, and severe prolonged shock. One patient died, one had gangrene of the toes, and all have had fine desquamation of affected skin and peeling of palms and soles during convalescence. Five patients were studied prospectively. Staphylococcus aureus related to phage-group I was isolated from mucosal (nasopharyngeal, vaginal, tracheal), or sequestered (empyema, abscess) sites, but not from blood. This organism produces an exotoxin which causes a positive Nikolsky sign in the newborn mouse and which is biochemically, pathologically, and immunologically distinct from phage-group-II stapphylococcal exfoliatin.


Possible role for impaired renal prostaglandin production in pathogenesis of hyporeninaemic hypoaldosteronism. A 57-year-old woman with hypertension and moderate renal insufficiency had chronic unexplained hyperkalaemia. Metabolic balance studies confirmed a diagnosis of hyporeninaemic hypoaldosteronism. Two observations suggested that impaired renal prostaglandin production contributed to the pathogenesis of the patient's disorder. Baseline renal-prostaglandin synthesis (as determined by urinary excretion of P.G.E and P.G.F) was was substantially depressed when compared with that in nine normal females. Infusion of low doses of P.G.A1 produced a significant increase in serum-aldosterone and urinary potassium excretion; it also led to a dramatic fall in blood-pressure and serum-potassium. It appears from these studies that a defect in renal prostaglandin synthesis has an important role in the pathogenesis of hyporeninaemic hypoaldosteronism.


Human embryonic prealbumin as a marker for tumours and fibroblasts. Embryonic prealbumin (E.P.A.) was demonstrated by agar immunodiffusion in 122 out of 505 homogenates of various tumours and in 7 out of 20 serum samples from patients with connective-tissue tumours. Analogous antigen was found in human embryonic and adult cultured fibroblasts. This newly identified antigen is probably actively secreted by fibroblasts into the circulation of patients with tumours.


Reduction of serum-1, 25-dihydroxyvitamin-D3 in children receiving glucocorticoids. Serum-1,25-dihydroxyvitamin-D3 (1,25-[OH]2D3) was subnormal in children receiving long-term glucocorticoid treatment for various glomerular diseases, including nephrotic syndrome. In children with chronic glomerulonephritis not treated with glucocorticoids who had similar serum-creatinine with glucocorticoids who had similar serum-creatinine concentrations, serum-1,25-dihydroxyvitamin-D3 concentrations resembled those in healthy controls, indicating that glomerular renal disease per se does not account for reduced serum-1,25(OH)2DE concentrations in steroid-treated patients. The reduction in concentration of this most active vitamin-D metabolite correlated with the dose of steroid administered and with reduction in forearm bone mineral content measured by the photon absorption technique. Reduced serum-1,25-(OH)2D3 concentration may be important in the pathogenesis of steroid-induced osteopenia.


Significance of HLA-D/DR matching in renal transplantation. A low mixed-lymphocyte-culture response, indicating matching for HLA-D, was associated with a relatively good chance of graft survival in 62 recipients of renal transplants from living relatives mismatched for one or two HLA A and/or B antigens. In 96 cadaveric transplants prospectively typed for HLA-DR antigens, compatibility for these antigens improved the prognosis, irrespective of matching for HLA A and B antigens. In cadaveric transplants, a positive B-cell cross-match test before transplantation tended to predict inferior graft survival.


Multiple sclerosis and canine distemper in Iceland. Iceland offers a favourable opportunity to examine the suggested relationship between canine distemper and multiple sclerosis. Distemper is not enzootic in Iceland and distemper immunisation is not practised. However, importations result in occasional epizootics, three of which have occurred since 1909. Careful enumeration of multiple sclerosis indicates that there were 129 cases during the period 1946--65. When these cases are subdivided into six regions, by place of birth, regional period-prevalence rates were highest in two regions partially involved by distemper only once in the past 70 years. Also, there was substantial prevalence in a third region, encompassing Reykjavik, where the dog population has been kept very low for over 50 years. The Icelandic experience indicates that multiple sclerosis can occur at high incidence in the virtual absence of canine distemper or in the presence of a very small dog population.


Migraine: A vasomotor instability of the meningeal circulation. The current view that the migraine aura arises from spasm of the major cerebral arteries and the ensuing headache from extracranial arterial vasodilatation is examined and refuted. It is proposed that the headache is due to stimulation of nociceptive nerve-endings in the walls of meningeal vessels (arterioles, venules, and particularly the dural venous sinuses); and that the aura arises from calibre changes in meningeal vessels that penetrate the outer cortex, resulting in localised inhibition or excitation. It is suggested that there are two types of migraine patients--vasodilators and vasoconstrictors.


Re-examination of some of the Framingham blood-pressure data. Mathematical smoothing of data for the Framingham study leads to the conclusion that there is no threshold of normality for blood-pressure. A reasonable therapeutic goal might be "the lower the better". However, examination of the unsmoothed Framingham data indicates that while systolic pressures fit this no-threshold model reasonably well, changes in diastolic pressure below about 90 mm Hg have little or no prognostic significance. The poor fit of the diastolic points to the no-threshold model may also help to explain why at Framingham raised systolic pressure seemed to have a greater impact than raised diastolic pressure.


Duration of breast-feeding after early initiation and frequent feeding. 111 primiparous women who had chosen to breast-feed their normal healthy term infants were assigned to one of four groups matched for age and social class. Two groups had the baby put to the breast within 10 min of delivery and the other two began breast-feeding 4--6 h after delivery. One of each pair of groups fed 2-hourly and the other 4-hourly. Follow-up over 18 months suggested that both early initiation and increased frequency of breast-feeding extended the nursing period, the former having the greater effect. 2-hourly feeding induced lactation at least 24 h earlier than did 4-hourly feeding.


Hepatitis B and primary hepatocellular carcinoma in a European population. The prevalence of serological markers of active of past hepatitis-B virus (H.B.V.) infection was determined in 80 Greek patients with primary hepatocellular carcinoma (P.H.C.), 160 age and sex matched controls and 40 patients with metastatic liver cancer (M.L.C.). The relative risk of the various patterns of H.B.V. serological markers for P.H.C. was calculated. Active H.B.V. infection, as indicated by positive tests for hepatitis-B surface antigen (HBsAg), or antibody to hepatitis-B core antigen (anti-HBc) without antibody to HBsAg) (anti-HBs), was associated with P.H.C. (relative risk 10.4) but not with M.L.C. (relative risk 1.2). Patients without markers and those who had recovered from hepatitis B (anti-HBs-positive) had approximately the same low risk for P.H.C. (relative risk 0.8). Active infection was more common in P.H.C. patients with co-existing cirrhosis than in those without cirrhosis (67% versus 26%). Thus the relationship between active hepatitis B and P.H.C. seen in African and Asian populations is now seen in a European Caucasian population with different racial, environmental, and dietary circumstances.


Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. The relations between the incidence of vascular occlusive episodes and packed-cell volume (P.C.V) and platelet-count in patients with primary proliferative polycythaemia were determined retrospectively in patients treated by venesection with or without chemotherapy. The incidence of occlusive episodes correlated positively with P.C.V. level. The risk of vascular occlusive episodes was increased at moderately increased P.C.V. levels and the optimum P.C.V. level was rather lower than is often assumed. There was no statistically significant association between platelet-count, either alone or in combination with raised P.C.V., and incidence of vascular occlusion, though, episodes of occlusion were 1.5 times more common with platelet-counts above 400 x 10(9)/l. The results of this study indicate that P.C.V. should be maintained at less than 0.45 and the platelet-count at less than 400 x 10(9)/l in primary proliferative polycythaemia.


Autoantibodies to parathyroid hormone receptor. Autoantibodies which block the binding of parathyroid hormone to membrane receptors for the hormone were detected in the sera (especially in the IgG fraction) of 49 out of 50 uraemic patients with secondary hyperparathyroidism (patients with high levels of C-regional parathyroid hormone). These antibodies are species-specific. Their presence in the serum in unaffected by dialysis. Inhibition of binding appears to be related to the rise in C-regional parathyroid-hormone levels and the duration of uraemia. The production of cyclic adenosine monophosphate by parathyroid-hormone-stimulated adenyl cyclase was reduced by the blocking antibodies. The findings show that secondary hyperparathyrodism in uraemia is another example of a receptor-antibody disease, but it is not known whether the antibodies act by modifying the affinity of the receptors for the hormone or by reducing the concentration of receptors available.


Hormonal and metabolic responses to an enkephalin analogue in normal man. An enkephalin analogue [D-Ala2, MePhe4, Met(o)-ol] enkephalin (DAMME), given intravenously to normal subjects raised serum prolactin and growth-hormone levels but lowered serum levels of luteinising hormone, follicle-stimulating hormone, cortisol, and corticotrophin. There was also a small fall in total glucagon and gastric inhibitory peptide (G.I.P.) and a rise in thyrotrophin. beta-Lipotrophin, motilin, vasoactive intestinal peptide, insulin, gastrin, and pancreatic glucagon were unchanged. Blood-glycerol increased, and blood lactate, alanine, and glucose fell. Prior administration of the opiate antagonist, naloxone, attenuated the hormonal responses to DAMME. This enkephalin analogue produces endocrine and metabolic changes in man which may be mediated through opiate-binding receptors both within and outside the brain. The enkephalins and related substances may provide an important link between perception, behaviour, and neuroendocrine regulation of hormone secretion and metabolism.


Myeloneuropathy after prolonged exposure to nitrous oxide. A neurological disorder developed after prolonged exposure to nitrous oxide in 15 patients, all but 1 of whom were dentists. 13 patients had abused nitrous oxide to some extent for periods ranging from 3 months to several years, but 2 patients were exposed to nitrous oxide only professionally, by working in poorly ventilated surgeries. Symptoms included early sensory complaints, Lhermitte sign, loss of balance, leg weakness, gait ataxia, impotence, and sphincter disturbances. Neurological examination showed sensorimotor polyneuropathy, often combined with signs of involvement of the posterior and lateral columns of the spinal cord. Electrodiagnostic tests pointed to an axonal polyneuropathy, but other laboratory results were normal, including examination of the spinal fluid. The neurological picture is similar to that of subacute combined degeneration of the spinal cord, and it is possible that nitrous oxide interferes with the action of vitamin B12 in the nervous system.


Radioallergosorbent and indirect fluorescent antibody tests in immunodiagnosis of schistosomiasis. Radioallergosorbent tests for specific IgE antibodies to Schistosoma haematobium and S. mansoni were positive in 82 and 72%, respectively, of sera from 136 African schistosomiasis patients. 99% of sera from controls (5 free of parasitic disease, 75 infested with hookworm, Ascaris, Trichuris, and/or Onchocerca) were negative. When titres in indirect fluorescent antibody tests were set at the same level of specificity only 38% of patients' sera were positive. A cut-off at a higher concentration increased sensitivity to 65% but lowered specificity (10% controls positive).


Treatment of lead poisoning by 2,3-dimercaptosuccinic acid. 2,3-Dimercaptosuccinic acid (D.M.S.), a new orally effective agent for the treatment of heavy-metal intoxication, was administered to five lead-poisoned smelter workers for six days at dosages ranging from 8.4--12.7 mg/kg/day on the first day to 28.1--42.2 mg/kg/day on the last day. Mean blood-lead concentration decreased significantly from an initial value of 97 +/- 6 microgram/dl to 43 +/- 4 microgram/dl on the last day. Urinary lead excretion was significantly raised. D.M.S. was very well tolerated with no signs of toxicity and no effect on urinary zinc, calcium, magnesium, or iron excretion. Urinary copper excretion was significantly increased, but the magnitude of that effect was not clinically important. D.M.S. seems to be safe and effective for the treatment of lead poisoning.


Serum-prolactin in female infertility.

Serum-prolactin in female infertility. 55 of 100 new female patients attending an infertility clinic had serum-prolactin concentrations greater than the upper limit of normal (360 mU/l). There was no significant correlation between serum-prolactin value and clinical features including age, duration of infertility, past reproduction, menstrual pattern, past use of oral contraception, or pregnancy-rate after treatment. The place of serum-prolactin estimations in the management of infertile women is unclear, particularly since the precision of currently available radioimmunoassays is questionable. The major value of serum-prolactin estimations lies in identifying those patients in whom further investigation for pituitary tumour is indicated both before treatment and during any ensuing pregnancy, and in selecting patients suitable for bromocriptine therapy.


Diagnosis of hyperprolactinaemia.

Diagnosis of hyperprolactinaemia. The significance of hyperprolactinaemia is poorly understood by many clinicians. Difficulties in interpretation have arisen because many endogenous factors can alter prolactin secretion, the scale of laboratory errors is not appreciated, and reference  ranges are inappropriately used. There is a need for improved communication between clinician and laboratory and for education on both sides.


Phenylethylamine overproduction in aggressive psychopaths. Plasma concentrations of free and conjugated phenylacetic acid, the major metabolite of phenylethylamine, were higher in ten prisoners serving long terms of imprisonment for violent crimes than in pair-matched non-violent control prisoners. Since amphetamine, a compound closely related to phenylethylamine, can reduce aggressiveness in some violent subjects, the increase in phenylethylamine production may be an attempt to compensate for the unknown derangement of function responsible for increased aggression.


Serum high-density lipoproteins in peripheral vascular disease. High-density lipoprotein (H.D.L.) cholesterol has been measured by the 'Autoanalyzer', and apolipoproteins A-I, A-II, and B by an immunochemical method, in 100 patients with peripheral vascular disease (P.V.D.) and in 93 age and sex matched controls with an approximately similar prevalence of hyperlipidaemia. The patients with P.V.D. had significantly lower levels of the H.D.L. apolipoproteins (especially of apo A-I) than the controls. Further analysis of the data showed low H.D.L. levels to be related to the presence (but not to the severity) of the arterial disease and to be independent of concurrent hyperlipidaemia and smoking habits. The changes in H.D.L. apoproteins were not so clearly reflected by H.D.L.-cholesterol measurements in the same patients, possibly because of methodological reasons. It is therefore suggested that studies relating serum-H.D.L. to arterial disease may be more informative if both the lipid and protein portions of these lipoproteins are measured.


Cancer-specific density changes in lymphocytes after stimulation with phytohaemagglutinin. A fluorescence polarisation technique ("S.C.M. test") for detecting responses to phytohaemagglutinin revealed that the responsive lymphocytes from patients with malignant disease had an abnormal distribution after centrifugation through lymphocyte separation medium. In a small blind series the technique accurately distinguished patients with histologically proven malignancies from those with nonmalignant disease and normal people.


Aldosterone in myxoedema.

Aldosterone in myxoedema. Ten patients with severe myxoedema were treated with regular increments of thyroxine. The urine aldosterone excretion rate and plasma-aldosterone level increased with each increasing dose of thyroxine. Two patients in whom the serum-aldosterone rose to abnormally high levels had cardiac failure which resolved when the thyroxine dose was reduced.


Failure of bran to protect against experimental colon cancer in rats. The ability of dietary fibre to prevent colon cancer was tested in rats injected with 1,2-dimethylhydrazine (D.M.H.), a substance which induces cancer of the colon. 60 rats were fed the same formula solid diet but allocated three different amounts of dietary fibre--20 were given 4.8% w/w crude fibre, 20 were given 20% w/w bran, and 20 received no fibre. Half of the animals in each fibre group received a course of subcutaneous D.M.H. and half were given subcutaneous saline. After a year's observation, there was no significant difference in the incidence of, or mortality from, colonic carcinoma between the D.M.H.-treated groups.


Inhibition of pancreas and gallbladder by pancreatic polypeptide. Stimulated pancreatic and biliary outputs were studied in seven healthy subjects during intravenous infusion of bovine pancreatic polypeptide (P.P.) (mean dose 65 pmol/kg/h). P.P. significantly inhibited outputs of trypsin and bilirubin at plasma concentrations similar to those observed after meals. In four cholecystectomised subjects, P.P. inhibited only trypsin output.


Effect of myo-inositol on peripheral-nerve function in diabetes. myo-Inositol, 500 mg twice a day, given to seven diabetic patients for two weeks, increased the amplitude of the evoked action potentials of the median, sural, and popliteal nerves by an average of 76%, 160%, and 40%, respectively. There was no significant change in the conduction velocities of these nerves, myo-Inositol may be valuable in the treatment of diabetic neuropathy.


How the lower oesophageal sphincter affects submucosal oesophageal varices. Oesophageal varices are found in the submucosa of the lower oesophageal sphincter (L.E.S.). Portagraphic studies after vasopressin administration showed occlusion of submucosal oesophageal varices and distension of the para-oesophageal veins. Oesophagography and endoscopy after administration of anticholinergics showed considerable dilatation of the submucosal oesophageal varices. Because vasopressin increases, and anticholinergics decrease, L.E.S. pressure it is suggested that L.E.S. pressure is an important factor in the development of submucosal oesophageal varices.


Some problems of alpha-fetoprotein screening. In two years of a routine screening programme for the detection of neural-tube defects over 6000 women had serum-alpha-fetoprotein (A.F.P.) measured. As a result, 80 women carrying live singleton fetuses were offered amniocentesis under ultrasound control. All neural-tube defects detected at birth were recorded and necropsies were done routinely on abortuses, thus permitting evaluation of the screening programme in terms of false negatives and false positives. 16 amniotic-fluid A.F.P.s were abnormal, 1 for an unaffected fetus; and 2 others were normal for fetuses which had closed lesions. At the serum-A.F.P. stage, 3 lesions were missed. The detection-rate compares favourably with those of other series. However, in a pilot study, routine ultrasonic assessment of gestation yielded a substantial proportion of cases where a serum-A.F.P. deemed normal or abnormal when gestation was assessed clinically would have been misleading. Loss of normal fetuses subsequent to amniocentesis (5 in this series) also has to be taken into account.


Maternal rubella at St. Thomas' Hospital: is there a need to change British vaccination policy? During the 28 weeks starting April 3, 1978, 269 pregnant women were assessed serologically because of exposure to or development of rubella-like illnesses, this number being four times greater than that during either of the previous 2 years. Only 33 (12%) of these patients had previously been given rubella vaccine. Rubella was confirmed serologically in 17 patients; among patients attending antenatal clinics the overall risk of acquiring infection was about 1 in 155. The mean age of patients acquiring maternal rubella was 27.9 years, and all but 1 had left school before the rubella vaccination programme started. 55 (92%) of 60 household contacts were children, of whom 24 (40%) were of preschool age and 13 (21.7%) aged less than 2 years. The interval between contact and presentation for serological studies was often long and, because of this, 79 sera had to be tested for virus-specific IgM. No drastic change in rubella vaccination policy is required but there should be more emphasis on vaccination of women of childbearing age.


Cyclosporin A in patients receiving renal allografts from cadaver donors. Seven patients on dialysis with renal failure received transplants from mismatched cadaver donors and were treated with cyclosporin A (CyA), initially as the sole immunosuppressive agent. CyA was effective in inhibiting rejection but there was clear evidence of both nephrotoxicity and hepatotoxicity. A cyclophosphamide analogue was added to the CyA treatment in six of the patients. Five patients are out of hospital with functioning allografts, and two of these have received no steroids. One patient required an allograft nephrectomy because of pyelonephritis in the graft. Another died of systemic aspergillus and candida infection. Further careful study of this potentially valuable drug will by required before it can be recommended in clinical practice.


Cyclosporin A for the treatment of graft-versus-host disease in man. Cyclosporin A was given to five patients with acute leukaemia in whom graft-versus-host disease (G.V.H.D.) had developed after bone-marrow transplantation from sibling donors. In all instances the acute erythematous skin reaction of G.V.H.D. resolved within two days, but four of the five patients died. Cyclosporin A in high doses produced anorexia, nausea, and a reversible rise in blood-urea. The four patients who died all had liver damage, but the histological changes varied. Cyclosporin A modifies the acute skin reaction of G.V.H.D. In the management of liver and gut G.V.H.D., and in prophylaxis of G.V.H.D., its role needs to be determined.


Serum angiotensin-converting enzyme (SACE) in sarcoidosis and other granulomatous disorders. Serum angiotensin-converting enzyme (SACE) activity was significantly higher in 90 patients with sarcoidosis (55 +/- [S.D.] 23 nmol min-1 ml-1) than in 80 healthy controls (34 +/- 9 nmol min-1 ml-1). Steroid therapy modified SACE activity; 60 sarcoidosis patients who were not being treated with steroids had significantly higher enzyme activities (58 +/- 24 nmol min-1 ml-1) than 30 steroid-treated sarcoidosis patients (40 +/- 19 nmol min-1 ml-1). In 50% of the non-steroid treated sarcoidosis patients SACE activity was more than 2 S.D. above the mean value for the controls. SACE activity was measured in 22 tuberculous patients (38 +/- 14 nmol min-1 ml-1), 20 leprosy patients (34 +/- 9 nmol min-1 ml-1), 31 with primary biliary cirrhosis (44 +/- 20 nmol min-1 ml-1), 26 with inflammatory bowel disease (31 +/- 9 nmol min-1 ml-1), 8 with hepatic granulomatous disease, 5 with Hodgkin's disease, and 2 with schistosomiasis. The combined false-positive rate for these non-sarcoidosis patients was 10%. Serial SACE assays provide useful information on the course of sarcoidosis and response to steroid treatment.


Alpha2-plasmin-inhibitor deficiency (Miyasato disease). A 25-year-old man, born in Okinawa, Japan, had a haemorrhagic diathesis characterised by prolonged bleeding and ecchymoses after minor trauma and spontaneous joint haemorrhage. The frequency and severity of these episodes were reduced by an antiplasminic drug. Routine coagulation studies revealed no abnormalities except for significantly sshortened euglobulin-lysis time and whole-blood clot lysis time. Activities of all known clotting and fibrinolytic factors were within normal ranges but no circulating alpha2-plasmin inhibitor was found in the plasma. alpha2-plasmin inhibitor is a potent and fast-acting protease inhibitor. Studies of family members indicated that this abnormality was inherited as an autosomal and recessive gene.


Severe cerebral disturbance in legionnaires' disease. In two cases of legionnaires' disease pneumonia was associated with severe cerebral disturbance. In one case legionnaires' disease was diagnosed retrospectively by serological methods, and in the other the development of similar cerebral symptoms in the course of pneumonia prompted a clinical diagnosis of legionnaires' disease and the institution of effective treatment.


Carcinoembryonic antigen concentrations in undiagnosed patients. Serum carcinoembryonic antigen (C.E.A.) levels were measured in 381 undiagnosed patients who presented with clinical problems commonly associated with gastrointestinal malignancy. The results were compared with the final diagnosis after follow-up for up to 5 years to see whether C.E.A.-testing added any useful information. Of 307 patients presenting with upper gastrointestinal symptoms, lower gastrointestinal symptoms, or irom deficiency anaemia, C.E.A. levels greater than 20 ng/ml indicated malignancy in 5 but in 3 of these malignancy was also diagnosed after routine investigation. Of 74 patients presenting with obstructive jaundice, hepatomegaly, or abnormal liver function, malignancy was diagnosed in 38. In 9 of these patients the diagnosis of malignancy could otherwise have been reached only by laparotomy. The serum-C.E.A. thus reached only by laparotomy. The serum-C.E.A. thus seems to be of value in the assessment of liver disease but not in patients with gastric or colonic symptoms or iron-deficiency anaemia.


Is a slow pulse-rate a reliable sign of digitalis toxicity? 64 of 910 hospital patients taking digoxin had a ventricular rate of less than 60 beats/min. In only 6 out of 57 of those investigated further could a diagnosis of digoxin toxicity be made on clinical, electrocardiographic, and biochemical grounds. No reason for the slow heart-rate could be found in 42 patients. Excessive vagal effects of digoxin in resting subjects may cause the bradycardia found in these in patients in the absence of digitalis toxicity.


Do plasma glycoproteins induce lymphocyte hyporesponsiveness and insulin resistance? Depression of lymphocyte transformation and an increase in insulin resistance are common to pregnancy, oral contraceptive use, widespread malignancy, infection, and tissue destruction. We suggest that these abnormalities are caused by a rise in the plasma-glycoprotein level which is also common to these clinical states. There is evidence that glycoproteins can inhibit cell division, lymphocyte transformation, and the action of hormones on target cells. Because of the increase in plasma glycoprotein the cells in many organs and their hormone receptors may have a thicker coating of glycoproteins which blunts their response to variuos stimuli.


Compactin inhibits cholesterol synthesis in lymphocytes and intestinal mucosa from patients with familial hypercholesterolaemia. Compactin (2000 nmol/l), a potent competitive inhibitor of the rate-determinign enzyme for cholesterol synthesis (3-hydroxy-3-methyl-glutaryl coenzyme-A reductase), inhibited by about 90% cholesterol synthesis from 14C-acetate in isolated lymphocytes from healthy control and from patients heterozygous for familial hypercholesterolaemia (F.H.). In isolated intestinal mucosa, a physiologically important tissue for cholesterol synthesis, compactin (2000 nmol/l) suppressed cholesterol synthesis by approximately 50% in controls and F.H. patients. Compactin or its derivatives may prove to be useful in the treatment of hypercholesterolaemia.


Results from a new renal transplantation unit. 158 kidneys, 9 from living related donors and 149 from cadavers, have been transplanted in the first 42 months of the establishment of a transplant unit at Oxford. Patients' ages ranged from 11 to 56 (mean 35) years. Azathioprine and prednisolone alone were used for immunosuppression, and a minimum-transfusion policy was in operation throughout. After cadaveric transplantation actuarial patient-survival is 70% and 68%, respectively, at the same intervals. 85% of patients who had a functioning graft are fully rehabilitated. Matching for HLA-DR, pregraft blood-transfusions, and the finding that a transplant could be performed in the presence of a positive B-cell crossmatch have proved to be the most significant of the many factors examined both prospectively and retrospectively. The function of the unit is based on dialysis and transplantation for all patients in end-stage renal failure, with transplantation being considered the first line of treatment for patients under the age of 56. The results of transplantation reported here, which have been achieved with conventional immunosuppressive therapy and minimum-transfusion policy, might be considered a standard against which modifications of the practice of renal transplantation can be compared.


Controlled clinical trials and medical ethics. During the past 5 years, a great deal of public attention has been paid in the Federal Republic of Germany to legal and ethical implications of controlled clinical trials. If a physician is bound by a contract for treatment, the ethics of individual benefit have to be applied and this might inhibit a controlled trial. To avoid ethical and legal difficulties, a contract for experimentation may have to be introduced.


Is there excessive use of gastric lavage in the treatment of self-poisoning? An attempt to identify those factors which influenced the decision to perform gastric lavage in 236 cases of deliberate self-poisoning seen over 6 months showed that 87% of patients seen within 4 hours of ingestion of the poison had a lavage, irrespective of the number of tablets and nature of drug taken. Overall, 77% had a gastric lavage. Most of the late lavages were carried out for salicylate ingestion. The changing pattern of drugs used for attempted selfpoisoning suggests that at least 50% of patients are being unnecessarily subjected to gastric lavage.


Classification of von Willebrand's disease. The classification of von Willebrand's disease should be based primarily on the mode of inheritance: thus, the main division would between autosomal dominant and autosomal recessive types. Phenotypic subdivisions within these major types may then be possible. A subgroup of the dominant type seems to be well defined by increased electrophoretic mobility of the VIII-related antigen.


One man's poison.

One man's poison. In an unrandomised uncontrolled study on boats and trains, capsules of flurazepam (30 mg) and temazepam (20 mg), when chewed, but not when swallowed whole (even with the ends pricked), gave a better night's sleep than 'Mandrax' (methaqualone 250 mg/diphenhydramine 50 mg) and a better night's sleep than nitrazepam 7.5 mg.


Ochratoxin a in retail flour.

Ochratoxin a in retail flour. Flour delivered to a school in the Bournemouth area was found by thinlayered chromatography to contain up to 6.25 mg/dg of ochratoxin. A. Penicillium cyclopium, a fungus known to produce this toxin, was found in discoloured portions of the caked flour. Ochratoxin was also found in a second sack delivered to the school, but not in samples of sound flour or in six samples of flour of varying quality from other sources. The health risk did not appear to be serious.


[Experimental investigations on the proportional inhibitory capacity of different proteinase inhibitors in cases of chronic otitis media and cholesteatoma (author's transl)]. Among the three investigated proteinase inhibitors alpha-1-antitrypsin ("acute phase protein") possesses the highest antiproteolytic capacity. Alpha-2-macroglobulin reaches as an average one fifth of the preoperative level of alpha-1-antitrypsin and postoperatively one quater of this inhibitor level. The average concentrations of the low molecular acid stable proteinase inhibitor of the mucous membrane in the preoperative phase are about equivalent to the concentrations of alpha-2-macroglobulin. In the postoperative phase the concentrations of the low molecular acid stable inhibitor are a slightly lower than those of alpha-2-macroglobulin. The samples of the middle ear secretions from cases with chronic otitis media or with cholesteatoma do not differ essentially in their concentrations of the different proteinase inhibitors.


Detection of antibodies to varicella zoster virus by radioimmunoassay and enzyme immunoassay techniques. An enzyme assay for the detection of antibodies to varicella-zoster membrane antigen (IPAMA) and a solid phase radioimmunoassay (RIA) which utilizes infected cell lysates as antigen are described. The results have been compared with those obtained by the indirect fluorescent antibody to membrane antigen (IFAMA) technique. It was found that IPAMA was equal in sensitivity to IFAMA. No cross-reactivity was found with other herpes group viruses. The IPAMA appears to give objective results, is easily and rapidly performed, and is recommended as a routine test for serological diagnosis of varicella-zoster infection. The RIA method is about 100 times more sensitive than IPAMA and IFAMA. The RIA is specific and has the potential of determining lower levels of antibody than other serological methods currently in use.


[Chemotherapy of brain-tumors in children (author's transl)]. The poor permeability of the blood/brain barrier for most cytostatic agents makes it difficult to achieve an adaequate drug concentration in brain-tumors. This is the main problem in developing a chemotherapy of brain tumours. On the other hand the therapeutic effect is difficult to evaluate not only because of clinically and hitherto also technically poor accessability of the brain but also because of differences in tumour classification systems, and consequently limited comparability. There is however definite knowledge on the effectiveness of several single drugs as well as strong evidence on the effectiveness of some polychemotherapeutic programs. The measure of success presently is rather prolongation of survival time for months than a change in cure rate. A general recommendation for the cytostatic treatment of brain tumors may not be given in that situation, but within a clinical study the use of cytostatic agents seems promising anyway.


Reverse transcriptase activity in extracts of human prostatic tissues. The extracts of human prostatic tissue specimens contain oncornavirus-like reverse transcriptase activity. This activity was isolated by banding the tissue extract in an equilibrium sucrose density gradient followed by phosphocellulose chromatography of the lysate of the material banding at a density of 1.14--1.20 g/cc. It was characterised by its utilisation of poly (Cm) as a template and its inhibition by selective inhibitors of viral reverse transcriptase. Human prostatic tissues of three histo-pathologic types--normal, hyperplastic and adenocarcinoma--were examined. One out of four normal, five out of six hyperplastic, and two out of two adenocarcinoma specimens displayed virus-like reverse transcriptase activity.


Importance of B2 microglobulin in primary bronchial cancer. We have performed B2 microglobulin determination in 18 non-cancer and in 38 cancer cases. We found a higher value in the control group in 11% (2 cases) and a pathologic value in 43.5% (17 cases) in the group of patients with primary bronchial cancer.


Comparison of the adjuvant effect of three BCG preparations in mice. Three preparations of BCG, currently in use for clinical trials in cancer, were tested for relative potency as an immunological adjuvant. Using a lymphocyte trapping assay, Pasteur Institute BCG was shown to be a more effective adjuvant than the Tice strain or the Glaxo preparation of BCG.


Bleomycin (review).

Bleomycin (review). Since the original observation and description of the various forms of Bleomycin (BLM), numerous articles have appeared dealing with the activity on mammalian cells and its possible clinical use. The present review on this very important compound, although not very comprehensive, deals with the important characteristics; such as the action of DNA and cells, and its chromosome breaking effects. The manner in which the minute detail of the action of BLM on cells has helped to implement in vivo chemotherapeutic regimes, is also discussed.


Early development of children with sex chromosome aberrations. A prospective study was made of 42 children who were found at birth to have sex chromosome aberrations. The mean developmental quotient of the XXY and XXX groups was in the dull-normal range, whereas developmental quotients of 3 XYY children were low normal. The commonest deficits were in language and gross motor skills, with highest incidence in the XXX group. Many of the children had behavior problems, but no specific pattern was associated with an individual chromosome aberration. The XXX group experienced a linear growth spurt after 4 years of age. With one exception there were only mild dysmorphic features, none of them specifically associated with any subgroup. Of 17 children followed up to school age, almost two thirds evidenced learning and/or behavior problems. There was a high incidence of birth problems particularly in XXX children (seven of ten), and of social problems, psychiatric illness and learning difficulties in their families. In 14 cases, the parent-child relationship was disturbed, resulting in behavior problems. These findings make it improbable that the children's generally poor developmental and behavioral performance were solely attributable to their chromosomal constitution.


[Can the cytological examination of the amniotic fluid be considered as a test of the fetal maturity? (author's transl)]. The progress in the biological evaluation of the fetal maturity takes into account the value of the cytological examination of the amniotic fluid. The technique is quite easy but delicate and implies, as well as any histochemical method, a quality control; a rather high percentage of errors is linked to the neglection of these simples advices. In most cases, the level of the oringe cells is related to the maturity of the fetus. The fetal epidermic origin of these cells, discussed for a long time, has been recently demonstrated by electron microscopy; it is confirmed that the increase of the level of the oringe cells corresponds to the thickening of the fetus' teguments, according to the age of the pregnancy; but it is not possible to establish a rigourous parallelism between the real age of the fetus and his aptitude to survive in case of premature delivery, which is mostly depending upon the maturity of his renal and pulmonary functions. The cytologic examination of the amniotic fluid should be interpreted in comparison with the others biological tests of evaluation of the fetal maturity.


Analysis of the 3'-terminal nucleotide sequence of vesicular stomatitis virus N protein mRNA. The sequence of 205 nucleotides adjacent to the poly(A) tract at the 3'-terminus of the mRNA encoding the N polypeptide of vesicular stomatitis virus has been determined by copying with reverse transcriptase and using 2', 3'-dideoxynucleoside triphosphates as specific chain terminators. The method appears highly suitable for sequence determination in any purified mRNA. An examination of the sequence did not locate without ambiguity the limit of polypeptide coding RNA. The hexanucleotide AAUAAA, previously found in all poly(A)-containing eukaryote mRNAs, is not present, although the sequence immediately adjacent to the 3'-terminal poly(A) has a high content of A+U.


Recognition sequence of restriction endonuclease KpnI from Klebsiella pneumoniae. We have determined the recognition sequence of the restriction endonuclease KpnI, previously isolated from Klebsiella pneumoniae. The enzyme cleaves the twofold rotationally symmetric sequence (see book for formula) at the positions indicated by the arrows, producing 3' protruding cohesive ends, four nucleotides in length. The specific cleavage site was unambiguously deduced using both 3' and 5' end analyses of KpnI generated restriction fragments of simian-virus 40 (SV40) DNA (1 site), adenovirus-2 (Ad-2) DNA (8 sites), and a plasmid (pCRI) DNA (2 sites).


Gaps and duplicated sequences in the leaders of SV40 16S RNA. In order to investigate the 5' terminal structural heterogeneity of the 16S size class of SV40 late RNA, we have bound an SV40 DNA fragment labeled at its 5' termini with P32 to the .939-.945 map unit region of late lytic cytoplasmic polyadenylated RNA, used reverse transcriptase to prepare cDNA copies of the 5' termini of this RNA, separated the cDNA products on an 8% polyacrylamide-7 M urea gel and subjected these products to nucleic acid sequence analysis. A number of discrete cDNAs were obtained. Analysis of these cDNAs has suggested the presence of three categories of 16S species all containing the same body extending from residues 1381-2592 (.939-.170 m.u.) but differring in the structure of their leader segments. Members of the first category contain leaders which are colinear with SV40 DNA, have a common 3' terminus at residue 444 and extend varying distances in a 5' direction. The most abundant 16S species contains a leader of 203 nucleotides and is a member of this group. RNAs of the second category contain leaders with an internal gap between residues 211-352. The single RNA comprising the third category contains a leader with a tandem repetition of nucleotides 351-443 at the 3' terminus of its leader.


Characteristics of excision repair of pyrimidine dimers in eukaryotic cells as assayed with anti-dimer sera. An antiserum that recognizes the three types of pyrimidine dimers induced by UV-light in DNA was used to monitor their removal from eukaryotic cell nuclei. Cells able to excise dimers display a similar removal pattern: a fast process completed within a few hours leaving many dimers in the DNA.


Reverse transcription of turnip yellow mosaic virus RNA primed with calf-thymus DNA hydrolysate: characterization of the purified cDNA product. Complementary DNA was transcribed from turnip yellow mosaic virus RNA, using the method of Taylor et al. (1). The purified cDNA thus obtained sedimented between 2 and 4 S and was a mostly uniform transcript of template RNA. It hybridized with a sharp transition to homologous TYMV-RNA (Crt 1/2 = 2.7 x 10(-2)), but showed a low level of hybridization (less than 5%) to the RNAs of two other tymoviruses, namely Andean potato latent virus and eggplant mosaic virus.


Cardiac electrophysiologic action of carteolol hydrochloride (OPC-1085), a new beta-adrenergic blocking agent. Cardiac electrophysiologic action of a new beta-adrenergic blocking agent carteolol hydrochloride, or OPC-1085, was studied in either isolated, perfused rabbit hearts or in atrial, ventricular or Purkinje fibers of dogs and rabbits superfused in the tissue bath. Transmembrane potentials were recorded with intracellular microelectrodes and atrioventricular conduction was studied by recording a His bundle electrogram. OPC-1085 at a concentration of 0.1 mg/L shortened the sinus node recovery time, while propranolol at a comparable concentration prolonged it. Isoproterenol-enhanced canine Purkinje automaticity was more markedly depressed by OPC-1085 than by propranolol. In rabbit atrial and ventricular muscle, OPC-1085 up to the concentration of 2 mg/L did not alter the action potential characteristics but tended to shorten the conduction time. At 20 mg/L, OPC-1085 significantly decreased the maximal rate of depolarization and maximal following frequency, and prolonged the action potential duration and conduction time in non-reserpinized as well as reserpinized preparations. On atrioventricular conduction, 0.1 mg/l to 5mg/L of this drug prolonged the St-A and H-V intervals but tended to shorten the A-H interval. All these intervals were prolonged at 20 mg/L. The action potential duration of canine Purkinje-ventricular block developed at higher frequencies of stimulation. In view of the clinical dosage levels, it is sugg ested that the antiarrhythmic effects of OPC-1085 depend predominantly on its beta blocking action. At higher concentrations, OPC-1085 may exert some beta stimulating action, whereas still higher and possibly toxic concentrations could depress conduction through a direct membrane effect.


Reciprocating tachycardia due to a right-sided unidirectional retrograde anomalous pathway (URAP). An 8 year-old boy had extensive electrophysiological evaluation of his recurrent supraventricular tachycardias. His ECG never showed delta waves but intracardiac stimulation and recording disclosed the following (1) eccentric retrograde atrial activation; (2) increased cycle length and retrograde conduction time following the development of right bundle-branch block; (3) constant retrograde conduction time for increasingly premature ventricular stimuli; (4) atrial captures by ventricular stimuli when the atrioventricular-His pathways were refractory; and (5) no delta waves upon stimulation of the atrial input site of the anomalous pathway. A diagnosis of reciprocating tachycardia involving retrograde conduction through an accessory pathway was made. Reciprocating tachycardias involving a unidirectional retrograde anomalous pathway can be easily misdiagnosed as atrioventricular node reentrant tachycardias if no evidence of preexcitation can be found, particularly if the anomalous pathway is on the right side. In order to exclude the participation of a concealed unidirectional anomalous pathway in a patient's reentry tachycardia, a complete map must be made of right and left atrial endocardial activity.


Acute ischemic sinus node dysfunctions in dogs. The effects of the occlusion of the two main atrial arteries irrigating the sinus node on sinus rhythm and postpacing sinus recovery were studied in 12 anesthetized dogs. Records of spontaneous rhythm and of  postpacing sinus recovery were taken at control and hourly for 6 hours after the occlusion. The spontaneous cycle length (AA interval) was 335 +/- 11 ms at control and 416 +/- 17 ms (mean +/- SE) (p less than 0.005) one hour after the occlusion. It remained nearly unchanged during the following 5 hours of observation. The occlusion also shortened atrioventricular conduction time (AV interval) and reduced P-wave amplitude in ECG lead II in 9  of these dogs. While the control postpacing sinus recovery time was 397 +/- 13 ms, the 1-hour value was 715 +/- 165 ms. This prolongation persisted during the first four postocclusion hours but was less marked during the last two hours of observation. Moreover, the postpacing mode of return of the AA intervals to their prepacing value (sinus recovery pattern) became characteristically slow and progressive after occlusion, complete postpacing recovery often occurring only after 100 or more beats. Sequences of escape atrial and/or AV junctional rhythms were frequently seen during this recovery. Atrial extrasystoles and short sequences of atrial tachycardias were observed in most dogs after occlusion. Conversely, none of these changes occurred during a 6-hour experimental time in 5 control dogs in which the same protocol, occlusion excepted, was repeated. These observations show that the sinus node function in the dog is consistently affected by impairing its blood supply. Ischemic dysfunctions include sinus slowing, pacemaker shift, prolonged sinus recovery time, delayed postpacing recovery and supraventricular tachyarrhythmias.


Comprehensive cardiac pacemaker information system: basis for a regional follow-up network. The capabilities of a mini-computer-oriented permanent pacemaker information system are described. Extensive patient and pacer functional data are maintained in readily accessible files which may be displayed on a CRT terminal or printed out. Selective sorting of stored information may be accomplished according to any desired set of inclusive or exclusive criteria. Intelligent, comprehensive patient follow-up has been greatly facilitated through application of the system. In view of the rapidly expanding pacemaker population, it is suggested that cooperative regional networks operating with comparable information storage and retrieval structures will provide the only means for adequate patient surveillance and compilation of necessary pacemaker data.


Unipolar ventricular electrogram in the diagnosis of right ventricular ischemic injury. Unipolar ventricular electrograms were recorded in the right ventricular apical area in five patients with clinical, hemodynamic features of the right ventricular infarction. The intracavitary potential exhibited a downward displacement of the ST segment (1.5 mV). This significant negative current of injury in the ventricular electrogram is consistent with ischemic injury of the free right ventricular wall in the area subtended by the intracavitary exploring electrode. We suggest that ventricular electrographic recordings be performed in patients who present with acute inferior wall infarction requiring temporary electrode catheter pacing for serious AV conduction disturbances. The presence of a significant downward ST segment displacement (1.5 mV) provides further support and an electrical criterion for right ventricular ischemic injury.


Pacemaker surveillance "à la francaise": an attempt to detect faulty series of permanent pacemakers at an early stage. Until the present, implantable pacemakers have not been subject to government regulation in France, as it had been feared that unreasonable controls would interfere with the development of this new form of therapy. Physicians were left to choose what seemed the most reliable device, and patients benefitted immediately from every manufacturing and technological advance. Despite advantages, the absence of restriction and regulation had a serious drawback--there was no governmental agency to ensure that manufacturers would inform physicians of an unreliable pacemaker, and once a manufacturer recognized a problem, it could inform the physician at the most commercially opportune time rather than the earliest, safest time for the patient. For this reason, several physicians decided to share their experiences with pacemaker function. The number gradually increased until they were able to set up a system of pacemaker suveillance and reporting which has had the capability of detecting defective pacemaker models at an early date. The center of this pacemaker group is at Hopital Fernand-Widal in Paris and is sponsored by the A.R.E.C. (Association de Recherche et d'Entraide Cardiologiques) and by the pacemaker group of the French Society of Cardiology.


Periodic pacemaker spike attenuation with preservation of capture: an unusual electrocardiographic manifestation of partial pacing electrode fracture. This report describes the electrocardiograms of a patient with an intermittent electrode fracture presenting with periodic attenuation of the pacemaker spike without loss of ventricular capture. There was infrequent prolongation of the spike-to-spike interval probably because the pulse generator interpreted random false signals as interference and reverted to its fixed-rate mode. These observations add to the spectrum of electrocardiographic abnormalities of electrode malfunction.


Unusual mechanism in the initiation of the paroxysmal supraventricular tachycardia in a patient with WPW syndrome. A heretofore unreported unusual mechanism in the initiation of the paroxysmal supraventricular tachycardia (PSVT) in a patient with WPW (Wolff-Parkinson-White) syndrome was observed using His bundle recordings. The patient initially had some degree of AV conduction disturbance at the level of the AV node. A premature atrial impulse initially activated the ventricle exclusively through the accessory pathway and the same impulse re-excited the ventricle via the AV nodal-His axis after finishing the pure pre-excitation with marked prolongation of the AH and the HV intervals. After finishing this double ventricular response it traversed to the atrium to produce the PSVT.


Polyarteritis presenting with thrombocytosis and palliated by plasma exchange. A 66-year-old patient with polyarteritis nodosa presented with thrombocytosis and was found to have circulating immune complexes. Treatment by plasma exchange produced symptomatic improvement and lowered both the platelet count and the level of immune complexes. While plasma exchange is a useful technique in investigating the pathogenesis of the disease, predisolone is a more convenient way of treating it.


Sodium pyrophosphate inhibition of RNA.DNA hybrid degradation by reverse transcriptase. Sodium pyrophosphate inhibits synthesis of anticomplementary DNA during a reverse transcriptase (RNA-directed DNA nucleotidyltransferase, EC 2.7.7.7) catalyzed reaction. In the presence of pyrophosphate, the complementary DNA remains stably complexed to the RNA template. In the absence of pyrophosphate, the DNA. RNA hybrid template is degraded and anticomplementary DNA is synthesized. High concentrations of additives containing phosphodiester bonds appear to inhibit the ribonuclease H activity (hybrid nuclease, EC 3.1.4.34) of the reverse transcriptase, therby preventing formation of RNA primers necessary for the synthesis of anticomplementary DNA.


Immunoreactivity and receptor binding of mixed recombinants of human growth hormone and chorionic somatomammotropin. The behavior in six radioligand assays of the recombinant obtained by the noncovalent complementation of the reduced and carbamoylmethylated 134-residue amino-terminal fragment of human growth hormore with the reduced and carbamoylmethylated 51-residue carboxyl-terminal fragment of human chorionic somatomammotropin was compared to that of the analogous recombinant of the 133-residue amino-terminal fragment of human chorionic somatomammotropin and the 51-residue carboxyl-terminal fragment of human growth hormone. The determinants for the hepatic growth hormone receptor binding and for the lactogenic receptor binding of human growth hormone are on the amino-terminal fragments. The antigenic determinants for both a monospecific antiserum to human growth hormone and a monospecific antiserum to human chorionic somatomammotropin also are on the amino-terminal fragments of their respective antigens. The mixed recombinant of the amino-terminal fragment of human growth hormone with the carboxyl-terminal fragment of human chorionic somatomammotropin retains full radioimmuno- and radioreceptor activity after lyophilization.


Temperature sensitivity of cyclic AMP production and catecholamine-induced refractoriness in a rat astrocytoma cell line. Intracellular cyclic AMP was increased more than 100-fold when rat C6-2B astrocytoma cells were treated with isoproterenol in the cold (4 degrees C). When the cells were treated with the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and isoproterenol, cyclic AMP levels rose more than 150-fold. The levels achieved compared favorably with the 250-fold increase in cyclin AMP produced by (-)isoproterenol at 37 degrees C.(-)Isoproterenol at 5 nM stimulated half-maximal cyclic AMP production at 4 degrees C and at 37 degrees C and was blocked by (-)propranolol at both temperatures. The concentrations of cyclic AMP attained by these cells after (-)isoproterenol stimulation in the cold may be accounted for, in part, by alterations in the efflux of the nucleotide from the cells since extracellular cyclic AMP, an indicator of cyclic AMP efflux, was found to be dramatically reduced in the cold. The cells, when exposed to (-)isoproterenol for up to 6 hr at low temperature, maintained normal responsiveness to this agent when rechallenged at 4 degrees or 37 degrees C. Thus, they did not display agonist-induced refractoriness during that period of exposure at 4 degrees C, although refractoriness is always seen within 90 min at 37 degrees C. Refractoriness, once established by (-)isoproterenol treatment at 37 degrees C, was not reversed by exposure of the cells to cold. These data suggest that the development of catecholamine refractoriness requires a temperature-sensitive step that lies distal to the hormone-receptor interaction and cyclic AMP generaton.


Serum stimulates the Na+,K+ pump in quiescent fibroblasts by increasing Na+ entry. Two ionophores (monensin and gramicidin) that carry Na+ into 3T3 cells markedly enhance the rate of 86Rb+ uptake. Ouabain prevents both ionophores from increasing 86Rb+ uptake, indicating that the ionophores activate the Na+,K+ pump. Measurements of 86Rb+ uptake and cell Na+ and K+ over a range of monensin concentrations show that the activity of the Na+,K+ pump in 3T3 cells is limited by the supply of internal Na+ and is extremely sensitive to small changes in internal Na+. Serum rapidly enhances the rate of 22Na+ uptake and net Na+ entry when Na+ exit is inhibited by ouabain. At 0.3 microgram/ml, monensin increases the rate of net Na+ entry and activates the Na+,K+ pump by the same degree as serum. The stimulation of 86Rb+ uptake by serum or the ionophores has an absolute requirement for external Na+. Thus, serum appears to stimulate the Na+,K+ pump in quiescent 3T3 cells by increasing its supply of Na+.


[Effect of heparin, heparin derivatives and heparinoids on blood sugar levels of diabetes mellitus patients]. The effect of heparin, its derivatives--sodium iodoheparinate (dioparin), diethylaminoethyltheophylline heparinate (milheparin), and also heparinoids--eleparon, "thrombo" Goltzinger and Sp-51 degrees on the blood sugar level in patients with diabetes mellitus and in healthy persons was studied. The preparations were administered by drop intravenous infusion for 4 hours in a dose corresponding to 10 000 U of heparin activity. Glycemia, lipoproteid lipase, blood lipid fractions, and blood endogenous heparin levels were studied before and after the drug administration. In diabetic patients these preparations decreased the blood sugar level and effected the blood lipid fractions level. Potential mechanisms of the influence on the blood sugar level are discussed; four action mechanisms are assumed--the effect on insulin secretion and on the sensitivity to it, the effect on the liver, on disturbances of fat metabolism, and on increase of glucose use in the peripheral tissues.


Enhancement of banding patterns in human metaphase chromosomes by energy transfer. Intermolecular energy transfer between appropriately chosen pairs of dyes can be used to induce or enhance banding patterns in human metaphase chromosomes. Energy transfer, calibrated by fluorometric studies on soluble dye.DNA complexes, can also be detected by photometric measurements on cytological preparations of metaphase chromosomes stained with pairs of fluorochromes. If a fluorescent dye with one type of binding or quantum yield specificity (e.g., quinacrine, 33258 Hoechst, or chromomycin A(3)) is employed together with a counterstain (e.g., actinomycin D, 7-aminoactinomycin D, or methyl green) exhibiting a complementary base pair binding specificity and satisfying spectral overlap criteria for energy transfer, contrast in fluorescence from the first dye is enhanced in specific subsets of standard chromosome bands. Extensive energy transfer presumably suppress donor fluorescence except in chromosomal region containing clusters of at least 20 base pairs predominantly of one type, within which the donor but not the acceptor can bind and fluoresce. Quinacrine-bright polymorphic regions are especially resistant to fluorescence quenching by counterstains with G.C binding specificity, strengthening the evidence that these latter regions are highly enriched for A.T base pair clusters. The ability to highlight selectively many such polymorphic regions may prove of further, practical, utility in a number of cytogenetic problems.


Lymphoblastoid cell lines from patients with chronic lymphocytic leukemia: identification of tumor origin by idiotypic analysis. Multiple lymphoblastoid cell lines have been derived from two patients with chronic lymphocytic leukemia with an associated monoclonal immunoglobulin (Ig) band. Idiotypic antisera raised against the monoclonal serum Ig bands were shown to be specific for the membrane Ig of the patients' leukemic cells. The idiotypic determinants in these patients thereby constitute tumor-specific antigens. Surface and intracellular immunofluorescence studies utilizing these idiotypic antisera were used to identify the cell lines of leukemic origin. These studies showed that certain cell lines from each patient were derived from the leukemic cells while other cell lines were derived from residual normal B lymphocytes. The leukemic cell lines were variable and contained different percentages of lymphoid cells with the idiotype-specific membrane Ig and, in addition, different percentages of plasma cells with intracellular Ig of the same specificity. Specific Ig synthesis was also demonstrated by hemagglutination-inhibition analysis of cell line supernatants. Aside from Ig specificity, no differences have been found between the leukemic cell lines and those derived from normal cells. One of the leukemic cell lines was cloned in soft agarose. All the clones were shown to be of leukemic origin.


The role of cytochrome P-450 in the toxicity of xenobiotics. The cytochrome P-450 containing mixed-function oxidase system bound to the ergastoplasmic membrane plays an essential role both in the detoxification as well as in the activation of numerous xenobiotics. In many cases, this enzyme system initiates the formation of reactive electrophilic intermediates (epoxides, free radicals, carbenes) which may induce cytotoxic, mutagenic and carcinogenic effects by reacting with various cell constituents. In most cases, the active metabolites are covalently bound to the proteins and nucleic acids, but the binding to lipids or the initiation of the lipid peroxidation is also important. In the activation of xenobiotics by N-hydroxylation or N-dealkylation an aminoxidase is of special importance which is independent of cytochrome P-450. The intermediates arising from this enzyme reaction frequently become biologically active only after being stabilized by an ester bond.


The emergence of the Bowery as a psychiatric dumping ground. The drastic reduction of State Hospital population in New York over the past decade has led to a demographic relocation of the mentally ill, rather than any real decline in the rate or severity of mental disorders. Unable to function on their own in society and without adequate supportive facilities available, many discharged patients live in the streets and eventually end up on the Bowery, where they are cared for at The Men's Shelter. Studies have shown that over 50% of the current Bowery population has a history of mental illness and that alcoholism is often a secondary, rather than primary diagnosis. The most frequently encountered diagnostic syndromes are mentioned and commented upon. Possible alternative treatment interventions are suggested.