Comparative study on antitumor effect of cell-wall skeleton of Mycobacterium bovis BCG and Nocardia rubra, with reference to T-cell dependency and independency. Antitumor activity induced by the oil-attached cell-wall skeleton of Nocardia rubra (N-CWS) was compared with that of the oil-attached cell-wall skeleton of Mycobacterium bovis BCG (BCG-CWS) in syngeneic BALB/c tumor-host systems. In normal BALB/c mice (+/+), N-CWS exhibited stronger suppressive effect on syngeneic Br-1 and MCA tumors than did BCG-CWS. In athymic nude mice (nu/nu), BCG-CWS was as effective as N-CWS for the suppression of growth of such tumors. Suppressive effect of N-CWS treatment appears to be stronger to some extent in +/+ mice than in nu/nu mice. Immune spleen cells obtained from +/+ mice after footpad inoculation of MCA tumor cells mixed with N-CWS were effective in suppressing the MCA tumor growth, although those obtained from mice after inoculation of MCA tumor cells mixed with BCG-CWS did not exhibit a suppressive effect. This antitumor activity of immune spleen cells may be attributed to tumor-specific killer T cells. The differences of antitumor activities induced by these agents were discussed with reference to T-cell dependency and independency.


Effect of coadministration of uracil or cytosine on the anti-tumor activity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents. Concentration of 5-fluorouracil (5-FU) in the tumor, blood, and various organs of AH130-bearing rats after administration of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and uracil was examined. The concentration of 5-FU in blood was less than 0.02 microgram/ml with all combinations of FT-207 and uracil except high molar ratios of uracil to FT-207 (ratio, 5 and 10), whereas high concentrations of up to a maximum of 0.200 microgram/g on administration of uracil plus 5 or 7.5 mg/kg of FT-207 (ratio, 4), was found in the tumor. On oral administration of FT-207 plus uracil in various combinations, the highest T/B (ratio of concentration of 5-FU in the tumor to that in blood) value was obtained at a ratio of uracil to FT-207 of 4. With this combination, 5-FU concentration in the tumor, muscle, and spleen was higher than that after administration of FT-207 alone (5 mg/kg). These results suggest that at the clinical doses the optimum molar ratio of uracil to FT-207 is 4. Coadministration of cytosine enhanced the antitumor activity of FT-207 on sarcoma-180 in mice. However, cytosine enhanced the antitumor activity of FT-207 less than uracil and its coadministration resulted in a lower concentration of 5-FU in the tumor than coadministration of uracil.


Activation of peritoneal macrophages by oil-attached cell-wall skeleton of BCG and Nocardia rubra. The effect of oil-attached cell-wall skeletons of BCG (BCG-CWS) and Nocardia rubra (N. rubra-CWS) on macrophage functions was examined regarding phagocytosis of zymosan particles, uptake of 2-deoxy-D-glucose (2-dG), and cytostatic activity against syngeneic tumor cells. A single intraperitoneal injection of either BCG-CWS or N. rubra-CWS in mice resulted in accumulation of a large number of macrophages in the peritoneal cavity. They demonstrated, in vitro, a significant cytostatic effect on target cells as well as increase in phagocytic activity and uptake of 2-dG. These results suggest that one of underlying mechanisms for the antitumor activity of BCG-CWS and N. rubra-CWS is possibly the activated macrophage-mediated system.


Antigen characteristics of nitrosamine-induced urinary bladder cancer in rats. Antigens expressed on urinary bladder cancer cells of transplantation and tissue culture lines, which originated in tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in individual ACI/N rats, were studied by several immunological methods. Tumor-specific transplantation antigen was determined by transplantability of cancer cells into syngeneic rats which had been immunized with the respective cancer cells by the ligation-and-release method. Two out of 6 bladder cancer lines showed high antigenicity but antigenicities of the other 4 lines were of low or undetectable level. Cross resistance was observed in the transplantation immunity among the 2 high antigenic lines but not in the other lines. Cell-mediated cytotoxicity was assayed by the microtestplate method. The lymphoid cells from ACI rats hyper-immunized with cancer cells of a high antigenic line showed a marked cytotoxicity against cancer cells of the immunizing line but not to cells of the other bladder cancer lines including another high antigenic line that induced a cross resistance in transplantation immunity. Tumor-associated cell-surface antigen was detected by membrane immunofluorescence test with serum which was raised in allogeneic Donryu rat by the high antigenic bladder cancer and absorbed with normal ACI rat tissues. The absorbed serum gave positive membrane fluorescence to cancer cells of the immunizing line and 2 other bladder cancer lines but not to cells of other 4 bladder lines and ACI tumors other than bladder cancer. The common antigen detected by the serological method was not reflected either in transplantation immunity or cell-mediated cytotoxicity of the immune lymphoid cells.


Cimetidine in the treatment of acute alcoholic pancreatitis. A randomized, double-blind study. A double-blind study was made of the comparative effectiveness of cimetidine in the treatment of acute alcoholic pancreatitis. The study group was composed of 27 patients with acute episodes of alcoholic pancreatitis of mild to moderate severity. The patients were randomized into 2 groups, either receiving cimetidine, 300 mg four times daily or a placebo. Both groups were given intravenous fluids and meperidine hydrochloride (Demerol) as needed. There were no significant differences between the 2 groups as measured by a variety of clinical and laboratory parameters. The mean value of the daily serum amylase in the placebo group declined steadily to normal; hyperamylasemia in this group persisted for 52 +/- 11 hr (mean +/- SE). By contrast, serum amylase in the cimetidine group peaked at 24 hr after the start of treatment and remained abnormal slightly longer; the duration of hyperamylasemia in the group was 69 +/- 10 hr. It is concluded that: (1) cimetidine is not superior to a placebo in the management of mild to moderately severe acute alcoholic pancreatitis and (2) serum amylase activity in patients with acute alcoholic pancreatitis given cimetidine tends to be greater and hyperamylasemia is of somewhat longer duration than in those treated with a placebo.


Cimetidine versus antacid in scleroderma with reflux esophagitis. A randomized double-blind controlled study. The effectiveness of cimetidine vs. antacid in the treatment of patients with scleroderma and symptomatic reflux esophagitis was studied in a double-blind cross-over controlled trial. Fifteen patients were initially randomized to either cimetidine (300 mg four times daily) with placebo antacid, or placebo tablet (1 four times daily) with Mylanta II (30 ml four times daily and PRN). After 8 wk of therapy on the initial regimen, each patient was crossed over to the alternate regimen for an additional 8 wk of therapy. The severity of symptoms during each treatment period was estimated by patient interviews and changes in esophagitis were evaluated endoscopically. Cimetidine gave significantly greater relief of heartburn than antacid regardless of the initial randomization. Cimetidine also resulted in significant endoscopic improvement of the esophageal mucosa whereas antacid was without effect. Neither cimetidine nor antacid produced any improvement in esophageal stricture size or lower esophageal sphincter pressure. Cimetidine was without toxicity whereas antacid therapy frequently produced diarrhea.


Clinical features and natural history of Crohn's disease. Records of 1084 patients entered into the National Cooperative Crohn's Disease Study were analyzed to gather information concerning the natural history and clinical features of Crohn's disease. The age of onset reached a single peak between the second and fourth decade and was evenly distributed in both sexes. There was an average interval of 35 mo from onset of symptoms to diagnosis. Involvement of both colon and terminal ileum was the most frequent pattern and was present in 55% of patients. The disease was confined to the terminal ileum, other areas of the small intestine, or colon-only in 14%, 3%, and 15% of patients, respectively. Sigmoidoscopic abnormalities were seen in 34% of all patients and 51% of patients with Crohn's colitis. Diarrhea, abdominal pain, weight loss, and fever were present in the majority of the patients. Lower GI bleeding, fever, and perianal complications characterized patients with colon-only involvement. The frequency of extra intestinal manifestations was similar in all groups. Among patients who were randomized to placebo, 32% achieved a spontaneous remission by the end of 17 wk, and 53% of these were still in remission at the end of 24 mo. Clinical remission was associated with an improvement in barium x-rays in 18% of the patients. The predicted factors associated with favorable outcome in placebo-treated patients were: previous surgical removal of all observable disease, absence of perianal disease, and Crohn's Disease Activity Index value under 200.


[Shute's suture in mediolateral episiotomy. A technique with many advantages (author's transl)]. A comparison of median with mediolateral episiotomy shows that mediolateral episiotomy offers notable advantages resulting naturally from its anatomical course and the possibility of eventual distension. -- The Shute seam is described as a suturing technique in episiotomy still largely unknown in Europe. Apart from easy and rapid suturing and much cleaner wound healing it offers the advantage of significant reduction of pain during childbed with very satisfactory functional and cosmetic results. -- Reduction of wound pain seems to be a decisive factor for the woman in childbed, especially in view of subsequent births, thus making it easier for the obstetrician to obtain the patient's consent for performing episiotomy.


[Yeast resistance to polyene antibiotics. I. Production of Saccharomyces cerevisiae mutants resistant to nystatin and their genetic analysis]. 239 nistatin-resistant mutants were selected after UV-irradiation of yeasts. Phenotypical analysis has revealed two main groups of the mutants: 1) resistant to nistatin and resistant or sensitive (in different combinations) to haptaens; 2) resistant to nistatin and having an increased resistance to haptens. It is found that the sensitivity dominates over the resistance and hyper-resistance. Genetic analysis of the mutant collection has shown that the resistance to nistatin is determined by 5 nuclear genes (hysr). Hyper-resistance is controlled by mutations in other genes, which are not connected with stable phenotype. Genes of hyper-resistance can be considered as minus-modificators of pleiothrophic cross-resistance, characteristic of hysr genes. Plus-modificator genes of polyenic resistance are described. The gene hysr1 is linked with its chromosome.


[UV-induced DNA degradation in Aspergillus nidulans cells]. UV-induced DNA degradation was studied in mycellial cells of Aspergillus nidulans wild type and several uvs mutants. It was shown to be an enzymatic specific process which possibly reflects the excision of pyrimidine dimers from UV-damaged DNA. Inhibition of DNA degradation by caffeine and 2,4-dinitrophenol shows the connection between degradation and repair of DNA. Two ways of DNA degradation were found in A. nidulans cells, one of them being glucose dependent and the other--glucose independent. The dependence of DNA degradation on protein synthesis before and after UV-irradiation was demonstrated. The scheme of ways of DNA degradation and its genetic control were suggested on the basis of uvs mutations effect on UV-induced DNA degradation.


[Genetic effects of sulfur-35 decay in Saccharomyces cerevisiae cells. V. Comparative study of the lethal and mutagenic effectiveness of the decay of 35S and 32P incorporated into cells of the radiosensitive mutant xrs2]. The lethal effect of 35S and 32P decays on cells of yeast radiation-sensitive mutant xrs2 was studied. The mutant is 7 times more sensitive than the wild type to transmutation of both isotopes. The survival curve for xrs2 was exponential. In spite of the lethal effect, mutant cells are not more mutable than the wild type under decays of both isotopes (the number of mutations in ade1 and ade2 genes was counted), xrs2 and wild type strains differ in kinds of mutations induced by the decay of incorporated 35S in ade2 locus. Namely, there are 82% of base substitutions and 18% of other types mutations induced in xrs2 strain despite 97% and 3% respectively for the wild type strain. Also it was shown that complete and mosaic mutants, induced by the the 35S decay in xrs2 strain, differ in a pattern of interallelic complementation.


[Control of plasmid incompatibility: characteristics of the bireplicon hybrid pAS8 and its deletion mutants]. The phenomenon of incompatibility has been investigated using deletion mutants of hybrid bireplicon plasmid pAS8. The hybrid pAS8 displays incompatibility specific for both components of its structure. In contrast to P-specificity of pAS8, functions of ColE1-specificity are not effectively expressed. Expression of ColE1-specificity in pAS8 plasmid and its derivatives is characterized by different directions and this is due to the presence or absence of genes of RP4 replication machinery in the plasmid DNA. Mutant plasmids show different efficiency of P-specificity depending on the extension of deletion in the region of essential genes of the RP4 component. Some of the mutants, in spite of the loss of replication genes, including origin of vegetative replication, are incompatible with the representatives of the Inc P group in both directions of testing. Different character and the level of expression of ColE1- and P-specificity in the pAS8 hybrid and its deletion derivatives are not associated with change in the number of plasmid DNA copies, for all of them are subjects to stringent control of replication. The data suggest the existence of incompatibility functions control mechanism which does not seem to include replication genes. Possible ways of realization of the inc genes functions are discussed.


Cloning and endonuclease restriction analysis of argF and of the control region of the argECBH bipolar operon in Escherichia coli. A 1.8 kb DNA fragment, liberated by endonuclease HindIII, contains the control region of the argECBH bipolar operon near one end and the weak secondary promoter of argH at the other extremity; it has been cloned in plasmid pBR322. The same plasmid vector has been used to clone the argF gene liberated from the chromosome by endonuclease BamHI. Restriction patterns for the two hybrid plasmids have been determined, using enzymes AluI, BglI, EcoRI, HaeIII, HincII, HindIII, HpaI and II, PstI and SalI. Two AluI sites situated on either side of and close to a HincII target delineate two short fragments covering the whole of the argECBH control region. The argF control elements are located in a region accessible to further dissection by BamHI, EcoRI, PstI and HindIII. Carriers of the argF plasmid produce extremely high amounts of ornithine carbamoyltransferase, a feature useful for purification of this enzyme.


High frequency of yeast transformation by plasmids carrying part or entire 2-micron yeast plasmid. By using two chimeric plasmids containing yeast ura3 gene and 2-micron yeast DNA linked to the bacterial plasmid pCR1, yeast transformation of a high frequency has been achieved. The first plasmid is such that the 2-micron DNA part, in which the ura3 gene is incorporated, can be removed in one step and thus the 2-micron-ura3 sequence can be considered as a "transposable" block. In contrast, the second one bears the entire 2-micron plasmid and the ura3 gene is inserted in the bacterial plasmid part. As shown through hybridization experiments and genetic studies, the ura3 gene was maintained as a cytoplasmic element. Plasmids recovered from the yeast transformants were used to transform Escherichia coli. Their analysis by EcoRI showed that in many cases the vector had recombined with the endogenous 2-micron DNA of the recipient strain. The specific activity of orotidine 5'-monophosphate decarboxylase (coded by ura3) in yeast transformants was 10- to 30-fold higher than in the wild type.


A coliphage lambda vector with enhanced biological containment: lambda gtALO.lambda B. The biological containment of the lambda gt family of cloning vectors has been enhanced by conditionally blocking DNA replication as well as head and tail morphogenesis. The vector, lambda gtALO.lambda B, was constructed by crossing the Oam29, Aama1 and Lam439 mutations into lambda gt.lambda B. The mutation blocking phage DNA replication, Oam29, is suppressed by suII+ or suIII+. The head gene mutation, Aama1, is suppressed by suIII+ but not by suII+ and the tail gene mutation, Lam439, is suppressed by suII+ but not by suIII+. This allows the option of increasing the biological containment by producing heads when a large amount of cloned DNA is being prepared from an individual isolate. A model recombinant, lambda gt Aama1 Lam439 Oam29.KmR' (lambda gtALO.KmR') was constructed and the containment of the vector was evaluated by the series of standardized experiments required for EK2 certification.


Cloning and biological characterization of the immunity region of Escherichia coli phage Mu. The construction of three hybrid plasmids containing different parts of the left or immunity and end of phage Mu DNA is described. The recombinant plasmids pKN05 and pKN54 carry the HindIII.C and PstI.C fragments of Mu DNA, respectively. Neither of these plasmids expresses the killing function. Moreover, they do not allow plating of superinfecting Mu phages. Plasmid pKN62 harbors the fragment located in between the left PstI and EcoRI cleavage sites on Mu DNA, allows plating of superinfecting Mu phages, but does not express the killing function. These data suggest that the gene coding for the killing function is either positively regulated by a product from the EcoRI.C fragment, or the killing function requires a second product not coded for by pKN62. Mu Vir A- or Mu Vir B- phages are able to grow on bacteria harboring the recombinant plasmid pKN001 which carries the left and EcoRI-C fragment of Mu DNA. This indicates that the superinfecting phages can induce the corresponding gene functions from pKN001. No such induction could be detected in cells harboring the hybrid plasmids pKN05, pKN54 or pKN62.


Cloning and expression of the yeast galactokinase gene in an Escherichia coli plasmid. This report describes the construction and isolation of a plasmid, derived from pBR322, which carries a BglII restriction fragment of DNA containing the galactokinase gene from Saccharomyces cerevisiae. This was accomplished by the following procedure: (1) Purified galactokinase mRNA, labelled with 125I, was hybridized to BglII digests of yeast DNA employing Southern's filter transfer technique to identify a restriction fragment containing the galactokinase gene. (2) This fragment was partially purified by agarose gel electrophoresis, ligated into the BamHI site of pBR322 and transformed into Escherichia coli to generate a clone bank containing the galactokinase gene. (3) This bank was screened by in situ colony hybridization with galactokinase mRNA resulting in the identification of a plasmid carrying this gene. This plasmid DNA hybridized with the galactokinase mRNA to the same extent in the presence of absence of a large excess of unlabelled mRNA from cells that were not induced for galactokinase synthesis, while the same amount of unlabelled galactose-induced mRNA reduced the hybridization by 95%. When this plasmid was introduced into an E. coli strain deleted for the galactose operon it caused the synthesis of low levels of yeast galactokinase activity.


The site controlling the specificity of N action is outside the promoter-operator region: a triple hybrid phage lambda N21 imm434nin5. A short interval of homology between imm lambda, imm434 and imm21 DNAs was identified near the leftward promoter-operator region. This homology, denoted Hs, was revealed by electron microscopic examination of lambda imm lambda/lambda imm21 and lambda imm434/lambda imm21 heteroduplexes, and permitted us to construct a special lambda hybrid (lambda hyB) which contains the N region of phage 21 and the adjacent imm region from phage 434. This triple hybrid, labmda N21 imm434nin5, was analysed by genetic, transcriptional and electronic micrographic techniques. Its leftward and rightward promoter-operator regions are of phage 434 specificity and are controlled by the 434 repressor. Surprisingly, the N21 gene of lambda hyB was found to be defective, perhaps to preserve the viability of the hybrid. Its leftward N-recognition system (nutL) is of phage 21 specificity since it responds only to the N21 function in complementation tests, as measured by antitermination of leftward transcription initiated at the pL promotor in the imm434 region. We conclude, therefore, that the pLoL region of 434 contains no information for the specificity of N antitermination. Both lambda imm21 and lambda hyB were found to be missing the tL1 terminator function (see also Salstrom and Szybalski, 1978b). In these phages, the tL2 terminator was found to be only 60% effective under N21 conditions, and therefore expression of their red-gam genes is sufficient to endow the lambda hyB and lambda N21- imm21nin5 phages with the Fec+ phenotype.


Double-blind trial of the use of transfer factor in the treatment of Crohn's disease. We have undertaken a double-blind controlled trial of the use of transfer factor in Crohn's disease. Thirty-three patients with known Crohn's disease completed the trial in which half the patients had three injections of transfer factor and the other half were given saline. After six months there was no significant difference in the clinical condition of either of the two groups compared with before receiving treatment. There was also no difference in their in vitro lymphocyte function, although a number of patients exhibited altered responsiveness to skin testing with tuberculin or streptokinase/streptodornase. A signficant fall on Crohn's disease activity index score occurred over the initial 'acclimatising period' before the trial was started, probably related to overcoming initial introspection and the placebo effect of being part of a trial.


Controlled trial of maintenance cimetidine treatment in healed duodenal ulcer: short and long-term effects. Forty-two patients with endoscopically diagnosed duodenal ulcer were studied in a double-blind trial after their ulcers had been healed with cimetidine. Cimetidine was effective in preventing relapse, only five of the 20 patients allocated to cimetidine 400 mg twice daily relapsing during the six months' treatment, compared with 16 of the 22 on placebo treatment (P less than 0.01). Cimetidine was safe in the dosage and duration used, no symptomatic, haematological, or biochemical abnormalities occurring during the trial. Subsequent follow-up at the end of the trial when treatment had been stopped showed that relapse was frequent, particularly in the cimetidine group, making the cumulative relapse rate eight months after completion of the trial similar in the two groups (75% in the cimetidine group, 86% in the placebo group). It seems likely that maintenance cimetidine treatment has to be continued indefinitely in patients with duodenal ulcer, and, until such treatment is shown to be safe and effective, surgical treatment remains a logical option for many patients.


Idiopathic portal hypertension (perisinusoidal fibrosis) after renal transplantation. We report the cases of two renal transplant recipients suffering from idopathic portal hypertension, a condition characterised by increased portal venous pressure in the absence of both histological lesion of the liver and obstruction of the portal vein. In these two patients, perisnusoidal fibrosis, invisible by light microscopy, was demonstrated by electron microscopy; it is suggested that partial obstruction of hepatic sinusoids by perisinusoidal fibrosis could be the mechanism for increased portal venous pressure in all the patients with idiopathic portal hypertension. In these two patients, who received 6-mercaptopurine and azathioprine, perisinusoidal fibrosis might be the consequence of prolonged administration of these drugs.


A comparison of UV-induction in exponentially growing and resting Escherichia coli B/r Hcr+. Using the method of two separate UV exposures the increase of UV resistance after various induction fluences in growing and resting Escherichia coli B/r Hcr+ was followed. In resting cells, the optimum induction energy fluence was found to be 30 J/m2. In exponentially growing cells testing of induction has proved to be possible only under conditions of postincubation of cells with chloramphenicol after the second fluence. Under these conditions the induction energy fluence up to the observed 50 J/m2 resulted in an increased survival.


Transport of manganese into Saccharomyces cerevisiae. The uptake of Mn2+ by Saccharomyces cerevisiae at the expense of endogenous sources of energy depends on the stage of culture development and is maximum in the middle of the exponential phase. The ability of cells to take up Mn+ is related to the content of intracellular potassium at all stages of growth, to the content of ATP during the exponential phase and it is not related to the content of inorganic polyphosphates. The uptake is inhibited by oligomycin (25 microgram/ml) by 50-85% and under anaerobic conditions by 10-50%, depending on the stage of growth, indicating the role of aerobic phosphorylation in the process. The uptake of Mn+ is apparently associated with a hydrolysis of low-molecular weight polyphosphates and ATP, as well as with the exit of K+ from cells.


The decreased in vitro chemotactic activity of polymorphonuclear leukocytes of newborns and infants. Using Boyden's technique, a statistically significant decrease in the chemotactic activity of polymorphonuclear (PMN) leukocytes was found during the early postnatal period, i.e. in the cord blood and in blood of newborns within the first 10-15 d of life after stimulation of cells with both zymosan-activated adult serum (ZAS) and with an abacterial filtrate of Escherichia coli broth culture (ECF). After this period, the responsiveness of leukocytes to both chemotactic agents increased and remained at the same level during the whole observation period, i.e. up to the age of 6 months. Nevertheless even then it did not reach fully the responsiveness of the leukocytes of mothers and pregnant women. Zymosan-activated serum was shown to be a more potent chemotactic stimulus to leukocytes of infants as compared to the E. coli filtrate.


Antimicrobial effect of 4-nitrophenylhydrazones, isonicotinoylhydrazones and N-4-nitrophenylglycosylamines of D- and L-aldoses. The antibacterial effect of 19 4-nitrophenylhydrazones, isonicotinoylhydrazones, and N-4-nitrophenylhydrazones, of 9 mono- and 2 disaccharides was tested with Micrococcus luteus, Bacillus licheniformis and Escherichia coli.


Secondary metabolism as an expression of microbial growth and development. A case is made out for regarding secondary metabolism as part of normal cell growth, related to its interactions with the environment. Secondary metabolism is widespread, especially in fungi and actinomycetes, and is not to be regarded as confined to the production of antibiotics and other special substances. It is part of the normal maturation process. Examples are given of the influence of secondary metabolism in ecological systems. It is also shown that cell productivity can be related to age structure. Secondary metabolism is thus linked with growth, although in many cases this may not be obvious in laboratory work. Initiation of production will arise from the system which regulates growth and differentiation. These processes are little understood at present, but it is clear that the factors involved differ in different instances and that they involve a very great variety of biochemical and physiological processes.


[Objectivation of tremor and motion disorders via computerisation (author's transl)]. The quantitative analysis of motion disorders of the upper extremities can be performed by means of a joystick connected with a minicomputer. Therefore a random squarewave curve is drawn on a computer display and the patient must follow it with the joystick. The deviation of the two curves are recorded, analysed and documented numerically and graphically.


An apraisal of the role of aldosterone and the sympathetic nervous system in essential hypertension. Of the various hypertensive disorders in which mineralocorticoid hormones are involved mainly those are reviewed in which, apart from aldosterone, hyporeactivity of the adrenergic nervous system may play a permissive role. The simultaneous occurrence and extent of participation of these two factors in essential hypertension are being appreciated increasingly. Their share in the mosaic of hypertension may add to the accumulating knowledge of this disease entity. In exploring the underlying mechanisms of hypertension common regulatory pathways involving aldosterone and the adrenergic nervous system may lead to new aethiopathogenetic insights.


The effect of (6-D-(O-TERT-B)-Ser)-gonadoliberin-(1--9) nonapeptide-ethylamide on gonadotropin release in prepubertal boys. (6-D-(o-tert-B)-Ser)-gonadoliberin-(1--9) nonapeptide-ethylamine, (HOE 766), a highly active LH-RH analogue, was studied with regard to its effects on the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in 29 prepubertal boys given different doses (1 microgram, 2,5 microgram, 5 microgram or 7,5 microgram respectively). The effect of HOE 766 is dose dependent for FSH, but not for LH. There are important differences in the reaction of these young subjects from those of adults. Whereas LH levels barely rose, FSH secretion was superior to that seen in adults.


Binding of luteinizing hormone releasing hormone to human serum proteins--influence of a chronic treatment with a more potent analogue of LH-RH. Binding of 125I-LH-RH and its analogue, 125I-6-D-Leu-10-Des-Gly-Ethylamide-LH-RH (6-D-LH-RH) in male serum was studied in 10 healthy males and in 11 patients with idiopathic gonadotropin deficiency (IGD) before and during treatment with 6-D-LH-RH. Using either equilibrium dialysis (A) or ethanol precipitation (B) 13.57 +/- 0.69% (A) or 19.32 +/- 1.73% (B) of LH-RH and 7.12 +/- 0.86% (A) or 14.56 +/- 1.06% (B) of the analogue were in the bound form, without difference between normal subjects and IGD. Capacity of this binding was high (greater than 9 less than 18 mu-Mol LH-RH/0.06 mMol of protein), affinity very low, and the binding almost completely disappeared following removal of albumins by affinity chromatography. Chronic treatment with 6-D-LH-RH did not alter these binding characteristics. These observations suggest non specific albumin binding of LH-RH in male serum and stress the role of this decapeptide as a rapid modulating regulator of gonadotropin secreting system.


Analogues of [3H] chloramphenicol for photoaffinity labeling. The synthesis of [3H]chloramphenicol and its erythro-diastereoisomer with specific activities of 1.25 Ci/mmol, and the further transformation of the [3H]chloramphenicol to a series of azido and diazo-substituted derivatives are described. The antibiotic activity of the compounds was considered insufficient for their use as photoaffinity labels.


Diagnosis of primary thyroid carcinoma by immunohistological demonstration of thyroglobulin. Thyroglobulin was found by the immunoperoxidase technique in routine histological sections of biopsies from all of 30 proven cases of well differentiated papillary or follicular thyroid carcinoma examined, in one of 20 anaplastic thyroid tumours and in none of 49 other tumours examined. Immunohistological demonstration of thyroglobulin in thyroidal or extrathyroidal tumours is of diagnostic value in confirming that the thyroid is the tissue of origin. Well differentiated tumours lacking thyroglobulin probably do not arise from thyroid epithelium.


Competition is Durenberger's response to system reform. The Minnesota senator contends that "no change" is not an option for the health care system and urges passage of his bill to spur competition.


Keeping them well is good business too. Health promotion. Many hospitals today regard motivating people to take better care of themselves, and teaching them how, to be as much a part of their mission as repairing the damage when they don't.


Evaluation of insulin secretory capacity in diabetes mellitus. The capacity of the pancreatic beta cells to secrete insulin can be evaluated in vivo by measurement either of circulating immunoreactive insulin or of C peptide, a by-product of insulin synthesis. Evaluation of serum levels is complicated, however, by the variable degradation rates and distribution spaces of these peptides. Also, interpretation of peripheral vein concentrations of insulin, and perhaps C peptide, is more difficult because of hepatic catabolism. Quantitation of these peptides in the urine may provide an integrated measure of insulin secretion. In insulin treated diabetic patients who develop circulating insulin antibodies, beta cell secretory capacity may be assessed by C peptide measurement, or by techniques that allow separate determinations of "free" and "total" insulin. A variety of stimulatory tests may be used to investigate insulin secretory capacity.


Glycosylated hemoglobins and diabetes mellitus. Glycosylated hemoglobins result from post-translational changes in the hemoglobin molecule, and their levels correlate well with glycemic levels over the previous six to 10 weeks. Their use as an aid in monitoring diabetic control appears to be well established, but their value in predicting complications of diabetes and in diagnosing milder forms of diabetes is as yet unknown. Of the numerous methods available for the analysis of glycosylated hemoglobins, none has been evaluated extensively in a routine laboratory setting. However, liquid chromatography, isoelectric focusing, and radioimmunoassay techniques all give adequate results. For the purposes of monitoring long term diabetic control, assay of the fast hemoglobin fraction (AIa+b+c) appears adequate. However, for investigative purposes, when optimal sensitivity may be required, specific measurement of hemoglobin AIc is recommended.


A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Two female sibs are reported with a possibly new lethal malformation pattern, the major anomalies of which are: coarse face with small eyes and cloudy corneae, cleft soft palate, hypoplasia and absence of lobulation of both lungs, diaphragmatic defects, digitalisation of thumbs and distal limb deformities.


B-cell precursors in early chicken embryos. The ontogeny of B-cell precursors in chicken embryos from day 3 of incubation onwards has been studied. Purified antibodies to chicken Ig L, gamma, mu, alpha chains were used in a sensitive indirect immunofluorescence assayed on fixed cell smears and wax-embedded tissue sections; the location and morphology of immunoglobulin positive (Ig+) cells were determined either in phase contrast or after histological staining. Lymphoid cells containing small amounts of cytoplasmic immunoglobulin were found in 3 day and older embryonic yolk sac, 11 and 12 day blood, 11, 12 and 13 day bursal mesenchyme. cIg+ large basophilic cells were first seen in 14 day bursal follicles. It is concluded that cells enter the embryonic bursa at different developmental stages: some appear to be uncommitted stem cells, whilst others have already commenced B-cell maturation in an extra-bursal site.


Mouse thymus reticulo-epithelial (RE) cells in vitro: isolation cultivation and preliminary characterization. The reticulo-epithelial (RE) cells of the thymus are presumably playing a crucial role in the differentiation of the T lineage lymphoid cells, but how this happens is still a matter for speculation. This paper describes a method for rapid preparation of thymic RE cells with as little damage as possible, their culture, and the analysis of their membrane antigens and of other cytological properties. The cultured cells are pleiomorphic, but at least two types can be distinguished, one being round and very villous, the other one being flat and very cystic. Thymus RE cells have species specific surface antigens and large amounts of H-2 antigen. The possible presence of theta antigen is unclear. Most cells have no detectable Tla antigen. In vitro, they show some uptake of normal mouse serum immunoglobulins. RE cells show a surface migration of ligand-bound membrane antigen; such a capping is much slower than for lymphocytes, and is inhibited by 10 mM NaN3; The drug also causes the apparition of long microprojections (or retraction fibres) on the villous RE cell type, as is also caused by a slight fixation with formalin. Type C virus particles are found in RE cells from AKR mice as young as 1 day.


Immunosuppressive ALS. II. Antibody to Ia antigens in heterologous anti-lymphocyte serum. The relationship between Ia alloantigens and xenoantigens detected by immunosuppressive heterologous anti-lymphocyte sera has been investigated. Three rabbit anti-rat lymphocyte sera were examined for the presence of antibodies to Ia antigens. Two of these sera, an anti-thymus membrane and anti-lymphocyte sera detected labelled cell-surface Ia antigens (mol. wt 35,000 and 27,000) present on rat spleen B cells. The third antiserum, prepared against fractionated soluble lymphocyte antigens, was essentially non-reactive with these antigens. Of these three heterologous antisera, the anti-membrane serum reacted with the same antigens detected by two alloantisera. It seemed possible that such an antiserum could modify a recipient animal's immune response in vivo in a fashion identical to alloantibody to Ia antigens. In fact, all three heterologous antisera, including one devoid of antibody to Ia proved immunosuppressive in vivo. These results suggest that antibodies to antigens other than Ia can induce prolonged allograft survival. Since heterologous sera bind Ia antigens, it remains to be determined whether monospecific heterologous antisera to Ia antigens can allograft survival. The results raise the prospect that more than one antibody specificity may contribute to the immunosuppression achieved with ALS.


Functional and morphological recovery of the T-cell compartment in lethally irradiated and reconstituted mice. The recovery of the T-cell compartment in mice after lethal irradiation and reconstitution was studied using functional and morphological parameters. T-helper cell activity, determined by the direct SRBC-plaque-forming cell (PFC) response, recovers in a similar fashion as T-memory function which was studied by adoptive transfer of carrier-primed cells. Both functions return to control levels in 2.5-3 months. Using immunoperoxidase staining of frozen sections with anti-T cell serum, the morphological recovery of the T-cell dependent areas in the white pulp of the spleen could be studied and compared with the functional recovery.


IgM rheumatoid factor as a source of non-specificity in murine anti-allotype sera. Anti-allotype sera have shown a breakdown of the expected specificity especially when used for the development of haemolysis of fragile target erythrocytes. IgM anti-IgG rheumatoid factor has been shown to be the source of non-specificity. Removal or destruction of IgM in an anti-allotype serum restores the expected specificity.


Dissociative effects of malarial infection on humoral and cell-mediated immunity in mice. The effect of malarial infection on immune responses was studied in mice. When sheep red blood cells (SRBC) were injected 2 days before or at the same time as infection with Plasmodium berghei, there was a marked increase in the number of splenic plaque forming cells (PFC) induced by SRBC as compared with uninfected controls. When SRBC were injected 2 days or more after the infection, however, the PFC response was significantly reduced. On the other hand, cell-mediated immunity, as exemplified by delayed-type hypersensitivity (DTH) to a number of antigens, was suppressed whether the infection was introduced before or after antigen stimulation. A similar effect could be produced by injecting the host with the supernatant obtained following incubation in vitro of peripheral blood from heavily infected mice. When this supernatant was injected i.v. into normal mice at the same time as SRBC priming, it enhanced the humoral response to SRBC, but suppressed the DTH to SRBC. The coincident induction of this inverse relationship between humoral and cell-mediated immunities was clearly borne out by a dose response study using different dilutions of supernatant. The active component appeared to be of large molecular weight (greater than 150,000), thermostable and not present in the serum of infected mice.


The use of the enzyme-linked immunosorbent assay (ELISA) for the detection and quantification of specific antibody from cell cultures. The solid phase enzyme linked immunosorbent assay (ELISA) has been used to quantify anti-keyhole limpet haemocyanin (anti-KLH) antibody in the serum of KLH-immune C57Bl/6 mice. When spleen cells from immune mice were cultured overnight in ELISA microtitre wells to which KLH had been adsorbed it was found that easily quantifiable amounts of anti-KLH antibody were synthesized and were detectable. It was found further that spleen cells from KLH-primed mice, when cultured in vitro in the presence of KLH, transferred to KLH-labelled ELISA plates, and cultured overnight, also produced detectable levels of antibody. Levels of antibody were detectable only after 4 and 5 days of in vitro stimulation. A comparison was made between detectable numbers of plaque forming cells to sheep red blood cells (SRBC) in SRBC primed CBA mice and levels of antibody detected by the ELISA procedure. It was found that the sensitivities of the two tests were comparable. The applications of this technique to the study of in vitro antibody synthesis using soluble antigens are discussed.


Natural resistance to Salmonella typhimurium in different inbred mouse strains. The mechanisms of natural resistance to intravenous challenge with Salmonella typhimurium C5 are complex. LD50 determinations showed inbred mouse strains of low, intermediate and high natural resistance, with BALB/c and B10 strains the most susceptible, A/J the most resistant. Delayed (footpad) hypersensitivity was not by itself a measure of natural resistance. Resistant mouse strains sensitized either s.c. or i.v. with an attenuated salmonella strain showed positive 48 h footpad reactions when tested 8 days later with a salmonella extract, but three very susceptible strains also showed positive reactions. Determinations of the in vivo net growth rate of salmonellae in the liver and spleen during the first phase of the infection (up to day 4) arrange the different mouse strains into two categories of fast and slow net growth rate. All fast net growth rate strains are susceptible, but not all slow net growth rate strains are resistant. Besides slow net growth rate, resistance requires the participation of other factors appearing in the second phase of the infection (towards the end of the first week) probably involving the cellular immune response, which halts further bacterial growth. Not all slow net growth rate strains are equally capable of suppressing bacterial growth in this second phase. The host mechanism determining slow net growth rate is inherited as a dominant trait, and appears to be operating before the main cellular immune response. The influence of this mechanism on net growth rate is reflected in the time to death following a given dose of salmonellae. The present results suggest that overall resistance to salmonellae is polygenic, but that the mechanism responsible for the differences in early net growth rate is less complex.


Genetics of natural resistance to salmonellae in mice. The genetics of natural resistance to salmonellae were studied in F1 hybrid and backcross mice. Overall resistance to Salmonella typhimurium C5 is complex, but one parameter, the early net growth rate of the organism in vivo, is controlled by a single autosomal gene or cluster of genes. 'Slow' net growth rate is necessary but insufficient, for resistance to S. typhimurium C5. Resistance requires the participation of other mechanisms, detectable by the end of the first week, which presumably involve an immune response. F1 hybrids bred from parents of low, intermediate and high natural resistance showed either high or low resistance. Most of the F1 hybrids were of a similar high resistance, and were bred from pairs in which at least one parent showed slow net growth rate. Hybrids of low resistance were only obtained when neither parent showed slow net growth rate. No hybrid was less resistant than the parents, many were more resistant. Backcross analysis on two hybrids challenged with S. typhimurium C5 supports the hypothesis of complex genetic control of overall resistance but with single gene control of the early net growth rate of the organism. Similar experiments were performed using a much more virulent organism, S. enteritidis 5694. All mouse strains were very susceptible (LD 50 less than ten organisms) to this strain given either i.v. or s.c. This organism produced an overwhelming infection which did not allow the cell-mediated immune response time to develop. This, however, did not interfere with the mechanism controlling early net growth rate, and genetic analysis using this organism gave similar results to those obtained with S. typhimurium C5. These results suggest that the mechanism regulating early net growth rate does not operate via the cell-mediated immune response, which develops later in the course of the infection.


The natural resistance of radiation chimeras to S. typhimurium C5. Differences in the in vivo net growth rate of Salmonella typhimurium C5 during the first week of infection in different mouse strains are controlled by a single autosomal gene. In lethally irradiated mice repopulated with semi-allogeneic bone marrow, the early net growth rate shows the phenotype of the donor of the bone marrow cell and not the phenotype of the irradiated recipient. Thus, genetically controlled differences in in vivo bacterial net growth rate are a consequence of mechanisms operating in cells which have originated from bone marrow precursors. Natural resistance to S. typhimurium C5 requires, in addition to slow net growth rate, other mechanisms which come into operation at the end of the first week of the infection. These later acting processes are more complex and can not be transferred to susceptible mice using bone marrow cells alone.


Adult and pre-adult thymectomy of mice: contrasting effects on immune responsiveness, and on numbers of mitogen-responsive and Thy-1+ lymphocytes. Peripheral lymphoid tissues of mice which have been thymectomized at 2 or 4 weeks of age, that is, before they achieve adult body weight, have been shown to be lacking in cells responsive to the T-cell mitogen, phytohaemagglutinin, when the animals became adult, and these mice have also been shown to have a deficient immune response against sheep erythrocytes. It is suggested these effects of pre-adult thymectomy are consequent upon removal of the prime source of T cells prior to the animal having acquired complete T-cell populations of the adult. Spleens and lymph nodes of mice thymectomized at 8 weeks of age were found to have reduced numbers of cells susceptible to the cytotoxic effects of anti-Thy-1 serum as early as 4 weeks after the operation, whereas the number of lymphocytes responsive to T-cell mitogens in these lymphoid tissues was not reduced at this time. The number of spleen-borne antibody-producing cells in a primary or secondary response was not affected by 8-week thymectomy, either when the response was tested in the operated animal, or after transfer of cells from such an animal to an irradiated recipient. The results are discussed with respect to other work on the effects of thymectomy of mice during the post-neonatal and pre-adult period.


Kinetics of phagocytosis of Staphylococcus aureus and Escherichia coli by human granulocytes. Although phagocytosis of micro-organisms by granulocytes is one of the most important defence mechanisms against infection, little is known about the kinetics of this process. The present study showed that the rate of ingestion of Staphylococcus aureus and Escherichia coli depends on the concentrations of the granulocytes and bacteria. Phagocytosis of bacteria at a bacteria-to-cell ratio in the range between 100:1 and 1:10 showed an exponential course during the first 30 min. At a bacteria-to-cell ratio of 1:1, application of a correction for the outgrowth of extracellular bacteria gave an exponential course of ingestion over the first 90-min period. Since it was found that the phagocytosis of bacteria by granulocytes at various bacteria-to-cell ratios can be described with Michaelis-Menten kinetics, we studied the kinetics of phagocytosis on the basis of the initial rate for the first 30-min period. The rate of phagocytosis and the maximal degree of ingestion of bacteria by granulocytes proved to be related to the concentration of serum used in the assay. The minimal serum concentration required for maximal ingestion was 2.5% for Staphylococcus aureus and 5% for Escherichia coli. When bacteria were pre-opsonized, the duration of pre-opsonization proved to be limiting for the rate of phagocytosis in dependence on the serum concentration. The effect of temperature on the phagocytosis of micro-organisms proved to be two-fold. First, at temperatures between 4 and 33 degrees a decrease in the functioning of the cells leads to a decrease in the rate of phagocytosis. Above 42 degrees, the temperature affects mainly the opsonization of the micro-organisms and has only a slight influence on the ingestion process. From the data obtained in this study, maximal rates of 6.3 X 10(6) Staphylococcus aureus/5 X 10(6) granulocytes/min and of 7.1 X 10(6) Escherichia coli/5 X 10(6) granulocytes/min were calculated for phagocytosis at a bacteria-to-cell ratio of 100:1 at 37 degrees, i.e. on average about one bacterium per granulocyte per min. The maximum calculated number of bacteria ingested by one granulocyte lies between 40 and 50.


Characterization of immunogenic properties of haptenated liposomal model membranes in mice. I. Thymus independence of the antigen. This paper describes a rather simple coupling method for tripeptide enlarged haptens to phosphatidylethanolamine (PE) and the incorporation of these conjugates into liposomal model membranes (haptenated liposomes). These haptenated liposomes evoke a hapten-specific humoral immune response in mice. The magnitude of the response as measured by the appearance of direct plaque forming cells in the spleen is dependent on the route of immunization and the dose and epitope density of the hapten-PE derivatives. It was not possible to evoke an IgG response after either primary or secondary immunization with haptenated liposomes (as measured by the production of indirect plaques or mercaptoethanol-resistant antibody). These data, in addition to the observations that mice depleted of, or deficient in thymus-derived (T) lymphocytes respond to haptenated liposomes, indicate that these haptenated liposomes are T-cell independent antigens.


Microtechnique for studies on the role of monocytes in the stimulation of lymphocytes. A microtiter technique was used to measure lymphocyte stimulation by antigen-pulsed monocytes. Monocytes from human blood were isolated on polyester film disks. The disks were exposed to antigen and incubated together with lymphocytes in the wells of a microtiter plate. The method was technically simple and required no expensive materials.


Passive immune hemolysis for detection of heat-labile enterotoxin produced by Escherichia coli isolated from different sources. Fifty-one strains of Escherichia coli isolated from humans, swine, food, and water and identified as enterotoxinogenic by the Y-1 adrenal cell assay, were examined for heat-labile enterotoxin (LT) production by the passive immune hemolysis test. Cholera antitoxin, anti-choleragenoid and anti-LT were used as antisera. Cholera antitoxin was much more potent than anti-choleragenoid and LT antiserum in the detection of LT-positive strains. All strains isolated from pigs and sausage were negative in tests made with LT antiserum. A few strains isolated from humans, food, and water also gave negative results. These data showed that the passive immune hemolysis test is not as efficient as the Y-1 adrenal cell assay in the detection of enterotoxinogenic E. coli strains.


Enterotoxins, O-groups, and K88 antigen in Escherichia coli from neonatal piglets with and without diarrhea. In a comparison between piglets (1-7 days old) with diarrhea and healthy piglets of the same age and 1 to 8 weeks old, 810 intestinal strains of Escherichia coli from 81 piglets from as many different herds in Sweden were investigated with regard to O-group, enterotoxicity, and possession of K88 antigen. A clear difference was found between the E. coli isolates from piglets with diarrhea and from representatives of healthy herds without diarrhea, with regard to (i) the homogeneity of strains in individual pigs and (ii) the distribution of O-groups, K88 antigen, and frequency of enterotoxicity. Strains from piglets with diarrhea showed a high frequency of O-group 149 (53%), enterotoxicity (61%), and K88 antigen (56%), while not more than 3% of the strains from healthy piglets of the same age harbored any of these characteristics. Of the isolates in O-groups 8, 64, and 115, 36% were enterotoxigenic. The corresponding data for O-group 149 and nontypable strains were 96 and 1%, respectively. Furthermore, K88 antigen was only found in O-groups 8 and 149. In O-group 149, 96% of the strains (n = 167) produced the K88 antigen as well as heat-labile enterotoxin. In contrast, strains producing heat-stable enterotoxin were mainly found in O-groups 8, 9, 64, 115, and 141. There was a significant difference in the frequencies of E. coli strains producing heat-labile enterotoxin between piglets with diarrhea and those without, whereas the pathogenic role of heat-stable enterotoxin-producing strains was less apparent.


Surface protein of a Streptococcus agalactiae isolate. A Streptococcus agalactiae isolate of bovine origin was cultured in broth; log-phase cells were washed and radioiodinated and subsequently extracted at low pH in the presence of a nonionic detergent. A protein antigen was purified from concentrated extract by ultracentrifugation, gel filtration, and ion-exchange chromatography. The molecular weight of the protein was estimated at 31,800. The agglutinogenic character of the protein indicated its localization at the cell surface.


Host defenses in murine malaria: analysis of the mechanisms of immunity to Plasmodium berghei generated in response to immunization with formalin-killed blood-stage parasites. Syngeneic B6D2F1 (C57Bl/6 x DBA/2) mice were immunized with a nonliving antigen prepared from mixed blood forms of Plasmodium berghei strain NYU-2. Consistently greater than 80% of the vaccinated mice survived virulent challenge, and protective immunity was demonstrable from 1 week through at least 4 months after immunization. However, vaccination did not prevent the development of patient infection after challenge. Instead, infections in vaccinated mice progressed to about 10% parasitemia and were then subsequently cleared. In contrast, infections initiated in nonvaccinated mice progressed beyond 10% parasitemia and were uniformly fatal within 4 weeks. Sera collected from normal mice, nonvaccinated mice infected with P. berghei, or vaccinated mice before challenge failed to passively protect recipients against virulent infection. On the other hand, sera collected from vaccinated mice after recovery from a challenge infection conferred upon passively immunized recipients protection from homologous virulent challenge, which was manifest as a delay in the onset of overt infection. It was concluded, therefore, that vaccination altered the immunological potential of the host in such a way as to allow the production of a protective humoral factor, probably specific antibody, in response to infection with the virulent parasites.


Unique lipid composition of Treponema pallidum (Nichols virulent strain). The lipid composition of Treponema pallidum (Nichols virulent strain) was determined after purification of the organisms from the infected testes of corticosteroid-treated rabbits by differential centrifugation, filtration through Nuclepore membranes, and sedimentation in Hypaque density gradients. The total lipids were comprised of 32.2% neutral lipids, mainly cholesterol, and 67.8% phospholipids consisting of phosphatidylcholine (32.1%), sphingomyelin (14.8%), cardiolipin (13.0%), phosphatidylethanolamine (6.2%), phosphatidylinositol-serine (1.2%), and lysophosphatidylcholine (0.4%). Monoglycosyldiglyceride, a glycolipid comprising 25 to 50% of thetotal lipid of all Treponema previously examined, was not detected. The fatty acid composition was similar but quntitatively distinct from that of the infected testes tissue.


Heat-labile enterotoxin production in isolates from a shipboard outbreak of human diarrheal illness. As reported elsewhere, an enterotoxigenic strain of Escherichia coli serotype O25:K98:NM was epidemiologically incriminated as the etiological agent in a shipboard outbreak of diarrheal illness. This enterotoxigenic E. coli strain and possibly other enteric isolates were found to produce heat-labile toxin and not heat-stable toxin. Since previous genetic analyses of enterotoxigenic E. coli strains producing heat-labile and heat-stable toxins have shown a plasmid location for both toxin determinants and since in this outbreak more than one bacterial strain appeared to produce only heat-labile toxin, the possibility of an extrachromosomal heat-labile toxin determinant was investigated. Results of endonuclease cleavage and hybridization experiments, as well as apparent heat-labile toxin phenotypic instability, strongly suggest a plasmid mediation of toxin production. Additionally, the stability of this heat-labile toxin production was evaluated after several traditional methods of bacterial cell preservation.


Comparison of enzyme-linked immunosorbent assay and passive hemagglutination method for quantification of antibodies to lipopolysaccharide and tetanus toxoid in rats. In a comparative study, the enzyme-linked immunosorbent assay, using peroxidase labeled anti-rat immunoglobulin M and immunoglobulin G, and the passive hemagglutination test were applied to determine the primary and secondary antibody response to lipopolysaccharide and tetanus toxoid in rats. In the enzyme-linked immunosorbent assay, the antigens were bound to the wells of polystyrene microplates, tetanus toxoid directly, and lipopolysaccharide after complexing it with methylated bovine serum albumin. After incubation with dilutions of the rat sera, the amount of antibody bound to the solid phase was quantified by means of peroxidase-labeled anti-immunoglobulin. The specificity of the enzyme immunoassay was tested by absorption of the sera with their respective antigens. The enzyme-linked immunosorbent assay proved to be more sensitive than the hemagglutination reaction, except when titers were determined during the secondary response to tetanus toxoid. Besides its specificity and sensitivity, the enzyme-linked immunosorbent assay is a convenient method for measuring both immunoglobulin M and immunoglobulin G antibodies. At low serum dilutions of lipopolysaccharide antisera, inhibition of the reaction in the enzyme-linked immunosorbent assay occurred. This phenomenon could be prevented by heating the sera at 56 degrees C for 30 min. Lipopolysaccharide was immunogenic in rats over an extremely wide dose range (from 10 pg to 1 mg); the optimal immunogenic dose of lipopolysaccharide for young adult rats was 0.1 to 1,000 mug when administered intravenously, and that of tetanus toxoid was 5 to 10 lines of flocculation, as determined by the Ramon flocculation test.


Identification of protective cell surface proteins in ribosomal fractions from Salmonella typhimurium. Cell surface antigen preparations from Salmonella typhimurium SR-11 prepared by either trichloroacetic acid extraction or boiling in sodium dodecyl sulfate were able to protect C3H/HeJ, C3H/HeDub, and A/J mice. Some of the proteins found in these preparations were shown to exist in the protective ribosomal fraction isolated from S. typhimurium SR-11. Passage of ribosomes isolated from S. typhimurium SR-11 and 6707 through a Sepharose 2B column removed the protective immunogen from 6707 ribosomes but did not completely remove it from SR-11 ribosomes. Immunity to salmonella infection in C3H/HeJ mice induced by ribosomal vaccines may be dependent on the presence of cell surface proteins in the ribosomal fraction.


Immunotherapy of guinea pig line 10 hepatoma with nonliving BCG cells in aqueous medium. Killed BCG cells suspended in 1.5% carboxymethylcellulose cured guinea pigs with established line 10 tumors in a high percentage of cases. The bacterial preparation of BCG in carboxymethylcellulose displayed a stronger tumor regressive activity and the process of healing was accelerated when endotoxin from a rough (Re) strain of Salmonella typhimurium was added to the BCG bacilli.


Shigella infection of Henle intestinal epithelial cells: role of the bacterium. Epithelial cell infection by Shigella flexneri 2a was studied in an in vitro model system. Using the Henle 407 human intestinal epithelial cell line as host cells, a standardized experimental protocol which allowed quantitative measurement of infection was developed. Intravellular residence of infecting organisms was confirmed by indirect fluorescent-antibody staining of unfixed and methanol-fixed (Henle 407) cells and by quantitative bacteriological culture of disrupted host cells after infection. The process of shigella entry into cells was evaluated by chemical or physical modulation of the bacterium under controlled experimental conditions. Shigella were subjected to mild heat, ultraviolet radiation aminoglycoside antibiotics, and immunoglobulins raised against S. flexneri 2a. The data show that heat-stable antigens on the bacterial surface are not solely responsible for infectivity of S. flexneri 2a. Furthermore, it was shown that physiological and synthetic functions of shigellae are required for entry into host cells.


B lymphocyte colony formation in renal infection. The effect of renal infection on B lymphocyte colony formation has been investigated in the belief that a study of the effect of infection on subpopulations of lymphoid cells might provide direct evidence of the effect of infection on the immmune system. Renal infection was induced in mice, and the specific immune response of the B lymphocyte compartment was quantitated by determining the serum antibody and plaque-forming cell response to infection. Under the conditions of the experiment, the ability of splenic lymphocytes to form B lymphocyte colonies was significantly depressed during the first 7 days of infection, and the results suggest that a study of the responses of lymphoid cells to infection may provide information of diagnostic and prognostic value.


Chlorpromazine reverses diarrhea in piglets caused by enterotoxigenic Escherichia coli. The effect of chlorpromazine (CPZ) on diarrhea caused by enterotoxigenic Escherichia coli was tested in piglets since CPZ has been shown to be a potent antagonist to enterotoxins in vitro in a cell system and in vivo in a mouse model. Experimental diarrhea was induced in three litters of newborn piglets which were infected by mouth with 2 x 10(9)E. coli bacteria, which produce heat-labile (LT) and heat-stable (ST) enterotoxins. Treatment with CPZ given intramuscularly 1 h after the onset of diarrhea reversed fluid secretion in small intestine as well as dehydration, as judged by clinical criteria. A dose of 5 mg of CPZ per kg of body weight completely normalized the intestinal-fluid content measured 4 h after diarrhea developed, whereas 1 to 2 mg of CPZ per kg of body weight was somewhat less effective but still caused significant reduction of fluid (P < 0.001). Studies with radioactive [(35)S]CPZ showed preferential and dose-dependent uptake of (35)S in the intestinal mucosa, the radioactivity being evenly distributed in the membranes of both crypt and villus cells. The enzyme adenylate cyclase, which probably mediates the cellular effects of LT, was shown to have two- to threefold higher activity in the infected than in the uninfected animals. This activation was reduced about 50% by the CPZ treatment (2 mg/kg of body weight). In a preliminary field trial the effect of CPZ was tested in a spontaneous outbreak of diarrhea in piglets due to enterotoxinogenic E. coli. The animals were treated either with oral electrolyte solution and standard antimicrobial agents only (controls) or with 1 mg of CPZ per kg of body weight intramuscularly in addition to this treatment. The mean duration of diarrhea in CPZ-treated animals was significantly shorter, 4.1 h (n = 23), than that in controls, 7.2 h (P < 0.05).


Phagocytosis and intracellular killing of pathogenic yeasts by human monocytes and neutrophils. The kinetics of phagocytosis and killing of four fungal forms with varying virulence by two types of phagocytic cells was examined. Human monocytes ingested Saccharomyces cerevisiae, Candida tropicalis, and the blastospores of Candida albicans more rapidly than did human neutrophils. There was no difference in the rate of phagocytosis of C. albicans pseudohyphae by these two cell types. Intracellular killing of each of the four fungal forms was consistently and significantly more rapid by monocytes than by neutrophils. Neutrophils were unable to destroy ingested C. albicans pseudohyphae. These experiments suggest that the monocyte plays an important role in host defenses against fungal diseases and that the relative virulence of the pathogenic yeasts in human disease may be related to the ability of these organisms to survival after being ingested by circulating phagocytes.


Evidence for two heat-stable enterotoxins produced by enterotoxigenic Escherichia coli. Heat-stable enterotoxins from a bovine and porcine strain of Escherichia coli were isolated and showed significant differences in amino acid composition and heat stability.


The removal of 14C labeled endotoxin by activated charcoal. Endotoxin shock due to Gram-negative enteric bacteria is of major medical concern with an estimated 100,000 fatalities in the United States per year. An effective therapy for endotoxin shock, particularly in combination with significant liver damage, has not been available to date. Since activated charcoal is known as a universal sorbent, the use of activated charcoal in a hemoperfusion apparatus to remove endotoxin has interesting possibilities. Current assays for endotoxin are inadequate. The Limulus Amoebocyte Lysate (LAL) assay was found to give nonreproducible results within our range of requirements for accuracy. We, therefore, grew Salmonella typhimurium in 14C-labeled glucose to obtain 14C labeled endotoxin. Radiolabeled endotoxin was used to measure the rate of adsorption on activated charcoal. The rates of removal of endotoxin from normal saline, plasma, and whole blood will be presented in graphical form for use in design calculations. This work provides a foundation for encouraging in vivo hemoperfusion experimentation now underway at the University of Oklahoma and the Veteran's Administration Hospital in Oklahoma City.


Notes for a radical gerontology.

Notes for a radical gerontology. The predominant theoretical perspectives in social gerontology reflect a normative bias toward adjustment of aging individuals to the society. This bias is reinforced through the methodological predelictions of most gerontologists. We outline the premises of a radical scholarship for gerontology which would provide an alternative, illustrating from selected works. A radical scholorship in gerontology would avoid the individualistic and adjustment biases, and would recognize that life in society is characterized by conflict, negotiation and compromise over politico-economic and other interests. Methodologically, it would seek to explicate the interests and aspirations of the aged in their own terms, and as relevant in the socio-historical context.


Solvent abuse: a review.

Solvent abuse: a review. The literature on solvent abuse is reviewed. Methods of use, symptoms of use, and effects of long-term solvent abuse are discussed. Several surveys on solvent use are summarized. The highest prevalence of solvent abuse seems to occur in native peoples undergoing periods of cultural change. Environmental conditions which are postulated as leading to psychological vulnerability and solvent abuse include: low social assets, parental drug use, peer and sibling influence, and acculturative stress. Solvent abuse seems to provide a pharmacological way out of a stressful environment for people who feel helpless to improve their situation in other ways. Methods of intervention that have been proposed for dealing with solvent abuse are discussed. Methods of intervention thus far employed generally have not been evaluated in any systematic fashion. Suggestions for future research are provided.


Individual psychotherapy with the aged: a selective review. While elderly individuals are still markedly underrepresented in facilities providing outpatient psychological services, clinical interest in individual psychotherapeutic intervention with the aged mentally ill has gradually risen during the past several decades. A broad review of the literature suggests that published descriptions of such interventions have generally been global and vague and that research reports, while collectively pointing to the feasibility of individual psychotherapy, have been infrequent and methodologically weak. In view of the rising numbers of elderly persons potentially requiring psychological services and a probable decrease in the mutual avoidance of therapists and the aged, the need for further theoretical development and empirical research is indicated.


Psychotherapy and behavior change with the non-institutionalized aged. This literature review discusses therapy with the aged person in the community. The discussion is based on the literature published since Rechtschaffen's review in 1959 [1]. The elderly are not receiving mental health services in proportion to their representation in the population or in proportion to their estimated need for such services. Major barriers to the utilization of such services by the aged are the prejudices of care providers, the poverty of the aged, and the lack of public commitment to the provision of services to this special population. A summary of the literature on the goals, content, and techniques of psychotherapy with the elderly client is presented and supports the conclusion that this therapy is different from similar work with the younger adult only in terms of a focus on different content areas. The potential contribution of behavior therapy to treatment programs for the elderly is discussed.


Why so little interest in whether or not old people talk: a review of recent research on verbal communication among the elderly. This paper is concerned with the spoken communication of chronically ill and aging residents of long term care institutions. Social gerontologists and speech pathologists have investigated areas related to spoken communication, however, there has been almost no investigation of communication from the patients' and staff perspective. Spoken communication is a vital component of social interaction and psychological well being and underlies such concepts as isolation, integration, and adjustment, and is a fertile area for investigation and analysis.


Comparative investigations on pirbuterol, salbutamol and placebo aerosols in bronchial asthma. In a single blind crossover study 12 asthmatics received in randomised order single doses of pirbuterol (200 and 400 microgram), salbutamol (200 microgram) and placebo-aerosols, in order to determine the extent and duration of bronchodilator activity, the optimum dosage, the incidence, type and degree of side effects and the cardiovascular as well as hematologic, renal and hepatic functions after inhalative administration. All patients were checked by repeated pulmonary function studies, ECG and extensive laboratory tests. No significant differences were found between salbutamol 200 microgram and pirbuterol 400 microgram when lung functions were studied over 4 hr following inhalation. Pirbuterol 400 microgram and salbutamol 200 microgram were significantly better than pirbuterol 200 microgram. There were no side effects or changes of clinical relevance in pulse rate, blood pressure, ECG or laboratory test results. Pirbuterol is a well tolerated bronchodilator which appears to be of clinical importance in inhalative treatment of bronchospastic disease.


Effects of tolmetin, paracetamol, and of two combinations of tolmetin and paracetamol as compared to placebo on experimentally induced pain. A double blind study. Previous studies in animals suggested that a coadministration of the anti-rheumatic/anti-inflammatory agent tolmetin (Tolectin) and of paracetamol potentiates the effects of these two drugs. The present study was carried out to assess whether or not the dosis of tolmetin necessary to obtain an analgesic effect can be reduced when paracetamol is coadministered in a model with experimentally induced pain in healthy human subjects. The effects of tolmetin 200 mg (T 200), paracetamol 400 mg (P 400), tolmetin 150 mg plus paracetamol 300 mg (T 150 + P 300), and of tolmetin 100 mg plus paracetamol 400 mg (T 100 + P 400) on pain threshold to electrical and thermal stimuli and on pain tolerance to electrical stimuli were compared to the effects of placebo under double blind conditions. Each of 20 healthy volunteers received all of the 5 treatments randomised according to four 5 X 5 Latin squares. The results showed that the combination T 100 + P 400 had better analgesic effects than the double dose of tolmetin, T 200, alone, while the effects of P 400 could not be discrminated from placebo. In a sequential t-test the effects of T 100 + P 400 could be discriminated from placebo already after 14 Ss. The effects of T 200, T 150 + P 300, and T 100 + P 400 respectively could not be differentiated, indicating that the dose of tolmetin can be reduced markedly by simultaneous administration of paracetamol without a loss in analgesic potency. Coadministration of tolmetin and paracetamol permits a marked reduction of the dose of tolmetin without any loss of analgesic potency as measured in a model with experimentally induced pain in healthy subjects.


Inactivation of bacteriophage lambda by combined X-ray and U.V.-light exposure. Extracellular phage lambda has been successively exposed to X-rays and U.V. light. The plaque-forming ability of the irradiated phages was determined on host cells with different repair capacities. No change in sensitivity was found with a pre-treatment of one type of radiation to lethal damage inflicted by the other. This indicates that a prerequisite for an interaction of different types of radiation is either an active metabolism or repair process occurring during the two radiation exposures.


The effect of large doses of vitamin C on leukocyte function and some laboratory parameters. Consumption of large doses of vitamin C has been ascribed several beneficial effects e.g. on serum cholesterol, haemoglobin synthesis, leucocyte function. Other authors have warned against large doses which could cause renal stones, disturbed vitamin C metabolism, a diabetogenic effect. To test certain statements 24 healthy women received either placebo, 1000 mg or 4000 mg ascorbic acid daily in a double blind study. Blood was drawn at regular intervals. Those women who received large doses of vitamin C increased their serum levels of vitamin C, during the medication, but otherwise we found no differences neither in leucocyte levels of vitamin C, leucocyte function nor other laboratory parameters between women who received placebo or large doses of ascorbic acid.


Nutrition and the immune response -- a review. This compacted overview of the nutrition-immune response connection underscores the role of nutrition as a deterrent to infection. Malnutrition enhances the propensity to and heightens the intensity of infections by weaknening the various host defense mechanisms. Thus: 1. Deficiencies of vitamin A, niacin, riboflavin, folic acid, vitamin B12, pyridoxine, ascorbic acid, iron and protein disrupt the tissue barriers to infection. 2. Protein-calorie, folate, iron, pyridoxine and zinc deprivations markedly depress the cell-mediated immune system. 3. Deficiencies of protein, pyridoxine, folic acid, pantothenic acid, thiamine, biotin, riboflavin, niacin-tryptophan, vitamin A and ascorbic acid inhibit humoral antibody formation in mammalian systems. 4. Vitamin A lack prevents the formation of lacrimal, salivary and sweat gland lysozymes. 5. Complement, properdin, interferon and transferrin concentrations are reduced in those nutritional deficiencies that interfere with protein synthesis. 6. Protein-calorie, iron and folate deficiencies impair phagocytosis by interfering with phagocyte microbial killing power or with phagocyte production. 7. Protein, ascorbic acid and zinc deficiencies retard wound healing that prevents spread of infectious lesions.


H. S. Sullivan and the phenomenology of human cognition. It is the purpose of this article to offer additional clarification of H. S. Sullivan's three-way division of cognitive experience. The investigation involves an analysis of C. S. Peirce's phenomenological categories of experience and their three Sullivanian parallels, i.e., prototaxis, parataxis, and syntaxis. It will be argued that the utilisation of these categories will provide psychiatrists with the following:(1) a set of non-psychiatric criteria for clarifying the underlying principles of psychiatric claims, (2) a broader base for analysing the nature of interpersonal relations, and (3) an additional means of preserving the self-correcting character of inter-personal psychiatry as a theory.


Experience of complete duplication of the collecting system: retrospective analysis of 23 cases with particular emphasis on the type of ureteral hiatus and its implication in the management of duplex. Twenty-three cases of complete duplication of the collecting system are reviewed. The type of ureteral hiatus was retrospectively studied to assess its relation to various abnormalities of the duplex system. It was stressed that the hiatal concept is quite important in understanding the multifarious problems of the pathophysiology of ureteral dilation, surgical management and faulty embryogenesis of the kidney and ureterovesical junction of the duplex system.


Daily bacteriological examination of urine during antimicrobial treatment of urinary tract infections. Bacteriologic examinations of urine were performed daily in 85 patients admitted for chronic recurrent urinary tract infections and treated with antibacterial drugs. The results have shown that the effect of therapy can be evaluated fairly accurately on the basis of bacteriological findings in urine within the first four days of treatment. When sterility was achieved as early as after one or two days of therapy, the urine remained sterile in more than 90% of the patients throughout the first post-treatment week; in more than 80% therapy had a long-term effect. A slowly subsiding urinary tract infection or reduced urinary bacterial count indicates that therapy will be ineffective.


Reversible acute tubular necrosis following severe acute renal rejection. The clinical observation of 6 out of 250 renal transplant patients showed that acute renal rejection may lead to reversible acute tubular necrosis (ATN) necessitating intermittent haemodialysis treatment. Despite missing early response to high-dose (methyl-) prednisolone therapy (during a mean period of 4.7 days) all 6 patients developed spontaneous diuresis 14.5 days on average after onset of rejection while on maintenance immunosuppressive therapy. From the clinical course the conclusion was drawn that in severe cases of renal rejection with arteriographic and histological findings consistent with acute tubular necrosis, prolonged therapy with high doses of (methyl-) prednisolone is not desirable, since after reversal of immunological rejection the onset of spontaneous diuresis will be determined mainly by the duration of the healing and recovery phase of acute tubular necrosis.


The aminogram of the urine produced by the preserved kidney. The function of autogenous canine kidneys may be considered even after successful preservation and reperfusion to be pathological for about 3 to 4 days, since a condition characterized by proteinuria and increased amino aciduria exists for a while.


Gamma camera scintigraphy in the diagnosis of lymphocele following renal transplantation. The symptoms and diagnosis of perirenal lymphocele following kidney transplantation are discussed. A case demonstrated by means of i.v. urography and gamma camera scintigraphy is reported. The value of the last mentioned method is stressed.


Acute glomerulonephritis with bacteriuria: a probable etiologic relationship. Twenty-one cases of acute glomerulonephritis in children with no previous history of renal disease were studied. Urinary infection with a rising titre of serum agglutinins against the organisms isolated from urine was found in 5 cases. No evidence of previous streptococcal infection was found in these cases. In the meantime all 8 cases with post-streptococcal glomerulonephritis remained without bacteriuria. In one case acute glomerulonephritis followed virus hepatitis, and in the remaining 7 cases the cause of glomerulonephritis was unknown. It is suggested that in predisposed patients the bacteria present in urinary infections might act as antigens starting immunologic reactions in the glomeruli, leading to glomerulonephritis. The final proof of this theory awaits immunofluorescence identification of these antigens in the glomeruli.


The origins of modern orthopaedics.

The origins of modern orthopaedics. The modern cult of "selfwareness", today so fashionable among young people, calls on past experiences to interpret modern attitudes and reactions; and gives a new credibility to the old Latin dictum "Historia, magistra vitae". It involves all aspects of human enterprise, not least the professional aspect, which undoubtedly gains by taking account of the contributions of previous generations. Orthopaedic surgery is no exception, and those of us who would aspire to a fuller understanding of our specialty will find benefit in retracting its history over at least the last 250 years. In taking such a backward glance, the writer tried to seek out those events and those men whose contributions have stood the test of time and earned them the recognition and prestige in which they are still held today.


Bone grafting in the reconstruction of the phalanges of the hand. In severe traumatic lesions of the fingers with loss of bone in the phalanges it is possible to avoid amputation and restore a useful finger, using skin replacement followed by bone grafting and, where necessary, tendon and nerve grafting. The technique of bone grafting in the phalanges is described. This is the most important step in restoring the length and stability of the digital ray.


Camptomelic syndrome. A rare type of congenital dwarfism associated with skeletal and other abnormalities. Three cases of the rare camptomelic syndrome are presented observed within fourteen months at the Mangiagalli University Clinic, Milan. The radiographic appearances and clinical characteristics are described, and compared with the thirty five cases in the literature. The differential diagnosis is discussed and the possibility of diagnosing this malformation prenatally is suggested.


Hospital case mix and average charge per case: an initial study. The use of case mix to explain hospital costs has been refined in previous research on the cost of hospital-based health care. This study demonstrates the significance of hospital case mix in explaining charges for health care treatment. By assuming that the variables which influence cost should also influence charges, an evaluative function is added to the basic investigative analysis potential of the hospital production process model. The relationship between case mix and charges is found to be weaker than the relationship between case mix and costs. This difference is qualified by methodological variation and possibly explained by cross-subsidization of patient services and lack of adequate controls on charge determination. Further, the relationship between case mix and charges is found to differ between Medicare and Blue Cross patients. This evidence suggests that hospital accounting may not be recovering costs evenly and equitably from clients.


[Acute and chronic experimental posttraumatic osteomyelitis in guinea pigs]. The model of an experimental posttraumatic osteomyelitis is described. Acute and chronic osteomyelitis was produced by inoculation of 10(5) Staph. aureus or E. coli to fractured femora--stabilised or not--with intramedullar nailing. The results are discussed. The model seems to be useful to further studies on posttraumatic osteomyelitis.


[Recipient conditioning with beagle plasma and beagle liver: prolongation of kidney-graft function without preoperative lymphocytotoxic antibody formation]. Donorspecific recipient conditioning in the non-related beagle produces prolonged kidney-graft survival without any postoperative immunosuppression. Besides 2 donor blood injections on days--18 and--11 followed by a 6-day preoperative immunosuppressive pulse (Procarbazine, ATS) donor plasma and a donor liver preparation are equally active. Additional long-term low dose preoperative immunosuppression with azathioprine tends to strengthen the effect. Lymphocytotoxic antibody formation is avoided in the recipient where no whole blood is used.


Contrast media in coronary arteriography: a review. Much knowledge of coronary artery disease and much of the progress in surgical treatment of coronary artery disease has been directly dependent upon the safety with which coronary arteriography has been performed. This safety depends upon the ease of placing the contrast media in the arteries and on the toxicity of the contrast medium itself. This review deals with contrast media toxicity in coronary arteriography, as distinct from toxicity in angiocardiography and other angiography.


Indicator dilution measurement of 5-hydroxytryptamine clearance by human lung. A double indicator dilution method to measure 5-hydroxytryptamine (5-HT) clearance by lungs of anesthetized patients is described. Immediately after a bolus injection of [3H]dextran and [14C]5-HT into the right atrial port of a Swan-Ganz catheter, blood from the radial artery is fractionated and the tritium and carbon-14 of each fraction is measured. The difference between the normalized curves of dextran and 5-HT vs. time reflect the extent to which 5-HT is extracted by the lung. This method gave a mean value of 61 +/- 3% (n = 10) for extraction of 5-HT, compared to 59 +/- 4% measured simultaneously by means of the pulmonary artery-left atrial gradient of 5-HT. Variations among three successive determinations in each patient made postoperatively were not statistically significant. This technique is applicable whenever Swan-Ganz and radial or brachial artery catheters are placed for routine clinical management and, therefore, may have wide application for measurement of pulmonary amine (or kinin) extraction in conscious human subjects or experimental animals. Because pulmonay clearance may be compromised by endothelial damage, 5-HT extraction measured in this manner could reflect early damage to human pulmonary endothelium--perhaps before clinical evidence of damage, such as interstitial edema and respiratory distress, is evident.


Breathing responses of unanesthetized man and guinea pigs to increased transrespiratory pressure. We compared the breathing responses of unanesthetized men and guinea pigs to externally imposed shifts in lung volume produced by steady pressures applied to the body surface while the mouth remained near atmospheric pressure. Lung inflation caused no consistent or significant changes either in frequency or end-tidal CO2 in the three men. In contrast, during lung inflation the guinea pigs breathed at low frequencies and smaller tidal volumes and showed consistent increases in arterial PCO2 lasting up to 10 min. The changes seen immediately on application of pressure, namely apneic periods followed by breathing in which inspiratory duration was shortened while expiratory duration was substantially increased, indicates that conscious guinea pigs have active inflation reflexes. We concluded that the reflex responses rather than mechanical factors probably account for the underventilation in the guinea pigs and that guinea pigs are not nearly as well equipped as is man to defend gas exchange in the face of nonmetabolic shifts in lung volume.


Liver blood flow and oxygen consumption during hypocapnia and IPPV in the greyhound. Pentobarbital-anesthetized greyhounds were passively hyperventilated using intermittent positive-pressure breathing (IPPV) and the effects of raised airway pressure, accompanied by hypocapnia and then by normocapnia, on liver blood flow and oxygen consumption were studied. Electromagnetic flowmeters were used to measure hepatic arterial, portal venous, and splenic venous blood flow. Studies were carried out at three levels of raised airway pressure, both at normocapnia and hypocapnia. It was found that hypocapnic hyperventilation produced a decrease in portal venous and hepatic arterial blood flow. Normocapnic hyperventilation resulted in a restoration of portal venous blood flow but with a further decrease in hepatic arterial blood flow. A decrease in oxygen consumption with hypocapnia, returning to control values with normocapnia, was seen. It is suggested that the reduction in liver blood flow and oxygen consumption seen with passive hyperventilation is chiefly an effect of hypocapnia and is largely reversed by restoration of normocapnia.


A kinetic model of prostaglandin metabolism in the lung. We have measured the instantaneous extraction of prostaglandin E1 (PGE1) after a single bolus injection of PGE1 and indocyanine green dye into the pulmonary artery of isolated cat lungs. The extraction ratio versus time curves exhibited a characteristic shape; at early times they  were concave upward and later in time concave downward. To evaluate this date we utilized a model in which themechanism of PGE1 uptake is saturable and follows Michaelis-Menten kinetics. The model assumes heterogeneous perfusion of the exchanging region of the lung and can be solved by regression analysis to obtain Km and Vmax from the data collected from a single bolus injection. The results indicate that the shape of the extraction ratio curve manifests the influence of nonlinear uptake and heterogeneous perfusion and that the kinetic parameters may be calculated from the data obtained after a single bolus injection ofPGE1.


Size of the pool of alveolar neutrophils in normal rabbit lungs. Morphometric methods and two unique characteristics of neutrophils enabled us to measure the size of the pool of neutrophils in alveoli of rabbit lungs. Rabbit lungs contained an estimated 6.11 x 10(4) alveolar neutrophils/g wet wt of lungs, and 9.57 x 10(5) alveolar neutrophils/rabbit. Lung lavage was successful in removing an average of 42.2% of the neutrophils in the air containing spaces of the lungs. An average of 2.5 +/- 3.5 (SD)% of the cells in the lung washes were neutrophils, but an average of 10.23 +/- 5.0 (SD)% of the cells that were free in the alveolus were neutrophils. Studies of the interaction of alveolar macrophages and neutrophils in vitro showed that neither cell phagocytoses or destroys the other in significant quantities; however, alveolar macrophages containing neutrophils have been observed.


Cardiovascular effects of positive-pressure ventilation in normal subjects. In normal subjects during 15-min positive-pressure ventilation with 10 cmH2O end-expiratory pressure (PEEP), cardiac output fell 19% due to a fall in stroke volume. Transmural mean right atrial pressure rose 3.1 cmH2O and right ventricular end-diastolic diameter increased 15%. Simultaneously, left ventricular end-diastolic diameter decreased 21%, ejection time increased 11%, and velocity of circumferential fiber shortening fell 30%. Thus, right ventricular filling increased and left ventricular filling decreased. The function of the right ventricle was impaired and the function of the left ventricle may have been impaired. Cardiac output gradually increased due to a 7% increase in heart rate as PEEP was continued for 1 h and transmural mean right atrial pressure also increased further by 2.4 cmH2O. Compensation for the reduced stroke volume occurred as filling pressures and heart rate rose, but ventricular function remained impaired for the entire duration of PEEP. On resuming spontaneous breathing, cardiac output and ventricular function returned to base-line levels. We conclude that the reduced cardiac output during PEEP is not due to a direct mechanical reduction in right ventricular filling.


Palatal process movement in the rat as demonstrated in frozen sections. During mammalian secondary palate development, movement of the lateral palatine processes from the vertical plane to the horizontal plane involves a complex interaction of the palatine processes and the tongue within a dynamic growing oronasal cavity environment. This study of pre-fixation facial profile photographs and frozen sections was undertaken to evaluate external and internal changes in the oronasal complex during secondary palate elevation without the shrinkage known to be present with routinhistological preparation of embryonic tissues. Frozen sections of Sprague-Dawley rat embryos between 15 and 17 days of (conceptual) age were prepared by hexane quenching and cryostat cutting. The results showed that, during the stages of palate development prior to shelf elevation, the tongue and mandible became positioned beneath the primary palate, and the vertical dimension of the oronasal cavity increased by the lifting of the nasomaxillary complex. The tongue and mandible maintained contact with the primary palate, whereas a space developed above the tongue in the middle and posterior palate regions. As the vertical dimension increased the volume of the palatomaxillary processes increased rapidly, the tongue became squeezed, and the palatine processes bulged medially above the level of the tongue. After shelf elevation extensive contact between the palatine processes was present, and the tongue became flattened. The results of this study support the observations of Lazzaro (1940) that rapid increase in shelf volume owing to increased intercellular volume contributes to movement of the processes above the tongue. But, rapid increase in shelf volume occurred contemporaneously with the time when the tongue and mandible outgrew the oronasal cavity and became positioned beneath the primary palate. Therefore, it would appear that the simultaneous occurrence of a lower and more forward tongue position, and an increased palatomaxillary process volume without change in maxillary width, contributed to the medial movement of the processes above the tongue.


PS-5, a new beta-lactam antibiotic. III. Synergistic effects and inhibitory activity against a beta-lactamase. PS-5 was shown to have synergistic activity in combination with other beta-lactam antibiotics and it markedly decreased the minimum inhibitory concentration values of ampicillin or cephaloridine with a beta-lactamase-producing Proteus vulgaris strain on agar plates. The synergistic activities were also shown in bactericidal activity in liquid medium. PS-5 was shown to be inhibitory against an extracted beta-lactamase of P. volgaris.


Antibiotic X-5108. IX. Chemical conversion of mocimycin to aurodox and derivatives of aurodox, goldinamine and mocimycin. Mocimycin was converted to the acylesters by selective acylation of the hydroxyl group of the 4-hydroxy-1-methyl-2(1H)pyridinone moiety. Subsequent N-methylation at the nuclear nitrogen and removal of the protective group from the resulting reaction products afforded aurodox. Mono-O-acetylmocimycin and several analogous aurodox esters thus prepared possess antibacterial activity in vitro and growth-promotion properties in poultry. Esters of aurodox involving the hydroxyl group of the 4-hydroxy-1-methyl-2(1H)pyridinone moiety are activated. Accordingly, acetic acid treatment of the aurodox esters generates O-acylgoldinamines which undergo transacylation furnishing N-acylgoldinamines. Alternatively, N-acylgoldinamines can be prepared by selective mono--o-arylsulfonylation of aurodox, liberating o-arylsulfonylgoldinamine by treatment with acetic acid followed by N-acylation and removal of the protective arylsulfonyl group. A third approach to N-acylgoldinamines consists in direct N-acylation of goldinamine itself which is prepared by acetic acid treatment of aurodox. None of these derivatives prepared, however, exhibited significant antimicrobial or growth-promoting properties, suggesting that goldinonic acid moiety, or a closely related derivative thereof, is required for biological activity.


Controlled biosynthesis of neoviridogriseins, new homologues of viridogrisein. I. Taxonomy and fermentation. Neoviridogriseins, new homologues of viridogrisein, were produced with viridogrisein and griseoviridin by Streptomyces sp. P8648 which was identified as a strain of Streptomyces griseoviridus.