A comparison of salbutamol and ethanol in the treatment of preterm labour. Intravenous salbutamol and ethanol were compared as treatments for preterm labour, 42 patients being assigned randomly to salbutamol and 46 to ethanol. There was no statistically significant difference in outcome between patients in the two groups, the mean delay in delivery achieved being 15 days with salbutamol and 20 days with ethanol. Neither treatment was very effective since only 10 patients given salbutamol and 14 given ethanol had their delivery postponed to 37 weeks or later. Salbutamol was more rapidly acting than ethanol but produced more cardiovascular side effects.


Comparison of placebo and bromocriptine in the treatment of patients with normoprolactinaemic amenorrhoea. Fourteen women with normoprolactinaemic amenorrhoea were treated with bromocriptine (2.5 mg twice daily) for a period ranging from 4 to 17 weeks, while a matched group fo 19 amenorrhoeic women were treated with a placebo (one tablet twice daily) for 4 to 12 weeks. About half of the patients in both groups had at least one episode of vaginal bleeding during treatment. There was no clear difference in the menstrual and ovulatory pattern between placebo and bromocriptine groups.


Group B beta haemolytic streptococci in the female genital tract: a study of four clinic populations. The carrier rate of group B beta-haemolytic streptococci (GBS) was assessed in pregnant and non-pregnant women attending four clinics. Multiple sites were sampled and standard methods were used to isolate GBS. Colonization rates were highest in patients attending a venereal disease clinic but were not associated with other sexually transmitted diseases. Higher colonization rates were detected when multiple sites were sampled. Serotypes II and III occurred most frequently.


Contractile proteins in retinal endothelium and other non-muscle tissues of the eye. The present study is the first investigation to demonstrate, by employing the combined approach of immunologically and electron microscope methods, the presence of actin-like contractile proteins in the mammalian retina, the corneal epithelium and endothelium, the iris, and the ciliary body, and to confirm their presence in lens epithelium. This is also the first report to demonstrate by these methods the presence of microfilaments and intermediate filaments in retinal vascular endothelium. Since we have shown that actin filaments are especially abundant in immature retinal endothelial cells, the question of their function arises, and we have discussed their possible relevance to the closure of immature retinal vessels when exposed to hyperoxia.


Nuclear magnetic resonance studies of inorganic phosphate binding to yeast inorganic pyrophosphatase. Yeast inorganic pyrophosphatase is a dimer of identical subunits. Previous work (Rapoport, T.A., et al. (1973) Eur. J. Biochem. 33, 341) indicated the presence of two different Mn2+ binding sites per subunit. In the present work, the binding of inorganic phosphate to the Mn2+-inorganic pyrophosphatase complex has been studied by 1H and 31P nuclear magnetic resonance. Two distinct phosphate sites have been found, having dissociation constants of 0.24 mM and 18 mM. The Mn2+-31P distance from tightly bound Mn2+ to phosphate bound in the low affinity site (6.2 A) is consistent with outer sphere binding. Binding to both phosphate sites can be simultaneously inhibited by the pyrophosphate analogue, hydroxymethanebisphosphonate, providing evidence for the physical proximity of these two sites. The weaker Mn2+ site is apparently far from both phosphate sites. From the magnitudes of the dissociation constants found for both phosphate and analogue binding and the recent work of P.D. Boyer and his co-workers (private communication) on enzyme-catalyzed phosphate-water exchange, it appears unlikely that the hydrolysis of enzyme-bound pyrophosphate is the rate-determining step in the overall enzymatic catalysis of pyrophosphate hydrolysis, at least when Mn2+ is the required divalent metal ion cofactor.


Metabolism of prostacyclin in rat.

Metabolism of prostacyclin in rat. Following a single intravenous administration of [11-3H]prostacyclin in rat, 77% of the administered dose was excreted within 3 days with 33% in urine and 44% in feces. Urinary metabolites were accumulated by chronic intravenous infusions of [11-3H]prostacyclin for 14 days. The drug was extensively metabolized and the structures of seven metabolites were elucidated by combined gas chromatography and mass spectrometry. The urinary products include the dinor and 19-hydroxy dinor derivatives of 6-keto-PGF1alpha and 13,14-dihydro-6,15-diketo-PGF1alpha, omega-hydroxy and omega-carboxyl dinor derivates of dihydro-6,15-diketo-PGF1alpha, and a dihydrodiketotetranordicarboxylic acid. The metabolic pathways of PGI2 in rat are similar to that of PGF2alpha.


Physical properties of Artemia salina ribosomes. Eukaryotic ribosomes were isolated from the cryptobiotic embryos and from the further-developed free-swimming nauplii of the brine shrimp Artemia salina. Analytical boundary sedimentation and photon correlation spectroscopy yielded, respectively, the standard sedimentation and diffusion coefficients at infinite dilution, s degrees 20,w = 81 +/- 1 S and D degrees 20,w = (1.41 +/- 0.02) x 10(-7) cm2/s, for the unfixed and formaldehyde-fixed ribosomes from different developmental stages and for ribosomes attached to a messenger RNA fragment. Also, the density increment was determined, from which the partial specific volume was derived (0.63 +/- 0.01 cm3/g). Combination of the different measured parameters gives accurate values for the molecular weight (3.8 +/- 0.1) x 106 and for size and solvation parameters. These results are compared with their counterparts for the smaller ribosomes from the prokaryote Escherichia coli.


Detection of the homology among proteins by immunochemical cross-reactivity between denatured antigens. Application to the threonine and methionine regulated aspartokinases-homoserine dehydrogenases from Escherichia coli K 12. The two isofunctional enzymes aspartokinases-homoserine dehydrogenases I and II from Escherichia coli K 12 are compared using immunochemical techniques. The antibodies raised against one of these two proteins when in its native state can only recognize the homologous antigen, whether it is native or denatured. Contrarily, the antibodies raised against one of these two proteins when in its denatured state can recognize both the homologous and heterologous denatured antigens. The existence of this cross-reaction only between the two denatured aspartokinases-homoserine dehydrogenases suggests that these two enzymes have some similarity since such a reaction is not detected with several other denatured proteins. The regions involved in this similarity are buried inside the native proteins, and become exposed only upon denaturation. The same results, the existence of a cross-reaction between denatured species and none between the native ones, is obtained with proteolytic fragments derived from these two proteins and endowed with homoserine dehydrogenase activity. This resemblance between the two aspartokinases-homoserine dehydrogenases suggests that these proteins derive from a common ancestor. It is also proposed that such a cross-reaction between two denatured proteins is evidence for an homology between their amino acid sequences, and that the use of denatured proteins as both immunogens and antigens could be useful in detecting sequence homologies.


Insertion of newly synthesized proteins into the outer membrane of Escherichia coli. The insertion of newly synthesized proteins into the outer membrane of Escherichia coli has been examined. The results show that there is no precurser pool of outer membrane proteins in the cytoplasmic membrane because first, the incorporation of a [35S]methionine pulse into outer membrane proteins completely parallels its incorporation into cytoplasmic membrane proteins, and second, under optimal isolation conditions, no outer membrane proteins are found in the cytoplasmic membrane, even when the membranes are analysed after being labeled for only 15 s. The [35S]methionine present in the outer membrane after a pulse of 15 s was found in protein fragments of varying sizes rather than in specific outer membrane proteins. This label could however be chased into specific proteins within 30--120 s, depending on the size of the protein, indicating that although unfinished protein fragments were present in the outer membrane, they were completed by subsequent chain elongation. Thus, outer membrane proteins are inserted into the outer membrane while still attached to ribosomes. Since ribosomes which are linked to the cell envelope by nascent polypeptide chains are stationary, the mRNA which is being translated by these ribosomes moves along the inner cell surface.


An estimate of the minimum amount of fluid lipid required for the growth of Escherichia coli. The lipid phase transition of Escherichia coli was studied by high sensitivity differential scanning calorimetry. A temperature sensitive unsaturated fatty acid auxotroph was used to obtain lipids with subnormal unsaturated fatty acid contents. From these studies it was concluded that E. coli can grow nromally with as much as 20% of its membrane lipids in the ordered state but that if more than 55% of the lipids are ordered, growth ceases. Studies with wild-type cells show that the phase transition ends more than 10 degrees C below the growth temperature when the growth temperature is either 25 degrees C or 37 degrees C.


High molecular weight, cell surface-associated glycoprotein (fibronectin) lost in malignant transformation. Fibronectin is a polymorphic glycoprotein found in blood and tissues of vertebrates and in cultures of adherent vertebrate cells. There are several forms of fibronectin is composed of two high molecular weight subunits held together by forms found in tissues and on and around the surfaces of cultured cells. Soluble fibronectin is composed of two high molecular weight subunits held together by disulfide bonds. Insoluble fibronectin may be covalently cross-linked in larger complexes. Fibronectin has affinities for collagen, fibrin, heparin, and cell surfaces. In culture, fibronectin in growth medium may mediate attachment of cells to substratum, and fibronectin synthesized by cells may mediate adhesion to substratum. The widespread occurrence of fibronectin in basal lamina indicates that may different cell types in vivo abut against a fibronectin-containing matrix. Cultured transformed cells usually lack cell-surface fibronectin, also called large, external transformation-sensitive (LETS) protein. The failure of transformed cells to synthesize or bind fibronectin is paralleled (at least in some systems) by failures to synthesize or bind collagen and proteoglycans. Abnormal synthesis of fibronectin and other matrix components and abnormal interactions with the tissue matrix may account for several phenotypic characteristics of transformed cultured cells and for some of the malignant behavior of neoplastic cells in vivo.


Effect of DNA denaturants on the lac repressor-operator interaction. The nitrocellulose filter assay was used to study the effect of the DNA denaturants glycerol and dimethylsulfoxide (Me2SO) on the lac repressor-operator interaction. Both glycerol and Me2SO decrease the rate of dissociation (kb) of the repressor-operator complex but do not significantly alter the rate of association of repressor and operator. In the presence of 10% Me2SO an almost 10-fold increase of affinity of repressor for operator is observed. A small increase in affinity of repressor for Escherichia coli DNA, chicken blood DNA, and poly(dA-dT) is also found. The results lead to the conclusion that lac repressor when interacting with the operator causes local destabilization of the DNA.


Influence of polyamines on the activity of DNA polymerase I from Escherichia coli. The influence of polyamines on the various activities of DNA polymerase I from Escherichia coli (EC 2.7.7.7) has been investigated. For all high molecular weight DNAs spermine and spermidine caused up to 80% inhibition when present in high concentrations, i.e. above 1 mM for spermine and 2 mM for spermidine. In the presence of low concentrations of polyamines a small activation was seen for some DNAs. The diamines cadaverine and putrescine had little influence on the rate of synthesis with natural occurring DNAs. In the case of d(A--T)n the activation/inhibition was found to be markedly dependent on the molecular weight of the samples used. With a low molecular weight DNA, 5.6 S, addition of spermidine resulted in up to 3-fold stimulation of activity. The activation was dependent on the concentration of MgCl2 and ionic strength; increasing concentration of these gave a decrease in the degree of activation. Polyamines also had a dramatic effect on the rate of synthesis using the homopolymers (dA)n . (dT)10 and (rA)n . (dT)10 . (20:1) as primers. Putrescine, in particular, increased the activity up to 10-fold with (rA)n . (dT)10 and somewhat less for (dA)n . (dT)10. The apparent Km for the primer (rA)n . (dT)10 decreased approx. 35-fold in the presence of 6.6 mM putrescine. There was no influence on the apparent Km for dTTP. The influence of polyamines on both the 5' leads to 3' and 3' leads to 5' nuclease activity was also investigated. Inhibition of nuclease activity was observed in the presence of polyamines, particularly with spermine. Thus with d(A--T)n and T7 DNA as substrates addition of 0.7 mM spermine resulted in almost complete inhibition of the activity. The dramatic inhibition observed with high concentrations of spermine (spermidine) both in the case of polymerizing and nuclease activity is thought to be due to polyamine-induced aggregation of DNA molecules.


Two novel growth cycle-reflecting proteins associated with Escherichia coli ribosomes. The isolation and characterization of two low molecular weight, growth cycle-reflecting proteins which are associated with Escherichia coli ribosomes is described. These proteins which show greatly enhanced stoichiometry in ribosomes derived from post-exponential cells, exhibit molecular weights of 16 600, and 11 700 on sodium dodecyl sulfate (SDS) gel electrophoresis. Both proteins are highly acidic, the larger being the most acidic protein associated with the ribosome. Their amino acid compositions are unique and distinguish them from all other ribosomal proteins. Neither of the proteins showed crossreaction with either anti-L7 or anti-S6 sera although their electrophoretic behavior resembles that of L7 and S6. During the purification we have also isolated small amounts of three low molecular weight proteins showing some immunological homology with L7/L12. The isolated proteins were found to be without effect on the in vitro translation of f2-RNA, indicating that these adaptive modifications of the ribosome do not seriously affect its intrinsic activity.


In vitro methylation of tobacco mosaic virus RNA with ribothymidine-forming tRNA methyltransferase. Characterization and specificity of the reaction. A novel method has been developed for the detection and study of tRNA-like moieties in viral RNAs. Tobacco mosaic virus RNA is an acceptable substrate for crude Escherichia coli ribothymidine-forming tRNA methyltransferase. Under optimum reaction conditions at least 85% of the methylation product is ribothymidine (rT). The reaction is essentially quantitative, 1 mol of rT being formed per mol of tobacco mosaic virus RNA. The optimum reaction conditions include the presence of 6.6 micrometers S-adenosyl-L-[Me-3H]methionine, 25 micrometers spermine, 25 mM ammonium acetate, and 50 mM HEPES, pH 8.0. Sequence analysis of (Me-3H)-labeled tobacco mosaic virus RNA shows that all of the methylation occurs at a single site and strongly suggests that this site is the 32nd residue from the 3'-end of tobacco mosaic virus RNA. This site closely resembles the normal position of rT in transfer RNA.


Polynucleotides. XLIV. Synthesis and properties of poly (2-azaadenylic acid) and poly(2-azainosinic acid). Chemically synthesized 2-azaadenosine 5'-diphosphate (n2ADP) and 2-azainosine 5'-diphosphate (n2IDP) were polymerized to yield poly(2-azaadenylic acid), poly(n2A), and poly(2-azainosinic acid), poly(n2I), using Escherichia coli polynucleotide phosphorylase. In neutral solution, poly(n2A) and poly(n2I) had hypochromicities of 32 and 5.5%, respectively. Poly(n2A) formed an ordered structure, which had a melting temperature (Rm) of 20 degrees C at 0.15 M salt concentration. Upon mixing with poly(U), poly(n2A) formed a 1 : 2 complex with Tm of 41 degrees C at 0.15 M salt concentration. Poly(n2A) and poly(n2I) formed three-stranded complexes with poly(I), and poly(A), respectively. Poly(n2A) . 2poly(I), poly(A) . 2poly(n2I), and poly(n2A) . 2poly(n2I) complexes had Tm values of 23, 48, and 31 degrees C at 0.15 M salt concentration, respectively. Poly(n2I) formed a double-stranded complex with poly(C), but its Tm was very low.


The effects of divalent cations on the rotational mobility of myosin, heavy meromyosin and myosin subfragment-1 and on the binding of heavy meromyosin to actin. The effects of the divalent cations Mg2+, Mn2+ and Ca2+ on the Brownian rotational motion of fluorescently labeled myosin, heavy meromyosin and myosin subfragment-1 were measured by the method of time-resolved fluorescence depolarization. When Mg2+ was added to solutions of myosin or heavy meromyosin and EDTA, their rotational mobility increased. Ca2+ had no effect. Mn2+ increased the mobility of heavy meromyosin but decreased that of myosin. None of these divalent cations effected the mobility of subfragment-1. The binding of heavy meromyosin to actin was affected very little by Mg2+ or EDTA over a wide range of conditions. Divalent cations appear to change the swivel about which the heads of myosin rotate, presumably by binding to light chain 2 (also called DTNB light chain). However, the heads are still able to bind actin in nearly the same way whether Mg2+ is present or not. The concentration of free Mg2+ for the mid-point of the change in heavy meromyosin mobility is in good agreement with that for EDTA activation of ATPase activity. This suggests that EDTA activation is due to removal of Mg2+ bound to myosin itself.


Interaction of thiabendazole with fungal tubulin. Thiabendazole, 2-(4'-thiazolyl)benzimidazole, at 80 micrometer completely inhibits mitosis in hyphae of Aspergillus nidulans, growing in liquid culture. DNA and RNA synthesis and mycelial growth are only partially inhibited at this concentration. Binding studies with cell-free mycelial extracts from Penicillium expansum showed that thiabendazole competitively inhibits [14C]carbendazim binding to tubulin, which suggests that the antimitotic activity of thiabendazole is based on interference with microtubule assembly. Tubulin from a thiabendazole-resistant and carbendazim-highly sensitive mutant of P. expansum has a lower affinity to thiabendazole and a higher affinity to carbendazim than tubulin from a wide-type strain. This indicates that in this mutant the structure of the binding site is affected. The data presented suggest that several sites of both the tubulin and ligand molecule are involved in the binding of benzimidazole compounds to fungal tubulin.


Testosterone and cellular response.

Testosterone and cellular response. With the possible exception of male germ cells, the androgen responsiveness of all the target cell types in the mammalian body appears to be mediated by a single species of nuclear-cytosol androgen-receptor protein which is apparently specified by the X-linked Tfm locus. Although this receptor has the highest binding affinity to DHT, it can in the absence of DHT function with TES, albeit less efficiently. For the testosterone-dependent differentiation of embryonic organs, the androgen responsiveness of underlying mesenchymal cells appears to be more important than that of epithelial elements. Some of the androgen effects on apparent target cell types are through the indirect route involving the hypothalamopituitary axis.


[Characteristics of heterologous antisera against stromal fibroblasts]. As shown with the use of heterologous rabbit antifibroblast sera (AFS) to stromal mechanocytes of guinea pig, the media from the cultured bone marrow, spleen, and thymus stromal fibroblasts contained specific trypsinoresistant fibroblast protein (AG-1), which was also present in the normal blood serum and on the surface of stromal fibroblasts. AG-1 was insensitive to collagenase effect and apparently differed from the chief surface protein of fibroblasts (CSP). AG-1 is referred to gamma1-globulin, and is probably a new specific surface fibroblast protein. AFS contained also antibodies to the nonspecific protein of fibroblasts (AG-2), alpha1,-globulin related to AG1.


[Immunoglobulin-positive cells in mouse bone marrow]. The content of Ig-bearing lymphocytes and their precursors in the mouse bone marrow was investigated 6 and 36 hours after the hydroxyurea treatment. Some increase of the B-cell content takes place in the trated bone marrow. Dividing and non-dividing B-cell precursors, except the stem cells, were practically absent.


[Effect of purine derivatives on regeneration and the immunologic reactivity of animals]. The effect of azathioprine and of KI-7 (the new purine derivative) on the immunogenesis and regeneration in mammals was studied comparatively, KI-7 with a lesser toxicity than azathioprine proved to suppress the synthesis of antibodies to the SRBC in mice in case of administration of the preparation one day before or on the day of immunization; it also considerably prolonged the survival of skin allografts in rabbits in comparison with control. At the same time it was shown that under conditions of suppression of the immunogenesis system hepatic regeneration did occur in rats, but the correlation of the proliferation processes and cellular hypertrophy differed from that under ordinary restoration conditions, depending on the immunodepressor used. Thus, in difference from azathioprine, KI-7 not only inhibited the mitotic activity of the regenerating liver, but even stimulated it somewhat.


[Nonspecific suppressive effect of Ehrlich tumor ascitic fluid on transplantation immunity]. The influence of syngeneic Ehrlich ascites tumour fluid on the survival of allogeneic skin allografts was investigated on CC57BR mice. A 3--4-day delay of the allograft rejection in mice injected with ascitic fluid was revealed. Preliminary transplantation of such allograft to mice with Ehrlich tumour produced no intensification of the immunodepressive action of the ascites fluid obtained from them. The data obtained indicated the preferential significance of the antigen-independent immunosuppressive factors of ascites tumour fluid in the suppression of the transplantation immunity in vivo.


Identification of young megakaryocytes by immunofluorescence and cytophotometry. The DNA-content of fluoresceine-labeled platelet antigen containing cells of mouse bone marrow was measured. For immunofluorescence highly specific anti-mouse-platelet-serum and fluoresceine-conjugated antigammaglobuline was used, applying the "sandwich" technique. Three hundred panoptically identifable megakaryocytes served as control group. The DNA-polyploidization pattern of megakaryocytes and immunofluorescence positive cells was almost identical. However, among the immunofluorescence positive cells a considerable amount of cells showed DNA-values lower than 4c, whereas the megakaryocytes of the Pappenheim stained smears revealed no DNA-values lower than 4c. The percentages of diploid and tetraploid cells, respectively, was 6 and 7% compared with 0 and 1% of panoptically identifiable megakaryoctyes. The results suggest that young megakaryocytic cells with diploid and tetraploid DNA-values can be detected by immunofluorescence technique, indicating that the flow from the uncommited to the committed megakaryocytic precursor cell appears at this early stage of megakaryocyte production.


Discussion of the indications for decompressive laminectomy in epidural spinal metastases. The authors have recently reviewed the results of their consecutive cases of decompressive thoracic or lumbar laminectomy for spinal cord compression from epidural metastatic neoplasia at the City of Hope National Medical Center over the 15-year period, 1960-1974. This limited series tends to demonstrate the effect of case selection on results, as well as contrast the type of patient with paraparesis seen at a cancer treatment center with that seen at a community or county hospital.


Health sciences librarians and mental health laws. Two U.S. Supreme Court decisions, O'Connor v. Donaldson and Bounds v. Smith, hold important implications for health sciences librarians serving in mental health facilities. The first, O'Connor, with its many ancillary holdings, puts mental health personnel on notice that patients have certain basic rights, which courts all over the country will now be required to enforce. In Bounds the court has ruled that prison authorities must assist prison inmates in preparing and filing legal papers. The ruling will most likely benefit all mentally disabled prisoners, and future litigation may expand this category to include: (1) persons committed under the criminal code, (2) persons under involuntary commitment not related to the criminal code, and (3) persons voluntarily committed. A selective annotated bibliography, consisting of background readings in mental health and the law, basic rights, law library materials, and mental health legal services, has been compiled to help librarians establish and develop legal collections in anticipation of court decisions that will expand the conditions of Bounds to include all mentally disabled patients.


How soon may the axial vessels of a surviving free flap be safely ligated: a study in pigs. The supplying vessels of microvascular free flaps in pigs were ligated at various intervals after transfer in order to study the revascularisation from the recipient bed. At 8 days of later survival occurred. Earlier, although necrosis was not inevitable, the results were unpredictable.


A clinical trial of BCG immunotherapy as an adjunct to surgery in the treatment of primary malignant melanoma. A preliminary analysis of a controlled trial of BCG immunotherapy as an adjunct to surgery in the treatment of primary malignant melanoma has been carried out. The length of follow-up varied from 5 years to 6 months. No obvious benefit from BCG immunotherapy has been found so far. On the other hand the treatment is painful with an appreciable morbidity. Skin tests for delayed hypersensitivity have shown no recognisable differences in patients treated with surgery and those who also had BCG, or in the pattern of responses in those who developed recurrences and those who did not. In view of these early findings trial entry has been closed.


Nasal reconstruction and lengthening with local flaps. A technique for nasal lengthening is described in 3 cases using nasolabial flaps for lining and an island forehead flap for skin reconstruction. It is basically a 2-stage procedure with short hospitalisation.


E. coli endotoxin shock in the dog; treatment with lidocaine or indomethacin. 1 Dogs treated with lidocaine (1 mg kg-1 h-1) or indomethacin (1.5 mg/kg) before and after an LD60 dose (1 mg/kg) of E. coli endotoxin survived for at least 72 h. 2 Although all dogs in both treated groups survived, only those treated with indomethacin were significantly protected against the fall in the arterial blood pressure 1 to 2 min following endotoxin administration. 3 Endotoxin increased the plasma prostaglandin F2alpha (PGF2alpha) concentration in the control and lidocaine-treated groups, however, no increase was observed with indomethacin treatment. 4 Neither lidocaine nor indomethacin alone had any significant effect on the parameters measured in this model. 5 Following the administration of endotoxin, lidocaine-treated animals had significantly decreased plasma fibrinogen concentrations when compared to the other groups. 6 This study suggests that lidocaine, a local anaesthetic and a drug widely used for cardiac arrhythmias, might offer protection in endotoxin shock.


Recirculation of prostacyclin (PGI2) in the dog. 1 The inactivation of prostacyclin (PGI2) in the circulation of anaesthetized dogs has been studied by the blood-bathed organ bioassay technique. 2 Spiral strips of bovine coronary and rabbit coeliac or mesenteric artery detected concentrations of PGI2 of 2 to 5 ng/ml. These tissues were insensitive to concentrations at least 200 fold higher of 15-oxo-PGI2 and 6-oxo-PGF1alpha. 3 PGI2 assayed on bovine coronary artery, rabbit coeliac artery or rat stomach strip, had a half life in blood of 3.0 +/- 0.3 min, indicating non-enzymatic degradation. 4 No disappearance could be detected by bovine coronary artery when PGI2 was infused across the lungs (0.1 to 0.5 microgram kg-1 min-1). However, PGI2 was partially inactivated in passage through vascular beds of hindquarters and liver. 5 Of PGI2 infused into the aorta 35 to 65% escaped inactivation in one complete circulation. Therefore, endogenous PGI2 released from the lungs may function as a circulating hormone.


The current role of cancer chemotherapy. Cancer chemotherapy has developed rapidly over the last twenty years. The majority of patients with cancer die from metastatic disease, so the major therapeutic advance now must be better systemic therapy. From its early beginning in the 1940's with oestrogen therapy for prostatic cancer, nitrogen mustards in the lymphomas, and folic acid antagonists in childhood leukaemia, there are now between thirty and forty active anti-cancer agents in clinical use. The main clinical pharmacological points of the major agents are briefly reviewed, together with their main dose-limiting toxic effects and their activity as single agents. Clinical chemotherapy has developed by the introduction of newer agents from the drug screening programmes and a better understanding of the scheduling to avoid serious toxicity. Although drug-resistance is still a major problem, by combining different active agents there has been a dramatic improvement in survival of patients with selected tumours. More recently, treatment of patients early, before they have gross clinical recurrence, has already shown some benefit in pre-menopausal patients with carcinoma of the breast and in patients with osteosarcoma. The limitations of clinical measurements in monitoring therapy are clear, and a major improvement could well be realised if therapy could be monitored on the basis of quantitative markers. The clinical impact of cancer chemotherapy has already been dramatic in drug-sensitive tumours, but these only contribute a small proportion of the total. Some of the common tumours fall into the group that are relatively drug sensitive where the lives of patients can be prolonged, but there is still a significant fraction of tumours which are insensitive to existing drugs and which will probably require the development of newer agents before chemotherapy can make any impact on the survival of patients with these tumours.


Isotope renography and long term follow-up of renal transplant patients. Isotope renography was carried out in 64 kidney transplant patients attending a follow-up clinic. Graft survival in these patients ranged from two months to ten years. Forty-one patients had normal renograms and 98% of these had satisfactory function (creatinine clearance greater than 50 ml/min). Eighteen patients showed a major renogram abnormality and 50% of these had impaired function. Five of these 18 have been explored and found to have graft complications (obstructive disease in four, chronic pyelonephritis in one). Exploration has not been undertaken in the remaining 13 but nine show evidence suggestive of graft pathology (proteinuria, impaired creatinine clearance, elevated urinary enzymes, calyceal distortion on IVP). A successful kidney transplant should result in a normal isotope renogram, and a major abnormality of the renogram suggests the presence of a graft complication, even when the creatinine clearance is unimpaired. We feel renography is useful for identification of renal transplant patients who require further investigation or closer follow-up.


Hepatobiliary imaging: a comparison of 99Tcm-dihydrothioctic acid and 99Tcm-pyridoxylidene glutamate in the non-jaundiced patient. A comparison of two hepatobiliary imaging agents, 99Tcm-dihydrothioctic acid (99Tcm-DHT) and (99Tcm-pyridoxylidene glutamate (99Tcm-PG) has been carried out in 44 non-jaundiced patients. Thirty-one patients were admitted for investigation of upper abdominal pain and 13 patients were volunteers who were undergoing treatment for unrelated conditions. Satisfactory liver images were obtained with both agents in patients without liver disease, but they were inferior to those seen after 99Tcm-sulphur colloid. 99Tcm-PG produced clearer images of the gall-bladder and bile ducts than 99Tcm-DHT. Non-visualization of the gall-bladder was interpreted as gall-bladder disease; in patients with inflammatory gall-bladder disease no gall-bladder image was seen (nine 99Tcm-DHT, nine 99Tcm-PG). The gall-bladder was also not demonstrated in two of the volunteers' group (one 99Tcm-DHT, one 99Tcm-PG), nor was a gall-bladder seen in five patients whose abdominal pain was not due to acute cholecystitis. Despite this, there was agreement between the results of imaging and oral cholecystography in 21 out of 22 subjects. 99Tcm-PG is non-toxic, cheap and rapidly excreted by the liver into the bile. A 99Tcm-PG scan would be useful when rapid diagnosis is required in suspected acute cholecystitis when conventional contrast radiology is unlikely to be of value.


Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the bladder. In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of carcinoma of the bladder a total of 241 cases were contributed by four radiotherapy centres in the United Kingdom. In this trial where in each centre identical radiotherapy was employed for both oxygen and air cases, no benefit was shown with the use of hyperbaric oxygen.


Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix. In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of advanced carcinoma of the uterine cervix a total of 320 cases were contributed by four radiotherapy centres in the United Kingdom. The use of hyperbaric oxygen resulted in improved local control and survival. The benefit was greatest in patients under the age of 55 who presented with stage III disease. There was a slight increase in radiation morbidity but it seemed that the benefit of hyperbaric oxygen outweighed this increase in morbidity and that there was a true improvement in the therapeutic ratio.


Hyperbaric oxygen: the Medical Research Council trials and their clinical significance. The clinical trials of the use of hyperbaric oxygen in radiotherapy conducted by the Medical Research Council's working party have shown that local cure and survival can be improved in head and neck and cervical cancer. Evidence for benefit has been presented in carcinoma of bronchus, but none has so far been found in carcinoma of the bladder. Although hyperbaric oxygen has produced increased effect upon normal tissues as well as upon tumour, a real improvement in therapeutic ratio appears to be present. The future use of hyperbaric oxygen in radiotherapy will depend upon a comparison of effectiveness with other methods now being tested to improve radiotherapy. The trials have yielded much fundamental and clinical data of general relevance in the radiotherapy of malignant disease.


Uretero-neo-cystostomy in renal transplantation. Is an antireflux mechanism mandatory? We report a retrospective analysis of 120 kidney transplantations in which a simple end-to-end ureteric implantation in the bladder without antireflux mechanism was made. From this study no greater incidence of vesico-ureteric reflux could be demonstrated and, even when present, reflux neither interfered with graft function nor caused an increased incidence of recurrent urinary tract infections. The incidence of other urological complications (leakage, obstruction) being equal, this very simple technique yielded in our hands the best results and we recommend its use in kidney transplantation.


The indications for simple closure of perforated duodenal ulcers. One hundred and sixty-one patients undergoing simple suture of a perforated duodenal ulcer are reviewed retrospectively. Nine patients (6 per cent) suffered a complication of their ulcer during the postoperative period and 3 (2 per cent) of them died. The mean length of follow-up was 26 months and during this period a total of 14 complications was seen in 12 patients. Five of these patients died after a complication of their ulcer. Analysis of the data from patients who had complications of their ulcers indicates that the operation of simple suture of a duodenal ulcer is indicated only in young and middle-aged women.


A double blind trial of the prolactin inhibitor bromocriptine in painful benign breast disease. A double blind crossover trial of the prolactin inhibitor bromocriptine in painful benign breast disease is reported. Twenty-nine women with cyclical mastalgia and 11 with non-cyclical pain were treated with bromocriptine, 5 mg daily, and placebo over six menstrual cycels. Assessment of response to treatment was made by a linear analogue system and clinical examination together with plasma prolactin estimations. Bromocriptine produced a significant improvement in breast symptoms and a significant fall in prolactin levels in the cyclical pain group, but had no effect in the non-cyclical group. These results suggest that bromocriptine offers a new and effective approach in the management of cyclical breast pain.


Preventing deaths from malaria.

Preventing deaths from malaria. To reduce the number of avoidable deaths from malaria in Britain the following five points are recommended. Parliament should pass a Malaria Prevention Act that compels travel agents and airlines to give written and verbal advice on prevention and diagnosis of malaria to people travelling to countries where the disease occurs. To improve diagnostic and therapeutic efficiency for all diseases the Department of Health and Social Security should prepare a procedure manual for the NHS that gives guidance for doctors and other medical staff. Avoidable deaths from all diseases should be the subject of open inquiries at district medical committees, with recorded evidence. Failure to perform diagnostic tests such as blood films for malaria in cases of sickness in people returning from the tropics should automatically be considered negligent. Compensation should be offered by the State to the next of kin of people who have died because of medical negligence from malaria or other diseases.


Treating heartburn in pregnancy: comparison of acid and alkali mixtures. A randomised crossover trial was performed in 55 pregnant women who complained of heartburn to see whether alkali or acid treatment alleviated it. Each woman was given a week's treatment with an acid mixture, an alkali mixture, and a placebo in randomised order. Both acid and alkali mixtures were better than placebo, but there was no significant difference between the acid and alkali treatments. Together with the inconsistent reports of some patients, these findings suggest that both acid reflux and bile regurgitation may cause heartburn in pregnant women and that other factors may also play a part. Because the cause of heartburn may be difficult to determine, treatment should be empirical. If the patient does not respond to seven days' acid treatment an alkali mixture should be prescribed; there is a 98% chance that one of these treatments will relieve symptoms.


Effect of propranolol and phentolamine on myocardial necrosis after subarachnoid haemorrhage. A study was set up to assess the effect on the clinical course of subarachnoid haemorrhage (SAH) of giving propranolol 80 mg eight-hourly plus phentolamine 20 mg three-hourly by mouth for three weeks. Out of the 90 patients studied, 14 died. Two of the deaths occurred in an open pilot study of 10 patients, the remaining 12 deaths occurring in patients in a randomised double-blind placebo-controlled study. Postmortem examination was carried out on 12 of the patients, six of whom had been receiving placebo and six propranolol plus phentolamine. Necrotic myocardial lesions were present in the hearts of all six patients (age range 30-59 years) who died while taking placebo (all had had abnormal electrocardiograms (ECGs). In contrast, no necrotic lesions were found in the hearts of the six patients (age range 28-59) who died while receiving the drugs (all had previously had normal ECGs). We conclude that the necrotic myocardial lesions were induced by catecholamines and that propranolol had a cardioprotective effect. While death from a further haemorrhage in cases of SAH is not affected by propranolol and phentolamine, propranolol may have a beneficial effect in other potentially lethal stresses.


Dexamethasone in acute stroke.

Dexamethasone in acute stroke. Over 13 months 118 patients admitted to hospital with acute stroke were allocated at random to treatment with either dexamethasone or placebo. At one year there was no significant difference in the numbers of survivors or in the quality of life between the two groups. The results suggest that there is no indication for the routine administration of dexamethasone to a heterogeneous group of patients with stroke.


The adverse effect of iron repletion on the course of certain infections. The incidence of infections was studied in 137 iron-deficient Somali nomads, 67 of whom were treated with placebo and 71 with iron. Seven episodes of infection occurred in the placebo group and 36 in the group treated with iron; these 36 episodes included activation of pre-existing malaria, brucellosis, and tuberculosis. This difference suggested that host defence against these infections was better during iron deficiency than during iron repletion. Iron deficiency among Somali nomads may be part of an ecological compromise, permitting optimum co-survival of host and infecting agent.


Evidence for a primary autoimmune type of diabetes mellitus. Sixty-eight patients with longstanding diabetes and persistent islet-cell antibody and 35 with coexistent diabetes and Graves's disease or primary myxoedema were studied with particular reference to the HLA system and autoantibody patterns. A higher incidence of HLA-B8 than normal was observed in the two groups. An additive relative risk exists when type I diabetes and autoimmune thyroid disease coexist, indicating that different HLA-linked genes may confer susceptibility to the pancreatic and thyroid disorders. Other characteristics, including female predominance, a later onset of diabetes, and a strong family history of autoimmune endocrinopathy, provide further evidence that this form of diabetes is aetiologically distinct from that generally seen in children. These results support the hypothesis of a primary autoimmune type of diabetes mellitus.


Specificity of the FTA-ABS and TPHA tests during pregnancy. In order to determine whether pregnancy influences the specificity of the fluorescent treponemal antibody absorption (FTA-ABS) and Treponema palidum haemagglutination assay (TPHA) tests, these tests, together with the quantitative fluorescent treponemal antibody (FTA) and Venereal Disease Research Laboratory (VDRL) tests, were carried out simultaneously on 2000 pregnant women who attended for compulsory prenatal screening. In only one patient (0.05% of the total investigated) was a positive result to the TPHA test obtained, the specificity of which it was impossibile to confirm. The FTA-ABS test gave a weakly reactive result of the borderline type but this was found to be non-specific in only four (0.2%) patients. The results of our investigations showed that the specificity of the FTA-ABS and the TPHA tests performed on pregnant women did not differ from the specificity of these tests when carried out on other population groups.


Influence of genital herpes on results of fluorescent treponemal antibody absorption test. Both the fluorescent treponemal antibody absorption (FTS-ABS) test and Venereal Disease Laboratory (VDRL) test for syphilis were performed routinely on 113 men with histories of genital ulcerations. The difference in negative VDRL and borderline FTS-ABS results between patients with and without herpes simplex virus in their genital ulcers and no evidence of previous or untreated syphilis was not statistically significant. Furthermore, use of the FTA-ABS test as a confirmatory rather than a screening test eliminates false-positive, borderline, or reactive results in patients with non-syphilitic ulcers.


Study of fluorescent treponemal antibody test on cerebrospinal fluid using monospecific anti-immunoglobulin conjugates IgG, IgM, and IgA. The fluorescent treponemal antibody test for cerebrospinal fluid (FTA-CSF) using monospecific conjugates anti-IgG, IgM, and IgA was used to determine the presence of anti-treponemal antibodies in the spinal fluid of 335 patients with primary, secondary, and latent syphilis and symptomatic and asymptomatic neurosyphilis and of patients with certain neurological disorders. Of these, 230 (68·65%) patients had non-reactive results to this test. Of the remaining 105 patients, 78, 63, and 10 had reactive results with anti-IgG, IgM, and IgA conjugates respectively. Of the 129 cases of known syphilis, 11 were diagnosed as primary, 32 as secondary, and 50 as latent, and 36 patients had neurosyphilis. None of the specimens from the patients with primary syphilis gave reactive results to the test. Specimens from 21 (65·62%) of the 32 patients with secondary syphilis, 30 (60%) of the 50 patients with latent syphilis, and all (97·22%), except one, of the 36 patients with neurosyphilis gave reactive results to one at least of the IgG, IgM, or IgA FTA-CSF tests. Among the specimens from patients with secondary syphilis twice as many gave reactive results with anti-IgG conjugate than with anti-IgM conjugate. However, with specimens from patients with latent syphilis and neurosyphilis this ratio was diminished to 1·5:1. The Kolmer complement-fixation test, although superior in sensitivity and specificity to the Venereal Disease Research Laboratory (VDRL) test, in patients with secondary and latent syphilis and neurosyphilis, was greatly inferior to the FTA-CSF test. Data indicate that anti-treponemal antibodies can be detected in the spinal fluid even in patients with no neurological symptoms in cases of secondary syphilis and that the FTA-CSF test can be a valuable tool in the early detection of an immunological response to treponemal infection in the spinal fluid.


Some problems in microscopy encountered in clinics for sexually transmitted disease. The actual field diameter of 24 microscopes used in clinics for sexually transmitted diseases has been measured by means of a stage micrometer. The variation in findings is given, and the difficulties in producing accurate measurements are discussed.


In vitro growth of glial cell-enriched and depleted populations from mouse cerebellum. Glial cell-enriched and -depleted populations isolated from 10-day-old mouse cerebella have been grown in vitro. There are marked differences in the cellular morphology between these two populations. The glial cell-enriched populations are very heterogeneous with respect to cell size, morphology and processes, whereas the glial cell-depleted populations are very homogeneous, containing a cell type with a small cell body and predominantly bipolar processes. Further characterization of the cell types has been affected using antiserum prepared against GFA protein and tubulin. The immunocytochemical localization of these proteins clearly identifies astrocytes and neurons. The glial cell enriched populations contain several types of astrocytes and neurons in addition to cells of non-ectodermal origin, whereas the glial cell-depleted populations contain predominantly a single neuronal cell type, the granule cells.


Effects of estrogen upon hypothalamic vulnerability to goldthioglucose in mice. Two groups of ovariectomized albino mice were given subcutaneous injections of either seasame oil or increasing doses of estradiol benzoate (EB) for 8 days. Mice were housed in groups of three; food intake (FI) and body weight (Bwt) were measured daily during this period. After 8 days, all mice were injected IP with 0.3 mg/g of goldthioglucose (GTG) and sacrificed 2 days later. The extent of hypothalamic damage after GTG was assessed histologically. Although EB did not depress FI or Bwt, perhaps because of some behavioral interaction within the groups of mice, the extent of hypothalamic damage after GTG was significnatly increased in EB-treated mice relative to that of oil-injected controls. These data support the view that estrogen may enhance the uptake and/or storage of glucose by the ventromedial hypothalamus.


A head holder and stereotaxic device for the rattlesnake. We describe an apparatus for immobilization of the rattlesnake head for brain experimentation. Its design also allows its use as a stereotaxic instrument for electrophysiological studies employing microelectrodes. Attachment of the head is at the two orbital ridges and the hard palate. The bregma provides a zero reference for the frontal, lateral, and depth coordinates.


A microwire technique for recording single neurons in unrestrained animals. A technique is described in which bundles of 25 mu dia. insulated wires can be stereotaxically implanted for single unit recording in the brain. With this method extremely stable recordings can be obtained lasting many hours and sometimes days. The unit activity recorded with these electrodes has been found comparable with that recorded from rigid etched microelectrodes in conscious animals. The fine wire electrodes have also been found to be durable for at least a month when chronically implanted in cats. The electrode assembly is easy to construct and the electrodes are easily implanted in any region of the brain.


Role of creatine phosphokinase in cellular function and metabolism. This paper summarizes the data concerning the role of the creatine phosphokinase system in muscle cells with main attention to the cardiac muscle. Creatine phosphokinase isoenzymes play a key role in the intracellular energy transport from mitochondria to myofibrils and other sites of energy utilization. Due to the existence of the creatine phosphate pathway for energy transport, intracellular creatine phosphate concentration is apparently an important regulatory factor for muscle contraction which influences the contractile force by determining the rate of regeneration of ATP directly available for myosin ATPase, and at the same time controls the activator calcium entry into the myoplasm across the surface membrane of the cells.


Use of a single infusion bottle to culture and prepare potentially hazardous microorganisms for biochemical analysis. A procedure is described to culture, harvest, kill, wash, freeze-dry, and store microorganisms for biochemical analysis. This method using a single infusion bottle is far less laborious than conventional procedures and reduces the risk of contamination.


Behavioural prevention of ischemic heart disease. Heart disease continues to be a major cause of disablement and death in Canada. Elevated serum cholesterol concentrations, hypertension and cigarette smoking are among the standard risk factors associated with ischemic heart disease. Research attention has also been directed at the role of behavioural factors in the development of atherosclerosis and myocardial infarction. Experimental findings support a conceptual approach to the interplay of psychologic stress, the type A "coronary"-prone behaviour pattern and pathophysiologic mechanisms that have been implicated in the development of coronary artery disease. It is concluded that type A behaviour and stress contribute substantially to the pathogenesis of cardiovascular disease. However, assessment of the manner in which these two variables influence the pathophysiology of ischemic heart disease requires further research, with systematic examination of physiologic and biochemical processes. Potential strategies for modifying type A behaviour are reviewed. However, unequivocal support for the preventive efficacy of behavioural approaches must await future research.


Louis Riel: a case study in involuntary psychiatric confinement. Louis Riel was confined against his will in insane asylums from March 6, 1876 to January 23, 1878. Psychiatrists and historians have generally interpreted his certification as an act of benevolence to Riel at a time when he was non compos mentis. However, detailed study of surviving records and manuscript sources shows that the commitment was legally suspect in a number of ways: proper signatures were lacking, pseudonyms were used, records were falsified, and so on. Moreover, while Riel was clearly a religious enthusiast with eccentric ideas, there was no proof that he was dangerous to himself or others at this time. We may thus wish to revise our interpretation of Riel's certification. It was not an act of benevolence but an illegal and unjustifiable deprivation of liberty.


William Henry Jackson (1861--1952): Riel's secretary: another case of involuntary commitment? Although there have been many studies of the trial of Louis Riel, following the 1885 rebellion, much less attention has been paid to the fate of his secretary William Henry Jackson, who was charged with "treason-felony" and found not guilty, reason of insanity. In an effort to throw some new light on this neglected aspect of midico-legal history, this paper describes the intense political and religious relationship between Riel and his secretary which culminated in the onset of Jackson's mental illness. After a trial lasting less than half an hour, Jackson was committed to the "Selkirk Asylum" under a warrant of the then Lieutenant-Governor. Two weeks before Riel was executed, Jackson escaped from hospital and made his way into the U.S.A. No attempt was made to capture him. Jackson, having changed his name to Honoré Jaxon, became a labour organizer. He died in the psychopathic ward of Bellevue Hospital in New York on 10th January, 1952 at the age of ninety.


Carcinoembryonic antigen (CEA) levels in benign gastrointestinal disease states. Elevated circulating CEA levels occur in patients with benign gastrointestinal and hepatic disorders. These are usually less than 10 ng/ml. Of clinical importance is the influence of liver disease on the interpretation of CEA. At least 50% of patients with severe benign hepatic disease have elevated CEA levels, most often active alcoholic cirrhosis, and also chronic active and viral hepatitis, and cryptogenic and biliary cirrhosis. Patients with benign extrahepatic biliary obstruction may have increased plasma CEA, the highest in patients with co-existent cholangitis and especially liver abscess. The liver appears to be essential for the metabolism and/or excretion of CEA. Hence, liver work-up is needed to assess any patient with an elevated CEA. A damaged liver may further augment elevated CEA levels due to cancer. The increased circulating CEA observed in some patients with active ulcerative colitis tends to correlate with severity and extent of disease and usually returns to normal with remission. CEA levels also may be mildly elevated in patients with pancreatitis and in adults with colonic polyps. Smoking may contribute to the increased CEA levels seen in patients with alcoholic liver disease and pancreatitis. Therefore, in interpreting mildy elevated circulating CEA levels in patients with GI tract diseases, one must consider benign as well as malignant etiologies.


Carcinoembryonic antigen assay: an adjunct to liver scanning in hepatic metastases detection. The radionuclide liver scan is a valuable study for detection of hepatic metastases; however, it has a false-negative rate of between 10 and 30%. In a double-blind study involving 377 patients, we assessed the value of CEA assay as an adjunct to liver scanning for detection of hepatic metastases. Fifty-seven patients studied by both methods were ultimately proven to have liver metastases. All patients with CEA levels above 9 ng/ml and focal defects on liver scan had hepatic tumor involvement, while only 4 of 291 patients with CEA values less than 9 ng/ml and negative scans were later shown to have liver metastases. CEA and liver scan results were discordant for 29 patients with proven hepatic metastases: the radionuclide study was positive in 21 cases with false-negative CEA results, while the CEA assay suggested the presence of metastatic disease in eight of the 12 patients with false-negative liver scans.


Cellular content of carcinoembryonic antigen in urothelial carcinoma. CEA containing cells can be demonstrated in 25--60% of urothelial carcinomas. No staining was seen with benign urothelial cells. Using microfluorometry of single cells, mean fluorescence intensity with anti-CEA antisera was 3--6 times that of preparations stained in parallel with nonimmune sera. A comparison of the IF results with RIA implies a possibility to detect less than 1 pg CEA/cell in unfixed specimens. The cells which stained with anti-CEA antisera did not have any apparent morphologic properties differentiating them from neighboring nonstained cells but it was mainly in the cell populations from well- and moderately well-differentiated tumors that CEA containing cells were seen. Therefore quantitative measurements of CEA amount/cell may be a parameter, in addition to morphologic differentiation, to study new properties of tumor cell populations.


Immunoperoxidase detection of carcinoembryonic antigen: an overview. The advent of immunoperoxidase histochemistry techniques has allowed the more convenient visualization by light microscopy of antigenic cellular constituents. Application of the unlabeled and labeled antibody enzyme methods to the localization of carcinoembryonic antigen in conventionally prepared tissue specimens has revealed the feasibility of using immunoperoxidase techniques in routine diagnostic pathology. The methods involved are well defined and once antibody specificity and antigen stability are determined, they are adaptable to the identification of other immunological markers that may appear in malignant tissue specimens.


Immunohistochemistry of carcinoembryonic antigen in the small intestine. Carcinoembryonic antigen (CEA) was demonstrated in formalin-fixed paraffin embedded sections of normal small intestine using an immunoperoxidase method. In all the sections studied the antigen was present over the surface of the villi, within goblet cells and lining the crypt lumens. At the electron microscopic level CEA was identified in mucin granules of goblet cells and in the glycocalyx but not intracytoplasmically. During the study cross-reactivity of antiCEA with Paneth cell granules, red blood cells and endothelium was observed. The shared antigenic determinants responsible for these immunological cross-reactions between CEA and other tissue glycoproteins were found to be carbohydrate in nature. Even when well controlled, misleading immunohistochemical results may be caused by immunological cross-reactions.


Overview on new immunologic markers for diagnosis of cancer. There is a large and increasing number of tumor-associated markers which can be detected immunologically and which may be useful for detection, diagnosis and monitoring of cancer. These include cell surface antigens and other components specifically associated with tumor cells, ectopic hormones, and normal materials which are produced in increased amounts by or in response to the tumors. Some of these markers are only antigenic in heterologous species, whereas others are reacted to by the tumor-bearing host. The major current problem is to determine which of these markers may be applied to practical problems of immunodiagnosis.


Combined cytotoxic and progestogen therapy for advanced breast cancer. Sixty-nine patients with advanced breast cancer treated with cytotoxic chemotherapy were randomized to receive concomitantly either norethisterone acetate (progestogen group) or a placebo (placebo group). Objective responses were seen in 53% of patients in the progestogen group and 61% of patients in the placebo group. The median duration of response was the same for both groups (38 weeks). Three out of ten patients in the placebo group, who received subsequently the progestogen on relapse, had a further objective regression. The overall survival in the two groups was similar, although in a sub-group of patients who had operable tumors, but a subsequent short disease-free interval, survival was significantly better in the placebo group. There was less myelosuppression in the progestogen group, who were able to receive higher doses of cytotoxic drugs. Less nausea and vomiting occurred in the progestogen group, but subjective side effects were similar. It is concluded that there is no advantage therapeutically in combining cytotoxic chemotherapy and progestogen therapy and, in some patients, better results are obtained using the two treatments sequentially.


Combined modality therapy for advanced, diffuse lymphocytic and histiocytic lymphomas. Forty-six previously untreated patients with advanced aggressive non-Hodgkin's (34 poorly differentiated and mixed diffuse, 8 histiocytic and 4 undifferentiated) were treated with a 3 phase combined modality program employing cyclophosphamide (C), hydroxyl-daunomycin (H), vincristine (O), prednisone (P), procarbazine (P) [CHOP(P)] combination chemotherapy in an initial induction phase, radiotherapy and nonmarrow toxic chemotherapy as a second consolidation phase, followed by a third phase of CHOP(P) chemotherapy for four more cycles. Long-term maintenance therapy was not given. High dose involved field radiation in phase II was limited to volumes encompasing less than 50% of the marrow bearing skeleton. The large majority of patients (82%) had such widespread involvement that this limitation precluded the use of local radiation and were treated instead with a mean of 132 rad of fractionated total body irradiation (TBI). Thirty-eight patients (83%) achieved complete remission. Twenty-nine (66%) of the 44 patients evaluable for follow-up, and 22 (61%) of the 36 patients receiving TBI, remain alive in complete remission for observation periods of up to 26 months.


Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP). Twenty-three patients with diffuse histiocytic lymphoma who had not had prior chemotherapy were treated with CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone). Sixteen of these patients had previously been treated with radiation therapy. Nine of these 23 patients had a pathologically documented complete response at the conclusion of CHOP with an overall complete response rate of 39%. In patients whose disease was confined to lymph nodes, the complete response rate was 7 of 8 or 88%, while in patients with stage IV disease, only 2 of 15 or 13% had complete responses. Although prior radiation therapy could not be demonstrated to be an adverse prognostic factor in this small series, it could have accounted for the low overall complete response rate noted. Complete response in this series was well sustained with an actuarial relapse-free survival of 75% and an actuarial survival of 89% at two years. No complete responses occurred in five patients who had received prior chemotherapy.


Effect of chemotherapeutic agents on metabolic and bactericidal activity of polymorphonuclear leukocytes. Blood was obtained on 36 occasions from 12 healthy adult volunteers and the polymorphonuclear leukocytes (PMNL) were separated. PMNL hexose monophosphate shunt activity of whole blood and ability of separated cells to phagocytize and kill E. coli were evaluated when the PMNL were incubated with normal pooled sera and sera containing therapeutic concentrations of either 15 cancer chemotherapeutic drugs singly and in combination or 9 antibiotics. Resting and stimulated HMPS activity was significantly (p less than 0.025 to p less than 0.001) decreased by cyclophosphamide, carmustine (BCNU), high dose prednisone (pred), vinblastine (vinbl) and vincristine (vinc) and significantly (p less than 0.025 to p less than 0.01) increased by combinations of vinc-pred, vinc-predasparaginase, 6-mercaptopurine (6MP)-methotrexate (Mtx) and 6MP-Mtx-pred when compared to controls. No significant differences in HMPS activity of PMNL were found when exposed to various antimicrobial agents singly or in combination. The killing of E. coli by PMNL was significantly (p less than 0.001) decreased when exposed to BCNU, high concentration pred or combinations of 6MP-Mtx-pred, 6MP-Mtx and vinc-vinbl-pred but not when exposed to other chemotherapeutic agents. This study shows a disparity in results obtained when evaluating PMNL function by HMPS activity and bactericidal assay. In addition, a functional impairment in PMNL exposed to various antimetabolites occurred at a time when they exhibited normal morphology.


An immunohistological study of steroid localization in Sertoli-Leydig tumors of the ovary and testis. Nine ovarian Sertoli-Leydig tumors, showing varying degrees of differentiation, one pure ovarian Sertoli cell tumor, and one poorly differentiated stromal tumor of the testis, were examined for the presence of testosterone, estradiol and progesterone with an indirect immunoperoxidase method on formalin fixed paraffin embedded tissue. Clinically all nine patients with Sertoli-Leydig tumors had evidence of increased androgen production, manifested by either hirsutism or virilization; elevated serum testosterone was found in all four patients in whom it was measured. The patients with the pure ovarian Sertoli cell and testicular tumors were asymptomatic except for the presence of a mass. Testosterone was identified in Leydig cells in nine instances, in Sertoli cells in six, and in poorly differentiated spindle cells resembling the mesenchyme of the embryonic gonad in two. Cells with vacuolated cytoplasm, both Sertoli and Leydig cells, though positive for lipid were consistently negative for testosterone. Estradiol was present in Leydig cells in nine instances, in Sertoli cells in five, and in primitive gonadal stomal cells in two. The pattern of distribution was similar to that of testosterone but the intensity of the reaction for estradiol was generally less than that for testosterone. Progesterone was identified in Sertoli cells in one instance and was weakly positive in Leydig cells in three instances. The presence of testosterone and estradiol in both Sertoli and Leydig cells as well as in primitive spindle cells resembling those found in the embryonic gonad suggests that the latter cell is the precursor for both Sertoli and Leydig cells.


Ultrastructure of cerebellar hemangioblastoma. Light and ultrastructural features of a cerebellar hemangioblastoma in a 56-year-old man are described in detail. The neoplasm was composed of three major cell types: endothelial cells, pericytes, and stromal cells. The endothelial cells lined the fenestrated vascular channels. The pericytes were ensheathed by their own basal lamina which separated them from the basal lamina covering the endothelium. The stromal cells contained, in addition to the conventional organelles, numerous membrane-bound lipid inclusions, annulate lamellae, and nuclear bodies. There were also present transitional cells which shared the fine structure of all the three major cell types. Histogenetically, the tumor was considered to be of vascular origin. The stromal cells represented the stem cells which, under the neoplastic influence, continued to proliferate and differentiate into "vasoformative" elements (pericytes and endothelium) which formed new blood vessels. The transitional forms between the stromal cells and the "vasoformative" elements suggested that the cellular components of a hemangioblastoma shared a common ancestry, most likely of an angioblastic lineage.


Carcinoembryonic antigen and other tumor markers in tissue and serum or plasma of patients with primary mammary carcinoma. 50 patients with primary breast cancer were studied to determine the CEA and HCG contents in their tumor cells before any treatment was initiated. Tumor cells were obtained by needle biopsy and each tumor cell population was stained by immunofluorescence. In 21 of the 50 patients, CEA containing cells were found in a frequency ranging from 5 to 80% of the tumor cell population. The results were confirmed by radioimmunoassay of tumor extracts. No apparent relation was seen to cytologic type or grade of differentiation. HCG was detected by IF in 4 tumors with an apocrine cytologic cell type. The level of CEA in plasma was determined before treatment and followed for 2-6 months in 72 patients. CEA was the only measured serum parameter that correlated initially with size and extent of the localized tumor. It was too low to be of use for monitoring primary disease, but should be of value in early detection of metastasis. Posttreatment a low or decreased plasma CEA was seen more often in patients who had had curative treatment than in those given palliative radiation. No raised serum HCG levels were found. Raised serum liver enzymes did not predict the extent of the primary tumor but may be an indication of distant spread. Tumor CEA content and CEA plasma concentration were correlated, although not very strongly. This means that CEA, although present in the tumor, is not always released in measurable amounts.


Squamous cell carcinoma of the cecum: a case report. Squamous cell carcinoma of the colon is a distinctly rare entity. Squamous cell carcinoma and adenoacanthoma occur in the colon and upper rectum 0.05% as frequently as adenocarcinoma. Squamous cell carcinoma of the cecum is an even rarer entity, this case appearing to be the seventh recorded case. A review of the literature concerning this topic is included in this report.


Bowenoid papulosis of the penis.

Bowenoid papulosis of the penis. During the past 18 months we have studied 36 biopsy specimens taken from 11 young men ranging in age from 21 to 36, each of whom had multiple, reddish to violaceous papules, some distinctly verrucoid or velvety on either or both the shaft and glans of the penis. The clinical diagnoses accompanying the biopsy specimens were lichen planus, psoriasis and condyloma acuminatum. In no instance was carcinomia in situ suggested in the differential diagnosis. Histologically, however, all specimens submitted showed indubitable changes of squamous cell carcinoma in situ.


Inverted papilloma and papillary transitional cell carcinoma of urinary bladder: report of four cases of inverted papilloma, one showing papillary malignant transformation and review of the literature. Four new cases of inverted urothelial papillomas are described and added to the 47 cases previously reported in the literature. Three papillomas present benign gross and microscopic characteristics. The fourth case, however, demonstrates inverted papilloma and papillary transitional cell carcinoma in a single polypoid lesion. This papillary malignant transformation, not previously observed in inverted papillomas, cautions against overconfidence in benign nature of inverted papilloma.


Primary hyperparathyroidism and chronic lymphocytic leukemia. Although hypercalcemia is a frequent event during the course of many malignancies it has only rarely been described with patients with chronic lymphocytic leukemia. Review of the literature revealed only eleven such case reports. The mechanism of the hypercalcemia in these patients was generally unclear although one patient was found to have a parathyroid adenoma and in another patient tested the level of osteoclast activating factor was high. Two additional chronic lymphocytic leukemia patients with hypercalcemia are described in this report and in each a parathyroid adenoma was found. The patient in whom the diagnosis was made ante mortem had an excellent response to parathyroidectomy. Osteoclast activating factor level was measured in one patient and found to be within normal limits. Since three of the thirteen reported cases of chronic lymphocytic leukemia with hypercalcemia have demonstrated parathyroid adenomas, it is suggested that consideration be given to that possibility in such patients so that appropriate surgery may be done.


Acute cardiac toxicity of antineoplastic agents as the first manifestation of pheochromocytoma. A 47-year-old male with histiocytic lymphoma and no previous history of heart disease developed significant fluctuations of blood pressure, electrocardiographic evidence of myocardial ischemia, and life-threatening arrhythmia after the first dose of BACOP (bleomycin, adriamycin, cyclophosphamide, Oncovin, and prednisone) chemotherapy. The presence of pheochromocytoma was suspected, and it was demonstrated by elevated urinary metanephrines, catecholamines, and vanillylmandelic acid, and finally confirmed on autopsy. The possible role of chemotherapeutic agents in stimulating excessive catecholamine release, thus causing transient cardiac injury, is suggested.


Subdural hematoma secondary to metastatic neoplasm: report of two cases and a review of the literature. Subdural hematoma secondary to dural metastases is a rare event. Vascular obstruction due to invasion of dural vessels is an important etiological factor. When this is associated with a clotting defect, the subdural hematoma can cause significant clinical symptoms and death. Two cases are presented with a review of the literature.


Primary gastric malignant lymphoma followed by gastric adenocarcinoma: report of 4 cases and review of the literature. Four cases of primary gastric malignant lymphoma followed years later by adenocarcinoma of the stomach are described. Review of the literature revealed eleven other cases of these two lesions occurring in the same patient. In our four cases gastric adenocarcinoma developed many years after successful treatment of primary gastric lymphoma by partial gastrectomy. In three patients gastrectomy had been followed by radiation treatment to the upper abdomen. The relationship between the two tumors is discussed, including the possible role of treatment of the lymphoma in the development later of gastric adenocarcinoma. It is important to consider the possibility of the later development of a second primary gastric cancer in a patient who develops gastric symptoms, after successful treatment for primary gastric neoplasm.


Phase I study of methanesulfonamide, N-[4-(9-acridinylamino)-3-methoxyphenyl]-(m-AMSA) using a single-dose schedule. Methanesulfonamide, N-[4-(9-acridinylamino)-30methoxyphenyl]-(NSC-249992), an acridine derivative with significant antitumor activity in animal tumor systems, was administered to 29 patients in a phase I clinical trial. The dose ranged from 10 to 160 mg/m2 with a single dose given every 28 days. The toxic effects included moderate to severe leukopenia and mild thrombocytopenia. Myelosuppression was more severe in patients with prior whole abdominal or pelvic radiotherapy. Superficial phlebitis occurred when the drug was diluted in a volume of less than 500 ml of 5% dextrose in water. Antitumor activity was detected in one patient with ovarian carcinoma. Phase II studies are indicated with this compound since it has reproducible and reversible toxicity with some evidence of antitumor activity. The starting dose of the drug for phase II trials should be 120 mg/m2 as a single iv dose repeated at 4-week intervals.


An enzymatic technique for measuring N-phosphonacetyl-L-aspartic acid in tissues. An enzymatic technique is presented for measuring N-phosphonacetyl-L-aspartic acid (PALA; NSC-224131) in biologic specimens. Tightly bound PALA is quantitatively detached from its target enzyme, L-aspartic acid transcarbamylase (ATCase), by heating at 95 degrees C for 5 minutes. Denatured proteins are removed by centrifugation. PALA in the supernatant fluid is quantitated by exposing intact splenic ATCase to representative aliquots or subdilutions of the resultant supernatant in the presence of L-[4-14C]aspartic acid and carbamyl phosphate. After 30 minutes' incubation at 37 degrees C, unreacted L-[4-14 C]aspartic acid is dissipated enzymatically and newly formed [4-14C]carbamyl-L-aspartic acid is quantitated by scintillation spectrometry. The percentage inhibition of ATCase responds in a linear way to the logarithm of the concentration of PALA between 0.10 and 1.00 micrometer. The PALA concentration of an unknown is determined indirectly by matching the percentage inhibition caused by the unknown to the inhibition caused by a known series of standard concentrations of PALA over the linear range. This assay is sensitive, adequately reproducible despite the use of an unpurified enzyme, and notably facile. It can be used to measure PALA in plasma, urine, tissues, and tumors of subjects treated with this new oncolytic drug.


Phase I clinical study of quelamycin.

Phase I clinical study of quelamycin. A phase I clinical study was done with quelamycin, a recently synthesized triferric derivative of adriamycin. Twenty-one good-risk patients were studied: 19 patients with non-small cell carcinoma of the lung and two patients with metastatic sarcoma. Acute toxicity occurred in all patients and consisted of high fever, flushing, hypertension, generalized body aches, tremors, and confusion, which lasted 3-6 hours. Potentially dangerous cardiotoxicity occurred in eight patients who had previous minor rhythm disturbances, and was characterized by tachycardia, atrial extrasystoles, atrial fibrillation, and branch block which lasted 6-14 hours. The dose-limiting hematologic toxicity was found to occur at 125 mg/m2 iv single-dose. Objective responses were observed in three of 19 patients with lung cancer and in one patient with metastatic osteogenic sarcoma resistant to adriamycin therapy. In conclusion, quelamycin is a new derivative of adriamycin with potential interest. However, the acute generalized toxicity and the immediate cardiotoxicity found in the presently used schedule are excessive. Further studies directed to suppress these side effects are in progress.


Clinical phase I-II study of cis-dichloro-diammineplatinum(II) given by continuous lv infusion. To determine the efficacy and toxicity of cis-dichlorodiammineplatinum(II) (DDP) by a continuous iv infusion (CIVI) schedule, 34 patients with a variety of solid tumors were studied. All patients were refractory to prior chemotherapy and received a loading dose of 5 mg/m2 of DDP iv followed by 20 mg/m2 by CIVI daily for 5 days. In 25 evaluable patients, there were four (16%) complete or partial responders, nine (25%) with stable disease, and 12 (48%) with tumor progression. One complete and one partial remission were seen in two patients with disseminated basal cell carcinoma, with partial responses also seen in cervical and head and neck squamous cancer. Patients experienced renal damage (21%) and audiotoxicity (10%). Nausea and vomiting was severe in only 6%. DDP by CIVI appears to have comparable toxicity to DDP administered by other schedules; however, the diminished gastrointestinal toxicity makes the drug better tolerated by patients for whom the inconvenience of a 5-day hospitalization is less than that caused by the nausea and vomiting of rapid infusion programs.


Clinical trial of rubidazone in advanced squamous cell carcinoma of the lung and adenocarcinoma of the large intestine. Sixteen patients with disseminated squamous cell carcinoma of the lung  and 26 patients with adenocarcinoma of the colon and rectum were given rubidazone. Only one partial remission was observed in a previously untreated patient who had local recurrence of a rectal adenocarcinoma. The main toxic effects observed in previously treated patients consisted of leukopenia and thrombocytopenia. Also observed were anorexia, nausea, vomiting, alopecia, fever, and chills. Cardiotoxicity was observed in one patient after a total dose of 720 mg/m2 of rubidazone. It is concluded that rubidazone is a relatively inactive compound in the management of these two diseases.


Chemotherapy for colorectal cancer with 5-fluorouracil, cyclophosphamide, and CCNU: comparison of oral and continuous iv administration of 5-fluorouracil. Forty-six adult patients with colorectal cancer were treated with cyclophosphamide and CCNU administered orally and 5-fluorouracil (5-FU) administered either orally or by continuous iv infusion (FCC-CIF), depending on the availability of hospital beds. The overall response rate in 37 patients with measurable disease was 25%. The response was greater in patients who had had no prior treatment (seven of 20 versus two of 17) and in patients treated with FCC-CIF (six of 19 versus three of 18). Among patients receiving FCC-CIF,  response was also greater in those who had received no prior therapy (five of nine versus one of ten). The overall median survival was 7.5 months, regardless of the route of administration of 5-FU. Further investigations are indicated to study the efficacy of 5-FU administered by continuous iv infusion in combination with other agents in patients who have had no prior treatment.


The physiologic basis for early ambulation after myocardial infarction. Early ambulation is a recommended component of care for appropriately selected patients with uncomplicated myocardial infarction, which is feasible, safe, and cost-effective. Benefits of this approach include the prevention of cardiovascular "deconditioning" and other complications of prolonged bed rest, the prevention or reduction of anxiety and depression, the enhancement of physical work capacity and of self-image and self-confidence at the time of hospital discharge, and the lessening of total disability as assessed at followup examination. Economic advantages to be derived are those of permitting a shorter hospitalization, a more effective hospital bed utilization, and an earlier and more complete return to work.


Demonstration of the display of components of the endoplasmic reticulum system by indirect immunofluorescence microscopy using antibodies against cytochrome b(5) from rat liver microsomes. Antibodies against the purified fragment of cytochrome b(5) released by trypsin treatment from rat liver microsomes were raised in rabbits and used for the demonstration of membranes rich in cytochrome b(5), in particular the endoplasmic reticulum (ER) system, by indirect immunofluorescence microscopy. The method allowed the demonstration of ER not only in frozen sections of various tissues, including liver and lactating mammary gland from different species, but also in cultured cells of a diversity of species and cell types. In the cultured cells the structures most prominently decorated with the antibodies against cytochrome b(5) were the nuclear envelope and the ER system which in many cells could be recognized as a system of smoothly bending, branching threads, extending from the perinuclear cytoplasm toward the cell periphery. Changes in the display of such elements during mitosis and cell plating and possible influences of the specific fixations used are discussed.


In vitro effects of methyprednisolone sodium succinate and E coli organisms on neutrophils in baboon blood. The corticosteroid methylprednisolone sodium succinate (MP) has been observed to prevent hypoglycemia in experimental septic shock; however, detrimental actions of various corticosteroids on polymorphonuclear leukocyte function have been reported. The present study was designed to determine if MP depresses glucose metabolism of leukocytes or adversely affects neutrophil survival, or whether it modifies the mortality rate of live E coli in baboon blood in vitro. Results show that therapeutically effective concentrations (13 micrograms/ml blood) and high doses (130 micrograms/ml blood) of MP exert no detrimental influences on glucose utilization or survival of neutrophils in the absence or presence of E coli organisms in concentrations of 4.2 x 10(7) and 2.3 x 10(8) organisms per milliliter blood. However, E coli organisms increase neutrophil mortality rate and glucose uptake of the blood. These findings support the view that MP does not adversely influence leukocyte metabolism and survival, nor does it modify the mortality rate of live E coli.


Asymptomatic coronary artery disease: angiographic assessment of diabetics evaluated for renal transplantation. Twenty-one insulin-dependent diabetics with azotemic nephropathy were evaluated for renal transplantation by selective coronary angiography and cine left ventriculography. All had hypertension, retinopathy, neuropathy, and required salt restriction plus diuretics for volume overload. There was no clinical or electrocardiographic evidence of ischemic coronary artery disease in twenty. Ten patients (five males, five females, mean age 29.3 years; mean duration of diabetes 21.9 years; mean serum cholesterol 239 mg%) had significant coronary artery disease, seven demonstrating focal abnormalities in left ventricular wall motion. Two patients (one male, one female; mean age 36.5 years; mean duration of diabetes 28.5 years; mean serum cholesterol 250 mg%) had no significant coronary artery disease, but demonstrated diffusely abnormal left ventricular wall motion with diminished ejection fraction. Thirty-eight percent had significant coronary artery disease unpredictable by electrocardiographic or clinical data. The finding of no significant coronary artery disease in 52% of a group with severe renal-hypertensive complications of diabetes is surprising. Two patients may have a demonstrated cardiomyopathy.


Cardiac effects of acute ethanol ingestion unmasked by autonomic blockade. We assessed the effects of ethanol and autonomic blockade on left ventricular function in nine normal subjects, age 20--35 years, using M-mode echocardiography and systolic time intervals. On day 1, measurements were made of heart rate, mean velocity of circumferential fiber shortening, and left ventricular pre-ejection period and left ventricular ejection time ratio (PEP/LVET), during a control period and after autonomic blockade. Autonomic blockade was produced with intravenous propranolol (0.2 mg/kg body weight) and atropine (0.04 mg/kg body weight). On day two, measurements were again made during a control period, then with ethanol alone, followed by addition of autonomic blockade to ethanol. One hundred eighty milliliters of ethanol were ingested over 60 minutes, resulting in a mean blood ethanol level of 110 mg/dl (range 77--135 mg/dl) at 60 minutes post-ingestion. There were no significant differences between the control data on days 1 and 2. Blood pressure was unchanged throughout the study. study. On day 1, autonomic blockade alone resulted in the expected increase in heart rate (p less than 0.001), with a proportional increase in mean velocity of circumferential fibr shortening (p less than 0.01), and an increase in PEP/LVET (p less than 0.01). On day 2, ethanol alone resulted in no significant changes except for a slight increase in PEP/LVET (p less than 0.02). Ethanol plus autonomic blockade, (day 2), compared with autonomic blockade alone (day 1), revealed a decrease in mean velocity of circumferential fiber shortening (p less than 0.05), and an increase in PEP/LVET (p less than 0.01), with a decrease in intrinsic heart rate (p less than 0.001). We conclude that in normal subjects: 1) autonomic blockade does not directly affect contractility; 2) acute ethanol ingestion alone does not produce important changes in cardiac function; and, 3) ethanol in the autonomic blockaded heart causes a significant decrease in contractility. Thus, we infer that ethanol has a negative inotropic effect which is masked by catecholamines and/or autonomic nervous system discharge.


Double-blind trial comparing flunisolide and placebo for the treatment of perennial rhinitis. The effectiveness of a new topical steroid, flunisolide, was evaluated for the treatment of patients with perennial rhinitis. The sixty-nine patients in this 8 week double-blind parallel trial received either 300 microgram/day of flunisolide or placebo. The flunisolide group showed statistically greater improvement than the placebo group in such symptoms as the duration of sneezing, stuffy nose, runny nose and nose blowing. 63% of the flunisolide group compared with 39% of the placebo group felt the test spray had provided substantial or total control of their nasal symptoms (P = 0.0026). When those patients who were skin test-positive (allergic) were considered separately from those who were skin test-negative (non-allergic), differences in responsiveness were noted. While those patients who had negative skin tests received greater relief of their symptoms with flunisolide than with placebo, patients who had positive skin tests showed a greater responsiveness to flunisolide and reported a higher incidence of significant or total control of their symptoms. Careful monitoring of plasma cortisol levels revealed no evidence of adrenal suppression in any of the patients in this trial. This lack of suppression may be due to two factors: (a) flunisolide is rapidly metabolized into a metabolite with a low degree of activity and (b) a very low dose of corticosteroid is administered.


A clinical environmental study of the aeroallergens of the islands of Bermuda. The major allergen responsible for allergic respiratory disease in the islands of Bermuda has been shown to be derived from Dermatophagoides pteronyssinus. 73% of the atopic group included in the survey gave weal and erythema reactions to extracts of this mite, whereas only 30% reacted to mixed pollen extracts and 10% to mould extracts. D. pteronyssinus was isolated from all house dust samples and it represented nature, with only a modest seasonal influence, and pollen counts were low throughout the year.


Fungal spores in lung and sputum.

Fungal spores in lung and sputum. A survey of fungal aerospora over a 2-year period was combined with an investigation of the fungi cultured from 295 samples of peripheral human lung and 2466 samples of sputum over the same period. 83% of lung and 88% of sputum samples contained culturable fungi, although in 16% of lung and 31% of sputum samples Candida albicans was the only one. Those fungi of small spore size tended to be found in lung tissue while those with larger spores were more likely to be found in the sputum. While their presence in the respiratory tract was related to their occurrence in the air, differences in their frequencies in the air and lung suggested that the lung had a selective inhibitory effect on the development of different spores. In particular, Aspergillus fumigatus was cultured more frequently than would have been anticipated from its profusion in the air.


The diagnostic value of antibodies to the traditional antigens of farmer's lung in Finland. Precipitating antibodies towards antigens associated with farmer's lung disease were studied in Finnish dairy farming and non-farming rural populations and the results were compared to those of serum samples of patients suspected of having a fungal allergy. The antigen panel consisted of Aspergillus fumigatus, Micropolyspora faeni and Thermoactinomyces vulgaris. All three microbes seemed to be important environmental inducers of antibody formation. The prevalence of antibodies towards all of them was higher in the patient group. The presence of A. fumigatus and T. vulgaris antibodies correlated best with the occurrence of respiratory disease. The difference in M. faeni antibody prevalence between patients and the control group was less significant. The results suggest that in Finland the relative importance of those microorganisms associated with farmer's lung disease may be different from that reported from other countries.


Evaluation of EMIT methods for the determination of the five major antiepileptic drugs on an automated kinetic analyser. We have evaluated the performance of enzyme-multipled immunoassay methods for the five major antiepileptic drugs on an automated system, the Perkin-Elmer Model KA-150 Kinetic Analyzer. The precision in the normal duplicate mode was found to be in the range of 6% to 10% for all five tests over a typical working day. All EMIT methods were compared to gas-liquid chromatographic procedures and, in addition, the phenytoin and phenobarbital assays were compared to a liquid-chromatographic method. The phenytoin assay was also compared to RIA and to a manual spectroscopic method. In general, most of the comparison studies resulted in acceptable correlation, although one gas chromatographic method did not correlate very well with the phenytoin and phenobarbital immunoassays.


A comparison of the "EMIT" assay with two iodinated radioimmunoassays for diphenylhydantoin. In the treatment of epilepsy, it is important for the laboratory to provide blood diphenylhydantoin levels accurately and quickly. However, physicians have often obtained laboratory results which have been inconsistent with the patient's clinical condition. We examined the "Enzyme Multiplied Immuno Technique" (EMIT) and two iodinated radioimmunoassay procedures for their suitability to provide quick and accurate blood diphenylhydantoin levels in laboratories that perform relatively few assays. The results indicated that all three procedures can be used with reasonable success. We found that the simplicity and the long shelf-life of the EMIT procedure made it very desirable for institutions that have a small volume of diphenylhydantoin assays.


Enzyme immunoassay for gentamicin.

Enzyme immunoassay for gentamicin. We describe a gentamicin assay in which a peroxidase-gentamicin conjugate competes with gentamicin for binding to a gentamicin antibody adsorbed to a polystyrene solid phase. The assay can be completed in 30 min and requires 50 microliter of diluted serum. The precision and accuracy are equivalent to that of a radioimmunoassay technique and the reagents are stable for several months.


Enzyme immunoassay and gas--liquid chromatography compared for determination of lidocaine in serum. Lidocaine, an anti-arrhythmic drug, was quantitated in serum by a commercially supplied enzyme immunoassay procedure. Replicate analyses of serum controls resulted in a within-assay coefficient of variation of less than 5.0 and a  between-assay coefficient of variation of less than 6.5. Regression analysis of 87 serum samples analyzed by this technique (y) and by gas-liquid chromatography (x) gave the equation y = 0.96x - 0.03 (r = 0.99). Clinical evaluation of the results indicates the enzyme immunoassay technique to be highly specific and sensitive for lidocaine.


Enzyme immunoassay for total oestrogens in pregnancy plasma or serum. We have developed an enzyme immunoassay for total oestrogens in pregnancy serum of plasma, using horseradish peroxidase (HRP) as the marker enzyme. A test combination consisting of an antiserum against oestriol-16/17-monosuccinyl-albumin and oestriol-16/17-monosuccinyl-HRP yielded a sensitive system, which reacted to approximately the same extent with oestrone, oestradiol, oestriol and their 16- and 17-conjugates. Samples had to be diluted 1 to 10 to avoid interference of plasma factors with the immune reaction. Bound/free separation was achieved with the double antibody solid phase (DASP) method. The HRP activity of the bound fraction was measured, after washing, to eliminate plasma factors disturbing the HRP reaction. The detection limit of the assay system was approx. 0.1 pmol/tube, while the index of precision lambda ranged from 0.02 to 0.06. To measure total oestrogens, including the 3-conjugated ones, we used an enzymatic hydrolysis with an extract of Helix pomatia. Hydrolysis was found to be optimal after 1 h at 50 degrees C and pH 5.0. The method was used on serum samples from normal pregnancies. The results showed a very good correlation (r=0.98) with those obtained by radioimmunoassay. Normal values for total oestrogens during pregnancy were determined in a multicentre clinical trial.


alpha-glucosidase activity in human leucocytes: choice of lymphocytes for the diagnosis of Pompe's disease and the carrier state. alpha-Glucosidase activity was assayed in polymorphonuclear cells and lymphocytes from human peripheral blood with 4-methylumbelliferyl-alpha-D-glucopyranoside as substrate in the presence of sodium taurocholate. The pH vs. activity curve of the alpha-glucosidase indicated that differential estimation between acid and neutral alpha-glucosidases was difficult to perform with polymorphonuclear cells, but easily accessible with lymphocytes. The use of peripheral blood lymphocytes for the enzymatic diagnosis of Pompe's disease seemed to be more reliable than the use of whole leucocytes; this also the case with a classical Pompe's patient. The lymphocytes from the parents had normal or low normal activity of acid alpha-glucosidase in the freshly isolated state, but when cultured with phytohaemagglutinin for 72 h, the stimulated lymphocytes of both parents showed about half the enzyme activity of the cultured controls. It was deemed possible in all probability to identify the carrier state by assay of the enzyme activity in phytohaemagglutinin-stimulated lymphocytes.


A micromethod for simultaneous estimation of blood levels of some commonly used antiepileptic drugs. The analysis of serum samples for the antiepileptic drugs carbamazepine, phenobarbital and phenytoin by a simple extraction technique and chromatographic analysis by high-pressure liquid chromatography is described. The method is a micro one which correlates well with gas-liquid chromatographic procedures. Coefficients of variation are smaller than 3%.