Mutants in transmission of chemotactic signals from two independent receptors of E. coli. We have characterized chemotactic mutants of E. coli that appear to be defective in a common linkage of two independent receptors to the central chemotactic components. The mutants do not respond to gradients of ribose or galactose and thus are called trg (taxis to ribose and galactose), after Ordal and Adler (1974b). These trg mutants are indistinguishable from their parent in tactic response to other attractants, swimming pattern, growth rates, and transport of ribose and galactose. The mutant cells contain the usual amounts of ribose and galactose receptors, and those proteins function normally in their other role, transport of their respective ligands. The mutations, generated by insertion of translocatable drug-resistance elements (transposons)8 are located near 31 min on the map of the E. coli chromosome, a locus far removed from the genes coding for the ribose and galactose receptors. Trg mutants do not resemble either specific receptor mutants or che mutants. The nature of the requirement for the trg product in the response to ribose and galactose is not defined, but evidence for interference of tactic signals from the ribose and galactose receptors (Strange and Koshland, 1976) supports the idea that the product functions directly in the transmission of tactic signals from the two receptors to the flagella.


DNA sequence analysis of Tn10 insertions: origin and role of 9 bp flanking repetitions during Tn10 translocation. The sequences of insertions of the translocatable tetracycline-resistance element Tn10 into the repressor (cl) gene of bacteriophage lambda have been analyzed. Each insertion contains the same discrete set of Tn10 sequences flanked by a direct repetition of a 9 bp cl-gene sequence. The flanking repititions are generated by duplication of information present only in the target DNA molecule rather than by a Campbell-type recombination event between one 9 bp sequence on the target DNA and a second one provided on the incoming element. The repetitions do not contain genetic or structural information important for translocation. A genetically constructed Tn10 insertion which lacks flanking repetitions is fully functional in translocation to a new position. Tn10 insertions cluster at preferred positions along a target DNA (Kleckner et al., 1979). Sequence analysis shows that four independently isolated cl::Tn10 insertions occur at identical positions in the cl gene. We speculate that homology between Tn10 and its target, at some distance from the site of the actual recombination event, could be relevant to the preference of Tn10 for particular insertion sites.


Evidence for transposition of dispersed repetitive DNA families in yeast. Dispersed repetitive DNA sequences from yeast (Saccharomyces cerevisiae) nuclear DNA have been isolated as molecular hybrids in lambdagt. Related S. cerevisiae strains show marked alterations in the size of the restriction fragments containing these repetitive DNAs. "Ty1" is one such family of repeated sequences in yeast and consists of a 5.6 kilobase (kb) sequence including a noninverted 0.25 kb sequence of another repetitious family, "delta", on each end. There are about 35 copies of Ty1 and at least 100 copies of delta (not always associated with Ty1) in the haploid genome. A few Ty1 elements are tandem and/or circular, but most are disperse and show (along with delta) some sequence divergence between repeat units. Sequence alterations involving Ty1 elements have been found during the continual propagation of a single yeast clone over the course of a month. One region with a large number of delta sequences (SUP4) also shows a high frequency of sequence alterations when different strains are compared. One of the differences between two such strains involves the presence or absence of a Ty1 element. The novel joint is at one inverted pair of delta sequences.


Identification and mapping of the transcriptional and translational products of the yeast plasmid, 2mu circle. We have identified two major and approximately ten minor poly(A)-containing RNA species in S. cerevisiae which arise from in vivo transcription of the yeast plasmid, known as 2mu circle. The two major species, which are 1325 and 1275 bases in length, are transcribed from the two unique halves of the plasmid and extend into the inverted repeat sequences which separate the unique regions. The map positions of the minor transcripts, which range in length from 350 to 2600 bases, indicate that except for a small region of the genome in which no transcription is observed, both strands of the entire 2mu circle genome are transcribed. We also present evidence demonstrating that RNA transcribed from 2mu circular DNA is used to program the synthesis of specific proteins in yeast: that is, yeast RNA complementary to 2mu circle DNA can be translated in vitro to produce specific polypeptides of substantial size. Finally, the pattern of transcription of 2mu circle suggests the possibility that messenger RNA species are derived by cleavage of larger transcripts, and in addition, that the intramolecular recombination of 2mu circle which occurs in yeast functions as a genetic switch to allow separate expression of two sets of genes on the 2mu circle genome.


Initial adhesion of human fibroblasts in serum-free medium: possible role of secreted fibronectin. Experiments were carried out to test the hypothesis that the initial attachment and spreading of human fibroblasts in serum-free medium occurs to cell fibronectin which has been secretd spread on tissue culture substrata in serum-free medium in 60 min. When potential protein adsorption sites on the substratum were covered with bovine serum albumin before initial human fibroblasts attachment, their subsequent attachment to the substratum was prevented. When substratum adsorption sites were covered immediately after initial attachment, subsequent cell spreading was prevented. The distribution of fibronectin on human fibroblast surfaces during initial attachment and spreading was studied by indirect immunofluorescence analysis using a monospecific anti-cold-insoluble globulin antiserum. The initial appearance (10 min) of fibronectin was in spots over the entire cell surface. Concomitant with human fibroblast spreading, the random distribution of sites disappeared, and most fibronectin was subsequently observed in spots at the cell substratum interface (60 min). A fibrillar pattern of fibronectin appeared later (2-8 hr). The sites beneath the cells could be visualized as footprints on the substratum following treatment of the attached human fibroblasts with 0.1 M NaOH. A second fluorescence pattern of fibronectin secreted on the substratum was characterized by a diffuse halo around the cells and a very faint, diffuse staining elsewhere on the substratum. Another cell type (baby hamster kideny cells) was used to assay biologically for the presence or absence of the factor secreted by human fibroblasts on the substratum. Human fibroblasts were found to secrete an adhesion factor for baby hamster kidney cells into the substratum in a time- and temperature-dependent fashion, and immunological studies indicated that the factor secreted by human fibroblasts was cross-reactive with cold-in-soluble globulin, the plasma form of fibronectin. The conditioning factor secreted by the human fibroblasts was also found to be an attachment and spreading factor for human fibroblasts in experiments measuring human fibroblast adhesion to fibronectin footprints of human fibroblasts. Substratum-adsorbed cold-insoluble globulin was also found to be an attachment and spreading factor for human fibroblasts. Based upon the timing of appearance of conditioning factors on the substratum and the immunofluorescence patterns, it seems that the diffusely organized fibronectin on the substratum constitutes the sites to which cell attachment occurs. The bright spots of fibronectin that appear beneath the cells may represent fibronectin reorganization during cell spreading.


Site-specific cleavage of DNA by E. coli DNA gyrase. E. coli DNA gyrase, which catalyzes the supercoiling of DNA, cleaves DNA site-specifically when oxolinic acid and sodium dodecylsulfate are added to the reaction. We studied the structure of the gyrasecleaved DNA because of its implications for the reaction mechanism and biological role of gyrase. Gyrase made a staggered cut, creating DNA termini with a free 3' hydroxyl and a 5' extension that provided a template primer for DNA polymerase. The cleaved DNA was resistant to labeling with T4 polynucleotide kinase even after treatment with proteinase K. Thus the denatured enzyme that remains attached to cleaved DNA is covalently bonded to both 5' terminal extensions. The 5' extensions of many gyrase cleavage fragments from phi X174, SV40 and Col E1 DNA were partially sequenced using repair with E. coli DNA polymerase I. No unique sequence existed within the cohesive ends, but G was the predominant first base incorporated by DNA polymerase I. The cohesive and sequences of four gyrase sites were determined, and they demonstrated a four base 5' extension. The dinucleotide TG, straddling the gyrase cut on one DNA strand, provided the only common bases within a 100 bp region surrounding the cleavage sites. Analysis of other cleavage fragments showed that cutting between a TG doublet is common to most, or all, gyrase cleavages. Other bases common to some of the sequenced sites were clustered nonrandomly around the TG doublet, and may be variable components of the cleavage sequence. This diverse recognition sequence with common elements is a pattern shared with several other specific nucleic acid-protein interactions.


Deletions of a tyrosine tRNA gene in S. cerevisiae. Genetic fine structure analysis of a tyrosine tRNA in yeast revealed that complete deletions of the gene occurred at an unusually high frequency. Among 56 spontaneous mutations at the SUP4 locus, 16 were classified as deletions as judged by their failure to recombine with any other mutations known to map within the gene. Physical analysis of each deletion confirmed the genetic result. The deletions fall into two size classes: ten are 2100 bp deletions and six are 2800 bp deletions. These results imply that the physical structure of the region surrounding the SUP4 locus, which is known to contain short repeated segments, has a direct role in promoting deletions.


DNA sequences of promoter regions for rRNA operons rrnE and rrnA in E. coli. The nucleotide sequences have been determined for the promoter regions of two ribosomal RNA operons, rrnA and rrnE, in E. coli. The sequences cover the two in vitro transcription start sites identified for each operon (Gilbert, der Boer and Nomura, 1979). The first two start sites are 283 and 291 bp preceding the mature 16S rRNA (m16S rNA) coding regions for rrnE and rrnA, respectively; the second start sites are 174 and 174 +/- 1 bp preceding the m16S rRNA coding regions for rrnE and rrnA, respectively. Each of these start sites has an identifiable "Pribnow box" sequence 6-7 bp upstream from the start site. The nucleotide sequences of the two operons have nearly complete homology from the m16S rRNA coding regions to positions 145 bp upstream from those regions, and at the regions surrounding the Pribnow boxes preceding the first start sites. The DNA sequences indicate that the RNAs transcribed from the first start sites of rrnE and rrnA are quite different in their first 150 nucleotides. These heterogeneous regions, however, precede the RNAse III cleavage sites (deduced previously by Young and Steitz, 1978), and the "precursor 16S rRNA" molecules are largely homogeneous. The nucleotide sequences of the promoter regions of the two rRNA operons are also compared with those or rrnD and rrnX, determined by Young and Steitz (1979), and some common features are discussed.


Identification of initiation sites for the in vitro transcription of rRNA operons rrnE and rrnA in E. coli. The transcription initiation sites of E. coli rRNA operons were determined using various DNA fragments derived from transducing phage lambda metA20 carrying rrnE and from hybrid plasmid pLC19-3 carrying rrnA. In vitro transcription products were analyzed for their 5' end sequences and their oligonucleotide compositions. The results are in full agreement with the nuceotide sequences of the DNA templates described in an accompanying paper (de Boer, Gilbert and Nomura, 1979) and allow us to make the following conclusions. First, there are two transcription, start sites on each of the rRNA operons; they are 109 bp apart in the case of rrnE and 117 +/- 1 bp aprart in rrnA. Second, the first start site is 283 bp upstream from the m16S rRNA coding region in the case of rrnE, while is 291 bp upstream in rrnA. Initiation starts with ATP in both cases. Finally, the second start sites are 174 and 174 +/- 1 bp from the m16S rRNA genes in rrnE and rrnA, respectively. Initiation starts with CTP in both cases. We have also shown that in the present in vitro transcription system, guanosine tetraphosphate (ppGpp) inhibits the synthesis of full-sized RNAs from both start sites in each rRNA operon.


Asymmetry and directionality in production of new cell types during clonal growth: the switching pattern of homothallic yeast. Homothallic Saccharomyces yeasts efficiently interconvert between two cell types, the mating types a and alpha. These interconversions have been proposed to occur by genetic rearrangement ("cassette" insertion) at the locus controlling cell type (the mating type locus). The pattern of switching from one cell type to the other during growth of a clone of homothallic cells has been followed by direct microscopic observation, and the results have been summarized as "rules" of switching. First, when a cell divides, it produces either two cells with the same mating type as the original cell or two cells that have switched to the other mating type. This observation suggests that the mating type locus is changed early in the cell cycle, in late Gl or during S. Second, the ability to produce cells that have switched mating type is restricted to cells that have previously divided ("experienced cells"). Spores and buds ("inexperienced cells") rarely if ever give rise to cells with changed mating type. A homothallic yeast cell thus exhibits asymmetric segregation of the potential for mating type interconversion--at each cell division, the mother, but not the daughter, is capable of switching cell types in its next division. Homothallic cells also exhibit directionality in switching: experienced cells switch to the opposite cell type in more than 50% of cell divisions. These results show that the process of mating type interconversion is itself controlled during growth of a clone of homothallic cells. By analogy and extension of these results, we propose that multiple cell types can be produced in a specific pattern during development of a higher eucaryote in a model involving sequential cassette insertion.


In vitro processing of B. mori transfer RNA precursor molecules. Ribonuclease P and 3'-5' nuclease, two enzymatic activities necessary for tRNA synthesis in E. coli, are also found in the silkgland cells of Bombyx mori. B. mori subcellular extracts containing RNAase P activity can cleave the E. coli tRNA precursor molecule endonucleolytically at the same site as the E. coli enzyme, and will also cleave in vitro all E. coli tRNA precursors (pre-tRNAs) which the bacterial enzyme recognizes. B. mori RNAase P will not cleave two E. coli RNAase P substrates that are structurally unrelated to tRNA. Pre-tRNAs from B. mori contain extra 5' and 3' nucleotides as judged by RNA fingerprinting and 5' terminal phosphate analysis. Crude silkgland extracts containing both RNAase P and 3'-5' nuclease can remove the 5' and 3' extra nucleotides from B. mori pre-tRNAs, whereas purified fractions containing RNAase P remove only 5' extra nucleotides. Only large silkworm pre-tRNAs were found to be susceptible to cleavage by B. mori RNAase P. This observation and sequence analysis of intermediates of in vitro processing reactions indicate a two-step process of pre-tRNA maturation in which extra 5' nucleotides are first removed by RNAase P and extra 3' nucleotides are then trimmed off by a 3'-5' nuclease.


In vitro transcription and processing of a yeast tRNA gene containing an intervening sequence. A gene for Saccharomyces cerevisiae tRNATrp has been sequenced which contains an intervening sequence of 34 bp (H. S. Kang and J. Abelson, unpublished results). The mutant yeast strain ts-136 accumulates a precursor to tRNATrp which contains mature ends and is colinear with the tRNATrp gene. A nuclear extract from Xenopus oocytes is capable of supporting transcription of the tRNATrp gene contained on plasmid pBR313. The products are precursor tRNAs which contain the intervening RNA sequence. The Xenopus extract accurately splices the precursor transcript to mature-sized tRNATrp.


Cell surface changes during muscle differentiation in vitro: a study with the probe 2,4,6-trinitrobenzene sulphonate. Cell surface changes during muscle differentiation in vitro, were investigated using the non permeant probe 2,4,6-trinitrobenzene sulphonate (TNBS) in order to label the aminogroups of proteins exposed on the outer surface of the plasma membrane. Surface proteins of chick myotubes and 'mature' unfused myoblasts (myoblasts grown for 7 days in a calcium-depleted medium) were found to bind an equal amount of probe, which is twice the amount bound by surface proteins in 'immature' myoblasts (1--2 days of culture) and fibroblasts. This indicates that a 'remodelling' of the plasma membrane outer surface takes place in the course of muscle cell differentiation even in the absence of cell fusion. Moreover, the total amount of TNBS bound to the surface was 4--5 times greater in myotubes than in unfused myoblasts. This appears to result from the surface expansion which occurs in myotubes during the development of the T tubule system.


Demonstration of the simultaneous presence of transferrin, hemopexin and albumin in the same adult rat hepatocyte. The location of three plasma proteins (transferrin, hemopexin, and albumin) in hepatocytes was investigated in adult rats. The synthesis of transferrin anf hemopexin has been established by ultrastructural studies showing a labeling of the rough endoplasmic reticulum (RER). By using an indirect immunoenzymatic method with monospecific antibody solutions, the three proteins were detected in the same hepatocyte. The simultaneous presence of different plasma proteins in hepatocytes seems to point to the fact that the synthesis in these cells could be a non-specialized type.


Cold-stable microtubules in the cytoplasm of mouse embryo fibroblasts. Treatment of cultured mouse embryo fibroblasts with Triton X-100 after prolonged incubation at 0 degrees C reveals a network of microtubules in the cytoplasm of cooled cells. This network of cold-stable microtubules was demonstrated by immunofluorescence microscopy, using a monospecific antibody against tubulin and by electron microscopy. The cold-stable microtubules, as well as the ordinary cytoplasmic microtubules, were sensitive to Ca ions and were not observed in the cells pre-treated with colchicine or vinblastine. The cold-stable microtubules do not seem to be in equilibrium with the pool of depolymerized tubulin at 0 degrees C.


Effect of intracellular injection of La3+ and Mn2+ on electrical coupling of heart cells. The effect of intracellular injection of La3+ and Mn2+ on the electrical coupling of canine Purkinje cells investigated. It was found that La3+ causes cell decoupling in about 100 sec, increased the input resistance of the injected cell too. Mn2+ injection reduced drastically the coupling coefficient but did not abolish cell communication. Intracellular injection of La3+ or Mn2+ also caused shortening of the action potential and hyperpolarized the the heart cells. La3+ seems to be as effective as Ca or even stronger than Ca in suppressing intercellular communication in heart fibres.


Size of poly (A) +-mRNA in Saccharomyces cerevisiae polysomes. The size of poly (A) +-mRNA in different classes of yeast polysomes is estimated. The average molecular weight of long-term labelled polysomal poly (A) +-mRNA is about 0,65 x 10(6) daltons. Approximately 60% of the poly (A) +-mRNA polynucleotide chains located at the 5' end, are unprotected by ribosomes and degraded by nucleases upon incubation of cell lysates, to yield a population of poly (A) +-mRNA with an average molecular weight of 0,25 x 10(6) daltons.


Effects in bacterial systems of Pt(II) complexes with antitumour activity. A series of alicyclic amine complexes of the cis-Pt(am)2Cl2 type, showed specific antitumour activity against various animal tumours. We have tested these compounds in a number of bacterial systems indicative of their interaction with bacterial DNA.


Mutagenicity of methyl-, ethyl-, propyl- and butylnitrosourea towards Escherichia coli WP2 strains with varying DNA repair capabilities. Methyl- (MNUA), ethyl- (ENUA), propyl- (PNUA) and butylnitrosourea (BNUA) have been tested for toxicity and mutation in a liquid suspension assay towards Escherichia coli WP2 and some of its repair deficient derivatives. A comparison of survival rates after nitrosourea exposure between WP2 and WP2 uvrA showed no difference between the two strains but a consistent difference in potency between the various nitrosoureas studied. Toxicity increased in the order MNUA less than PNUA less than ENUA less than BNUA. ENUA and PNUA induced a greater number of trp+ revertants in both strains than did MNUA and BNUA, particularly at low survival rates. None of these differences in biological potency could be accounted for by differences in rates of hydrolysis. ENUA, PNUA and BNUA were non-mutagenic towards WP2 lexA, WP2 recA and WP2 uvrA lexA, whereas MNUA did induce mutations. Ethyl methanesulphonate (EMS) was able to mutate WP2 lexA. These results are discussed in the light of current theories regarding the mechanism of action of these compounds.


Intrarenal blood flow distribution during endotoxemia in dogs. Intrarenal blood flow distribution during the stages of endotoxemia in the dog was studied using radioactive inert gas washout. Intrarenal blood flow distribution was determined: a) at control, b) 0.5 hours following injection of a lethal dose (3 mg/kg) of E coli endotoxin, and c) 2.5 hours following endotoxin injection in control dogs and dogs pretreated with 4 mg/kg of phenoxybenzamine. One-half hour following endotoxin injection, components I and II of the inert gas washout curve fused. Presumably this fusion occurred because component I flow decreased to a level indistinguishable from that of component II. Following 2.5 hours of endotoxemia, components I and II were both present. Pretreatment with phenoxybenzamine completely prevented the fusion of components I and II, although the mean arterial blood pressure was substantially lower than in dogs not pretreated with phenoxybenzamine. After 2.5 hours of endotoxemia, four of the five phenoxybenzamine pretreated dogs still had two clearly defined washout components. It  is concluded that the renal cortical vascular response in endotoxemia is similar to that reported following hemorrhage and that the alpha-adrenergic nervous system plays a major role in decreasing renal cortical blood flow.


Beneficial effects of methylprednisolone in patients on cardiopulmonary bypass. Methylprednisolone sodium succinate (MPSS) was given to 50% of patients undergoing coronary artery bypass graft in a 50-patient double-blind clinical study to ascertain the beneficial effects of this glucocorticoid in decreasing ischemic injury to the heart. MPSS (1 gm) was given intravenously at the start of cardiopulmonary bypass and another gram was given during the course of the open-heart procedure. Steroid-treated patients demonstrated a favorable response compared to placebo-treated controls in a variety of physiologic variables: Bypass graft flow rates measured prior to operative closure were 51-62% greater; urine output in the first 24 postoperative hours was 67% higher; fewer abnormalities were found in both chest x-ray and microbiology results. Thus, methylprednisolone sodium succinate treated patients exhibited more favorable trends for all critical variables measured.


Increased insulin responsiveness in endotoxicosis. The relation of endotoxicosis to insulin responsiveness was evaluated in male Holtzman rats. Salmonella enteritidis lipopolysaccharide at 0.5 or 1.0 mg per 300 g rat increased lethality in convulsive seizure deaths to 0.25, 0.50, or 1.0 U insulin sc. The hypoglycemic nadir induced by 0.05, 0.10, or 0.25 U of insulin sc was greater in rats rendered endotoxic with 1 mg of lipopolysaccharide IV. Oxidation of U-14C-D-glucose to 14 CO2 by endotoxic tissues in vitro was augmented in liver slices, epididymal fat pads, hemidiaphragms, and spleen slices; no pronounced glucose oxidation increases occurred in lung, heart, stomach, cerebrum, kidney, or whole blood. Epididymal fat pads from endotoxic rats (100 g) manifested increased basal glucose oxidation as well as an enhanced maximal response to incremental insulin doses of 0.01 to 25 mU/ml. It is suggested that altered tissue responsiveness in concert with hyperinsulinemia underlie the profound alterations in glucose homeostasis during endotoxicosis.


Pulmonary vascular response to endotoxin in normal and lymphocyte depleted sheep. The cardiopulmonary effects of intravenously administered Escherichia coli endotoxin were studied in unanesthetized sheep. One group of animals was depleted of circulating T-lymphocytes while a non-depleted group served as control. T-lymphocyte depletion was accomplished by chronic thoracic duct drainage of lymph, removal of lymphocytes by continuous flow centrifugation and return of the cell free lymph intravenously. The T-lymphocyte depleted sheep demonstrated markedly obtunded increases in pulmonary arterial pressure and pulmonary vascular resistance following endotoxin when compared to the effects of the lipopolysaccharide in control animals. additionally, the lymphocyte depleted group showed a significant augmentation of myocardial contractility which occurred at the same time as marked systemic hypotension. This period of extreme hypotension following endotoxin is presumed to be accompanied by a reflex increase in the activity of the sympathetic nervous system. The control sheep, although equally hypotensive at this time, did not demonstrate a significant increase in myocardial contractility from the preendotoxin value. The results of these experiments indicate that T-lymphocytes may mediate some of the pathophysiological effects of bacterial endotoxin on the cardiovascular system.


Microvascular plasma velocity and indicator dispersion with hemorrhage. The effects of stepwise hemorrhages on plasma flow velocity and indicator (FITC-Dextran) dispersion in series and parallel coupled microvascular vessels has been studied. The mesentery of cats (0.6 kg) anesthetized with Dial-Urethane was exposed and studied with a microscope equipped for fluorescense microscopy. Indicator was injected as a bolus (0.1 ml in 0.5 seconds) in a small branch of the mesenteric artery. Indicator curves were recorded from a video tape recording of the passage of the indicator by a video sampler with intensity sensitive windows. The mean transit time (t), appearance time (t(a)), peak time (t(p)), curve duration (t(E)), plasma velocity and vessel diameter changes were determined. Arterioles 68 +/- 8 micron and 35 +/- 3 micron and venules 55 +/- 6 micron constricted gradually with hemorrhage. Arterioles 20 +/- 2 micron constricted with mild hemorrhage and remained constricted with further hemorrhage. Arteriolar and venular plasma velocities decreased abruptly with mild hemorrhage and then continued to decrease gradually with further hemorrhage. Capillary flow ceased after moderate hemorrhage and was not reestablished until at least an hour after reinfusion. Arteriole t increased with hemorrhage but t increased much more in capillaries and venules. t(E) changes paralled t changes. The ratio t(a)/t was lower for venules than arterioles and both decreased with hemorrhage but the venular ratio decreased significantly more. Venular t(p)-t(a) and t(E)-t(p) increased more than arteriolar values. Hemorrhage increased indicator dispersion with the greatest effect occurring between the arteriolar and venular vessels.


Second-degree atrioventricular block.

Second-degree atrioventricular block. 1) While it is possible only one type of second-degree AV block exists electrophysiologically, the available data do not justify such a conclusion and it would seem more appropriate to remain a "splitter," and advocate separation and definition of multiple mechanisms, than to be a "lumper," and embrace a unitary concept. 2) The clinical classification of type I and type II AV block, based on present scalar electrocardiographic criteria, for the most part accurately differentiates clinically important categories of patients. Such a classification is descriptive, but serves a useful function and should be preserved, taking into account the caveats mentioned above. The site of block generally determines the clinical course for the patient. For most examples of AV block, the type I and type II classification in present use is based on the site of block. Because block in the His-Purkinje system is preceded by small or nonmeasurable increments, it is called type II AV block; but the very fact that it is preceded by small increments is because it occurs in the His-Purkinje system. Similar logic can be applied to type I AV block in the AV node. Exceptions do occur. If the site of AV block cannot be distinguished with certainity from the scalar ECG, an electrophysiologic study will generally reveal the answer.


Differences between Welsh and Canadian children on parts of the test of motor impairment. Four subtests, which measured hand function, were taken from the Test of Motor Impairment and given to 53 10-year-old children of normal intelligence. The results showed a wide variation in achievement with one test at a very inappropriate level of difficulty. Girls were consistently faster than boys, achieving a result which was statistically significant in one instance. It is suggested that this test requires restandardization for use among British populations. The provision of separate norms for the sexes would improve the disciminatory value of this instrument.


Analysis for diazepam and nordiazepam by electron-capture gas chromatography and by liquid chromatography. We describe the use of electron-capture gas chromatography or reversed-phase "high-performance" liquid chromatography for concurrent analysis for diazepam and nordiazepam in serum. In the gas-chromatographic analysis our use of a new chemically deactivated stationary liquid phase, SP 2250-DB (Supelco, Inc.), resulted in improved chromatographic sensitivity and peak symmetry for the two benzodiazepines as compared to that obtained with either OV-17or OV-1 phases. Steady-state concentrations of diazepam and nordiazepam in serum as determined by gas-liquid chromatography correlated closely with those found by liquid-liquid chromatography.


Gas-chromatographic analysis for valproic acid as phenacyl esters. We describe a novel isothermal gas-chromatographic procedure for measuring valproic acid. Plasma, with cyclohexanecarboxylic acid added as internal standard, is selectively extracted with pentane to minimize the extraction of other acidic drugs. To convert carboxylic acids to their phenacyl esters, alpha-bromoacetophenone is added to the organic extract before evaporating the solvent. These esters are relatively less volatile than the acids themselves and the extracting solvent can be removed without any loss of valproic acid or internal standard. The phenacyl esters, when chromatographed on 3% OV-17, produce sharp, well-shaped peaks and show high response for the flame ionization detector. Valproic acid is well separated from the internal standard, from reagents and plasma constituents, and from some commonly prescribed drugs that we examined. When alpha-bromo-p-nitroacetophenone is sued as the derivatizing agent, the resulting nitrophenacyl esters can be analyzed with use of a nitrogen-specific detector.


Determination of aminoglycoside antibiotics in biological fluids: a review. We describe current procedures for measuring aminoglycoside antibiotics. Although many of these techniques are suitable for clinical adaptation, selection of a method for use in a clinical laboratory will depend on the budget and availability of equipment and expertise.


Solid-phase enzyme immunoassay for serum ferritin. We describe a solid-phase enzyme immunoassay for ferritin in human serum, with use of a horseradish peroxidase-labeled antibody and a highly sensitive chromogen, 2,2'-azino-di(3-ethyl-benzthiazoline-6-sulfonate). The assay requires only 10 microL of serum per assay, relatively less time and labor than other assys for ferritin, and as little as 10 pg of ferritin can be measured. We believe this assay offers a reliable alternative to radioimmunoassay for serum ferritin.


Evaluation of homogeneous enzyme immunoassay of serum thyroxine with the Gilford 3500 analyzer. I evaluated homogeneous enzyme immunoassay (EMIT) of serum thyroxine with the Gilford 3500 analyzer. The samples are pretreated before quantitation on the Gilford 3500; the procedure thereafter is entirely mechanized. Forty-four samples may be analyzed per run. Precision and accuracy are good, and results correlate well with those by radioimmunoassay.


Homogeneous enzyme immunoassay for thyroxine compared with a radioimmunoassay technique. A homogeneous enzyme immunoassay (EMIT) for serum thyroxine determination has been evaluated. It was also compared to our routine method, a radioimmunoassay with use of a commercial kit, Tetra-Tab RIA. Within-day precision was very similar for the two methods, the CV ranging from about 2.5% at 150 nmol of thyroxine per liter to about 5.7% at 25 nmol/L. The two methods were compared by running 100 patients' serum samples. The resulting linear regression equation was: y = 1.088x - 17.9, with a correlation coefficient r = 0.979. The deviation from the theoretical line, y = x, wash shown to be primarily caused by the calibration of the methods, shown by running the EMIT calibrators in the radioimmunoassay method and vice versa. The choice of thyroxine method in the individual laboratory will then depend on considerations other than methodological factors.


Determination of 3,4-dihydroxyphenylethyleneglycol in urine by gas chromatography with a flame ionization detector: a new rapid method. 3,4-Dihydroxyphenylethyleneglycol, a major metabolite of noradrenaline in rat brain, is estimated alone or with 4-hydroxy-3-methoxyphenylethyleneglycol in rat and human urine by gas chromatography with a flame ionization detector. The samples are hydrolyzed and extracted at pH 2 with ethyl acetate. Then, to analyze only 3,4-dihydroxyphenylethyleneglycol the reaction with n-butaneboronic acid is carried out directly; if 4-hydroxy-3-methoxyphenylethyleneglycol also has to be estimated, preliminary acetylation in alkaline aqueous solution is performed. The advantages of the specificity due to the reagents used is discussed.


The pituitary-gonadal response to the gonadotrophin releasing hormone analogue D-Ser (TBU)6-Des Gly10-LHRH-ethylamide in normal men. We have studied the dose-response characteristics of the LHRH analogue D-Ser (TBU)6-Des Gly10-LHRH-ethylamide administered subcutaneously to five normal male volunteers. The relative potency of the analogue is about sixty times (FSH) and forty times (LH) that of the parent peptide and the increased potency and duration of action of the analogue lead to enhanced biological effect in terms of testosterone release. The prolonged duration of action of the analogue suggests that a single daily dosage regime could be used although further chronic studies with this potent analogue should be undertaken in normal volunteers to determine optimum dosage schedules.


The role of circulating immune complexes in the glomerular disease of experimental hepatosplenic schistosomiasis. The serological and renal changes were studied simultaneously in 115 mice infected with Schistosoma mansoni. IgG and IgM, but not IgA anti-S. mansoni antibodies were detected in the sera, together with circulating immune complexes containing schistosomal antigen. Glomerular mesangial deposits of IgA, IgM and C3 were observed. Despite the strong correlation observed between the occurrence of the circulating immune complexes containing schistosomal antigen and the glomerular deposits, results concerning the behaviour of IgA suggest that portal hypertension and liver damage have a role in the pathogenesis of glomerular lesions.


The interaction of anti-glomerular basement membrane antibody deposition with immune elimination of bovine serum albumin in the rabbit. We studied the interaction of two different forms of immune glomerular damage occurring simultaneously: anti-glomerular basement membrane (GBM) antibody fixation and immune elimination of bovine serum albumin (BSA). 125I-radiolabelled BSA anti-BSA immune complexes, formed in response to a single small intravenous dose (150 mg/kg) of 125I BSA, did not cause proteinuria in control animals within 15 days, despite evidence of immune elimination of the antigen. Similarly, a small dose of nephrotoxic globulin (NTG)(3.0 mg/kg) did not cause immediate proteinuria in controls. Test animals received the BSA injection followed by the NTG injection 5, 7 or 9 days later. In this way, antibody fixed to glomerular basement membrane antigens at various times after BSA anti-BSA complexes first appeared in the circulation. Animals were killed on day 15. Fifteen of the eighteen test animals developed moderate to severe clinical nephritis. The onset of the nephritis coincided with BSA elimination irrespective of when the NTG was given. Greatly increased amounts of nonlinear immunofluorescent deposits were demonstrated in the glomeruli of test animals. We concluded that there was a marked synergistic effect between two forms of immune glomerular damage (i.e. that mediated by anti-GBM antibody and immune complexes), which appeared to be due to the increased deposition of complex material in the presence of active fixation of anti-GBM antibody. The relevance of this finding to human glomerulonephritis is discussed.


Antibody penetration into living cells. I. Intranuclear immunoglobulin in peripheral blood mononuclear cells in mixed connective tissue disease and systemic lupus erythematosus. We have shown recently (Alarcón-Segovia, Ruíz-Argüelles & Fishbein, 1978) that an IgG anti-RNP antibody obtained from a patient with mixed connective tissue disease (MCTD) can penetrate viable mononuclear cells (MNC) from normal donors via their Fc receptors. Live MNC from twelve MCTD patients incubated with goat anti-Ig antibody had intranuclear antibody with a speckled pattern in a mean of 5.5% of all MNC and 57.3% of all Fc receptor-bearing MNC. We found intranuclear immunoglobulins in all twelve patients with MCTD which were present only in cells with Fc receptors. Only three out of twenty-one patients with systemic lupus erythematosus (SLE) were found to have intranuclear antibody in a mean of 17.2% of their Fc receptor-bearing cells. Further experiments with MNC from SLE patients revealed a partial blocking of penetration of antibody via Fc receptors. MNC from ten scleroderma, ten rheumatoid arthritis patients and eleven normal controls did not have intranuclear immunoglobulin. In vivo penetration of autoantibodies into Fc receptor-bearing cells in MCTD, and probably in SLE as well, may represent an important pathogenetic mechanism.


Pregnancy-induced involution of the thymus can be prevented by immunizing with paternal skin grafts: a strain-dependent effect. C57Bl female mice immunized and then mated to CBA males do not show the normal pregnancy-dependent involution of the thymus. In the reciprocal mating combination thymic involution is normal.


The pathogenetic role of Staphylococcus aureus in primary human glomerulonephritis. Antibody levels to a cell product of Staphylococcus aureus, antistaphylolysin antibody (AStaL), were determined in the sera of 185 patients with various renal diseases using the hemolysis inhibition test. Detection of Staphylococcus aureus antigen in renal biopsy specimens was performed by the immunofluorescent technique. Elevated AStaL values were observed in eleven patients. In four of them, Staphylococcus aureus antigen was clearly detected in the glomerular mesangial area associated with deposits of immunoglobulins and complement. Most of these patients showed marked elevation of AStaL values with low serum complement levels and had diffuse proliferative glomerulonephritis. These results suggest that Staphylococcus aureus may act as a specific antigen and play an important role in the pathogenesis of primary human glomerulonephritis.


Late hypertension following renal allotransplantation. Post-transplant hypertension has been observed in 98 renal allograft recipients who had good renal function and whose follow-up was more than 15 months. The role of the original diseased kidneys as well as the role of the renal pressor system was studied with emphasis on late hypertension. Post-transplant hypertension was found to be a multifactorial phenomenon with frequency decreasing as a function of prolonged graft survival. Renal artery stenosis was an infrequent but significant cause of hypertension and was found in 10 of 29 arteriograms performed. Renin studies performed in 34 hypertensive patients and in a control group of 11 recipients showed that elevation of plasma renin activity and of plasma aldosterone level is frequent but difficult to interpret, particularly when a renal artery stenosis is observed. These investigations may be useful in recognizing the role of retained diseased kidneys in sustaining hypertension. Plasma aldosterone was found elevated in nearly all of the patients. The role of corticosteroids and the similarity of post-transplant hypertension, in some cases, with the one kidney model of experimental hypertension are discussed.


Membranoproliferative glomerulonephritis type 1: comparison of natural history in children and adults. Clinical, laboratory and pathological data on 46 patients (29 children and 17 adult) with Type 1 membranoproliferative glomerulonephritis (MPGN) were reviewed in order to compare the natural history of the disease in two age groups. The nephrotic syndrome was the most common presenting clinical feature in both age groups. Established renal failure at time of biopsy was seen in adult males only. All the adults males, but none of the women, were either dead or in renal failure after a mean duration of diseases of 17.7 months. In contrast 43% of the children (both sexes) were in renal failure after a mean duration of disease of 51.6 months. Statistical analysis disclosed that only up to 48 months was there a significant difference in survival between the two age groups (P less than .01). Beyond this time the difference was not statistically significant. The difference in behaviour of MPGN in the two age groups is similar to that observed in other glomerulonephropathies.


The role of plasmapheresis in renal transplantation. Plasmapheresis has been studied in ten patients who received cadaveric renal allografts. In six patients (group A), plasma was carried out on the first post-operative day and then on alternate days until six treatments had been completed. No beneficial effect was observed but treatment was well tolerated and there were no complications. One patient retains a functioning graft. Plasma exchange was carried out on six consecutive days in five patients (group B) who were actively rejecting their grafts and in whom conventional methods of treatment had failed. All five patients showed improvement in graft function. Rejection was reversed in four patients and was contained in one patient. Subsequently rapid recrudescence of graft rejection occurred in one patient, extended graft survival was seen in two patients, and the other two patients have retained life supporting grafts. Plasmapheresis may have a part to play in the treatment of renal allograft rejection and further evaluation of this treatment is indicated.


Aminoglycoside nephrotoxicity: pathogenesis and prevention. Nephrotoxicity resulting from aminoglycoside antibiotics is a serious clinical problem and the incidence is probably increasing. The mechanism of renal toxicity is unclear but these agents affect several nephron functions including glomerular filtration, proximal tubular reabsorption, and urinary concentration. The degree of toxicity appears to correlate with the level of renal tissue concentration of aminoglycoside. Clinical nephrotoxicity is most likely to occur in the presence of volume depletion, advancing age, preexisting renal dysfunction and exposure to other nephrotoxins. Despite the use of dosing nomograms, nephrotoxicity still occurs in some patients and the decline in renal function may only become apparent after completion of the antibiotic course. Subclinical nephrotoxic effects from aminoglycosides probably occur in all patients treated with these agents and only the most severely affected have clinically apparent nephrotoxicity.


Cartilage cell differentiation: review.

Cartilage cell differentiation: review. Differentiation of cartilage cells from embryonic precursor cells is characterized by the onset of biosynthesis of at least two cartilage-specific gene products, type II collagen and cartilage-specific chondroitin sulfate proteoglycan (CSPG). Biochemical and immunological assays for these compounds now allow rapid, quantitative, and specific determination of the onset of cartilage differentiation, and present several advantages over assays that use histochemical stains or [35S]-sulfate incorporation into glycosaminoglycans. Chondrogenic differentiation also is associated with the formation of extracellular, high MW proteoglycan (CSPG) aggregates containing hyaluronic acid and the loss of fibronectin, or LETS protein, a cell surface glycoprotein found on presumptive chondroblasts, fibroblasts, and several other cell types. Comparatively little insight has been gained recently regarding the mechanism of cartilage cell differentiation. A number of factors or "inducers" of cartilage differentiation, such as chondroitin sulfate proteoglycan, notochord, spinal cord, low oxygen tension, and collagen substrates, increase the amount of glycosaminoglycan synthesis per cell, but the question remains open as to whether these factors also selectively increase the number of cells differentiating from precursor cells into chondroblasts, or whether they only increase cell viability. Other factors, such as conditioned medium from chondrocyte cultures, increase significantly the number of chondrocyte colonies arising in mass cultures of limb bud mesenchyme, but differentiation of nonchondrogenic cells is stimulated as well. Similarly, many inhibitors of cartilage differentiation, such as BrdUrd and 6-amino nicotinamide, also inhibit myogenic differentiation. It is possible that a unique and specific inducer or regulating factor of cartilage cell differentiation may not exist, for cartilage differentiation of normal embryonic mesenchyme can be triggered by a variety of environmental conditions, such as cell density, pH, potassium ion concentration, and fetal calf serum. These results imply that the temporal and spatial controls of cartilage differentiation are governed by environmental influences that are each of rather low specificity, but which together synergistically generate a morphogenetic control of high specificity. Signals which appear able to mimic those controlling normal cartilage differentiation seem to be exchanged during formation of ectopic cartilage. Muscle tissue and periosteum can be triggered to form cartilage by demineralized bone matrix. Chick limb bud epithelium induces type II collagen synthesis in embryonic mouse tooth germ, whereas homologous, oral epithelium induces the formation of dentin (type I collagen). Thus, the type of response elicited from mesenchyme cells can be determined by nearby epithelia, and that response frequently can be the formation of cartilage.


Sodium valproate in the prophylaxis of simple febrile convulsions. Thirty children with simple febrile convulsions were treated with sodium valproate following their second convulsion. Twenty-two of the 30 (73%) had no further convulsions during the one-year period of observation compared with 17 of 28 in the control group (61%). This was not a statistically significant difference. Side effects attributed to sodium valproate treatment were noted in 7 patients (23%), although 4 of these showed only mild transient gastrointestinal symptoms at high dosage. The study did not confirm any advantage in the use of sodium valproate as a prophylaxis for febrile convulsions, although compliance was good and significant side effects infrequent.


Acute dislocation of the patella in children. The natural history. On the basis of a survey of 55 cases, we can predict that one child in 6 with acute dislocation of the patella will develop recurrent dislocation. Two in 6 children have minor symptoms and the remainder are asymptomatic. The majority of patients show the radiological signs of patellofemoral dysplasia.


Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients. 20 routine patients with endogenous depression were investigated in a kinetic and 4 week treatment study. Steady-state plasma nortriptyline concentrations above 200 microgram/L were associated with a highly significant poorer therapeutic outcome. The correlations between the 24, 48 and 72 hour concentrations and steady-state concentration were very good (r = 0.81, 0.97, 0.94; p less than 0.0001) and better than the correlation between half-life and steady-state (r = 0.65; p less than 0.01). The Spearman rank correlations (Rs) between amelioration of depression measured by the Hamilton Rating Scale (HRS) and the 24, 48 and 72 hour concentrations were highly significant (Rs = 0.74, 0.79, 0.79; p less than 0.001) but for half-life (Rs = 0.33) the correlation was not significant. The single 48 hour plasma nortriptyline concentration following a single oral dose is recommended as a reliable simplified monitoring test suitable for a busy clinic. The test is useful for dosage adjustment to maximise antidepressant action and minimise toxicity. A tentative dosage adjustment schedule for individualising antidepressant treatment with nortriptyline based on the 48 hour or the 24 hour plasma concentration is proposed.


Clinical pharmacokinetics of propranolol. Propranolol is completely absorbed after oral administration and widely distributed throughout tissues. Elimination occurs almost wholly by metabolic transformation in the liver and excretion of the resultant products in the urine. An active metabolite, 4-hydroxypropranolol and possibly other active compounds have been identified; the former only after oral administration. After intravenous administration, hepatic extraction is so efficient that drug clearance is dependent on liver blood flow. After oral administration, propranolol kinetics depend on both dose and duration of therapy, but hepatic extraction remains relatively high and leads in presystemic ('first-pass') elimination and low systemic availability. During continued administration, plasma concentrations vary quite widely due to genetic differences superimposed on which are certain constitutional factors, such as age, and environmental factors such as smoking, other drugs, and perhaps diet. Hepatic, renal, thyroid and some gastrointestinal diseases as well as hypertension, malnutrition and hypothermia may be associated with alterations in propranolol disposition, all of which are consistent with the pathophysiology of these diseases.


Hematologic perturbations associated with salicylate. Interactions of salicylates with the hematopoietic system are reviewed. Development of anemia is discussed with respect to fluid retention, gastrointestinal bleeding, and hemolytic anemia. Alterations in polymorphonuclear leukocyte and platelet function are evaluated. Interactions with anticoagulants and with the coagulation system are identified.


Ticrynafen and probenecid in hyperuricemic, hypertensive men. In a double-blind crossover study of ticrynafen (TCN) and probenecid (PBC), 9 hypertensive, hyperuricemic men completed 12-wk courses of each drug. With a TCN dose of 125 mg daily, the fall in serum uric acid was prompt, dramatic, and lasting; it was equal to that after PBC, 500 or 1,000 mg daily. There was a small but significant early weight loss (diuresis) after TCN but no antihypertensive effect. Twelve days after resuming TCN for a proposed additional extension study 1 patient suffered acute, reversible bilateral ureteral obstruction, probably caused by sudden urinary uric acid precipitation.


Total body irradiation as a primary therapy in non-Hodgkin lymphoma. Thirty-three patients with non-Hodgkin lymphoma have been treated with total body irradiation (TBI). A very high remission rate is obtained in lymphocytic lymphomas (83%), but response in histiocytic lymphoma is extremely poor. Bone marrow study suggests that marrow depression following TBI is transient and complete recovery occurs provided the bone marrow is not already compromised by previous chemotherapy and radiation therapy. Extreme caution is required when TBI is repeated as this may lead to progressive marrow hypoplasia.


The torture or stretch arthritis syndrome (a modern counterpart of the medieval 'manacles' and 'rack'). A characteristic symmetrical bilateral polyarthritis syndrome is described, affecting the compartements of the wrist joints in a characteristic sequence. The pisiform-triquetral joint gives first, exposing the inferior radioulnar joint so that pisiform pain and tenderness are followed by painful supination. The proximal radiocarpal joint slackens next, followed by the mid-carpal joints. The lunates subluxate as their posterior attachments stretch. Synovial oedema may produce additional median and ulnar carpal tunnel syndromes. The best radiologic sign of this distraction is anterior subluxation of the lunates. Nocturnal arthralgia becomes severe; grip and the ability to write are lost and stretching now shows as a traumatic arthritis in the clavicular joints. The patient is incapacitated and therfore progression halts. A history of excessive straining and lifting is obtained eg with a wheel-barrow, iron pots or strenuous rowing. All serologic tests for rheumatoid disease are negative. Serum uric acid levels and blood sedimentation rates remain normal. There are clear analogies with old descriptions of the effects of torture by stretching from manacles or gauntlets or by the rack.


Concentration dependent plasma protein binding of salicylate in rheumatoid patients. Acetylsalicylic acid in daily doses from 3 to 6g was prescribed to 8 patients with rheumatoid arthritis. Various assessments of clinical effect, as well as steady-state plasma concentrations and degree of plasma protein binding, were determined at each dose. The unbound fraction of salicylate increased with the dose, resulting in very high free concentrations of drug in some patients. No statistically significant relationship between total or unbound plasma concentration and the measurements of clinical efficacy were obtained. The marked increase with the dose in unbound salicylate concentration is interpreted as the result of the saturable elimination known to occur for this drug.


Bioavailability of phenytoin: clinical pharmacokinetic and therapeutic implications. Phenytoin (diphenylhydantoin) is still the most commonly used anticonvulsant drug. It has certain physicochemical characteristics which make it liable to bioavailability problems. Due to the dose dependent metabolism of phenytoin and to its narrow therapeutic range even small changes in the bioavailability can cause major changes in serum phenytoin concentration and have serious clinical consequences. Numerous studies have demonstrated that there are products in general use with considerable differences in their bioavailiability. If the epilepsy is well controlled, a change from one phenytoin product to another should be avoided. Such a change might lead to phenytoin intoxication or to poor control of epilepsy, if the products do not have the same bioavailability. There seems to be no systematic difference in the bioavailability of phenytoin sodium and phenytoin acid, if products of high quality are used. On the other hand, various biopharmaceutical factors, e.g. particle size of phenytoin and the nature of excipients in the product, can have a marked effect on the oral absorption of phenytoin. Gastrointestinal diseases, the concomitant use of other drugs and dietary factors might also modify the bioavailability of phenytoin. The absorption of intramuscularly given phenytoin is rather slow and erratic. The existence of phenytoin products with different bioavailability is a serious practical problem which should be corrected as soon as possible.


Phototoxic polyacetylenes and their thiophene derivatives. (Effects on human skin). Polyacetylenes and their thiophene derivatives were tested for their effects on human skin. Topically applied alpha-terthienyl evoked bi-phasic phototoxic dermatitis and the appearance of 'sunburn' cells in human epidermis. None of 11 polyacetylenes had the same effect although they mimicked alpha-terthienyl in their phototoxic effects on Candida albicans and certain pathogenic microorganisms. The UV-mediated antibiotic activity of the compounds and their apparent lack of phototoxicity towards the skin suggest a potential topical therapeutic role for them in yeast, fungal and bacterial infections and light-responsive dermatoses. Their topical sensitizing capacity, however, has not yet been studied.


Induction of ovulation in the pregnant rat with luteinizing hormone-releasing hormone (LRH). Injection of luteinizing hormone-releasing hormone (LRH) induced ovulation in the pregnant rat on days 4 through 22. Only rats autopsied on days 2 and 3 failed to ovulate. Reduced responsiveness occurred between days 12 and 19; the least sensitive day was 16. Based on the number of ova recovered, day 21 was the most sensitive to LRH stimulation.


Reversal of the anti-implantational effect of luteinizing hormone-releasing hormone (LRH) by estradiol-17 beta and progesterone, alone and in sequence. The use of estradiol-17 beta and progesterone, alone or in sequence, to reverse the anti-implantational effect of 100 and 500 micrograms LRH has been studied. Sequential administration of the steroids was most efficacious in reversing the effect of 100 micrograms while progesterone alone proved to be the only treatment inhibiting the effect of 500 micrograms LRH. A possible difference in mechanism of action of the two doses of LRH is discussed.


2,3-Diphosphoglycerate: its role in health and disease. 2,3-Diphosphoglycerate (2,3-DPG) was first discovered and isolated in 1925. However, it was not until 1967 that the function of 2,3-DPG was explained. This resulted in multiple research projects devoted to elucidating the mechanism by which 2,3-DPG exerts it effect on the oxygen affinity of hemoglobin. In addition, a vast amount of research has been devoted to assessing the role of 2,3-DPG in oxygen transport in various physiological and pathophysiological states. In many instances, the results of this research have produced conflicting data which have dampened the initial enthusiasm which followed the discovery of the function of 2,3-DPG. However, much of this conflicting data can be explained by the fact that 2,3-DPG is only one of a number of factors influencing the transport of oxygen to the tissues. Several of these factors influence oxygen transport independently as well as by altering the synthesis of 2,3-DPG and modifying its effect on hemoglobin. In spite of the conflicting results, the overall data gathered thus far appears to be sound enough to warrant the extensive research now being done, particularly in the area of blood storage and transfusion therapy.


SI units.

SI units. The development of the International System of Units (Systeme International d'Unites--SE Units), based on seven fundamental quantities--length, mass, time, electric current, thermodynamic temperature, luminous intensity, and amount of substance is described. Units (coherent and noncoherent) for other measurable quantities that are derived from the seven basic quantities are reviewed. The rationale for the use of SE units in medicine, primarily as applied to clinical laboratory data, is discussed, and arguments are presented for the rigid adoption of SI units in medicine and for exceptions. Tables are given for the basic and derived SI units used in medicine and for conversion factors from the quantities and units in current use to those in SI units.


Serum ferritin.

Serum ferritin. (1) Brief introduction to iron metabolism and the biochemistry of ferritin. (2) Early studies of circulating ferritin. (3) Methods for measuring serum ferritin concentrations -- immunoradiometric, radioimmuno- and enzyme-linked immuno assays based on liver or spleen ferritin -- an evaluation of these techniques. (4) Serum ferritin concentrations in normal subjects -- definition of normality -- relationship between storage iron and serum ferritin concentrations -- changes during development from birth to old age -- iron deficiency -- variability of serum ferritin concentration -- evaluation of use of ferritin assay for assessment of storage iron levels. (5) Serum ferritin concentrations in disease -- hemochromatosis -- secondary iron overload -- liver damage -- infection and chronic disease -- cancer. (6) Assay of serum ferritin with antibodies to ferritins other than liver or spleen -- ferritinemia and cancer. (7) Properties of serum ferritin -- molecular weight -- iron content -- isoelectric focusing patterns -- carbohydrate content -- immunological properties. (8) Physiology of circulating ferritin -- release of ferritin from tissues -- origin of circulating ferritin -- clearance from the plasma -- iron and protein turnover. (9) Summary -- factors influencing serum ferritin concentrations and clinical use of ferritin estimations.


The effect of short-term discontinuation of high-level PEEP in patients with acute respiratory failure. PEEP is the most important therapeutic intervention in the management of acute respiratory failure. Transitory PEEP disconnection to perform clinically relevant maneuvers is often necessary, but its effect upon PaO2 and physiological shunt in patients requiring high-level PEEP is not clear from the literature. Nine adult patients in severe respiratory failure requiring high-level PEEP therapy were studied. The elimination of PEEP decreased the PaO2 and increased the physiological shunt. Maximum values were reached in about 4 min. Restoration of PEEP after 7.4 min in zero and end-expiratory pressure caused an increase in the PaO2 and decrease in the physiological shunt. Baseline values were restored in about 5 min. In 4 patients having endotracheal suction under hand ventilation with 100% oxygen, the continuous PaO2 recording showed an increase in PaO2 during the maneuver. Therefore, necessary manipulations can be accomplished without fear of negating the salutory effects gained by high-level PEEP therapy.


Use of the central venous pressure catheter to obtain blood cultures. The results of aerobic and anaerobic blood cultures obtained from a peripheral venopuncture and from the central venous pressure catheter were compared in critically ill patients admitted to the ICU to determine if pain and anxiety from multiple venopunctures could be alleviated while the physician's task is facilitated. The results were identical in 93.5% of the 92 comparisons. The discrepancies were evaluated and it was concluded that the method was easy, quick, and reliable. We recommend it as a suitable alternative to venopuncture.


The inaccuracy of using 100% oxygen to determine intrapulmonary shunts in spite of PEEP. The use of 100% oxygen to determine intrapulmonary shunting has been widely advocated. This study was performed to determine the clinical application of this technique in critically ill patients on PEEP. Determinations of intrapulmonary shunting using FIO2 of 0.45 and 1.0 were performed on 18 patients. Machine error was also calculated. Shunt calculations increased by an average of 52% (29% corrected for machine error) with the use of an FIO2 of 1.0 and returned to previous levels when an FIO2 of 0.45 was reinstituted. There was no statistical difference in shunt increase between patients on high (greater than or equal to 15 cm H2O) or low (less than 15 cm H2O) PEEP. The use of 100% oxygen to calculate intrapulmonary shunting in patients on PEEP is misleading in both physiological and methodological terms.


Multisystem failure: a review with special reference to drowning. Near-drowning represents an insult that can affect all organ systems. A common pathway for injury is hypoxemia, acidosis, and hypoperfusion. Pulmonary insufficiency and CNS dysfunction are major causes of morbidity and mortality. Variations in vascular volume, heart failure, renal failure, coagulation disorders, and electrolyte disturbances may also be present. Patients should be observed for multisystem failure and therapy tailored to the particular needs of each victim.


A simple technique for managing a bronchopleural fistula while maintaining positive pressure ventilation. The development of a bronchopleural fistula (BPF) is an infrequent, but potentially devastating complication of positive pressure ventilation. A case report is detailed in which a BPF arose in a patient on controlled ventilation with a PEEP of 22 cm H2O. Within 12 hours, fistula flow was continuous and accounted for 75% of the delivered tidal volume. PEEP fell rapidly during expiration; oxygenation steadily deteriorated as the aAO2 fell 0.27 to 0.14. Conventional treatment methods were unsuccessful, and a system was constructed for adding controlled levels of positive pressure ot the pleural space on the side of the BPF. By decreasing the expiratory transpulmonary pressure difference (PEEP minus pleural pressure), the fistula leak was greatly decreased, and PEEP and oxygenation were stabilized. This system can be rapidly constructed at the bedside with equipment routinely available in most hospitals and offers the ability to adjust the expiratory transpulmonary pressure, lung volume, and BPF flow while maintaining positive pressure ventilation with PEEP.


Orange juice quality with an emphasis on flavor components. This review studies the chemistry of the flavor of citrus juices with emphasis on the components of the flavor of orange juice and their origin in the different parts of the orange fruit. Citrus processing and the nature of the various products as they affect flavor are discussed. The composition of peel oil, aroma oil, orange juice, orange essence, and orange essence oil is presented. The relationship between flavor and color are discussed and the role of lipid components as they affect flavor stability and off-flavors are described. Spoilage resulting from microbes is briefly treated. The nutritional value of orange juice is cited.


The nutritional and physiological impact of milk in human nutrition. The nutritional value of milk as an important source of energy, high-quality protein, calcium, and riboflavin has been recognized for many years. Currently, the widespread use and promotion of milk in the U.S. as well as developing countries has been questioned. This review examines the nutrient composition of dairy products, factors that account for variability in composition of milk, milk processing, preservation, quality control, and contaminants (such as minerals, radionuclides antibiotics, microorganisms and their metabolites, herbicides, and insecticides) in milk. Consumption patterns for milk and evidence for its nutritional value, especially in children, are presented. Milk consumption has been related to disease or conditions such as atherosclerosis, milk allergy, lactose intolerance, anemia, dental problems, and others. Recent recommendations for dietary changes for individuals in the U.S. and other developed countries could affect the use of milk. In addition, the use of feeding programs in the U.S. and developing countries which are based primarily on milk has been criticized. The preparation of new types of milk designed to offset certain difficulties encountered with cow's milk are now being evaluated in humans.


Iron sources used in food fortification and their changes due to food processing. The effect of food processing on the biological availability of iron in iron-fortified foods is critically reviewed. Studies on changes in the chemistry of the iron in processed foods are examined. Various iron sources currently used in food fortification in the U.S. are defined with emphasis on their biological availabilities under various conditions. The availability of iron in foods depends upon numerous factors, most of which are not fully understood. A factor which is often overlooked is the interaction of the iron with the food during events such as cooking or processing. Chemical changes in the iron compounds occur which may correlate with changes in the biological availability.


Food extrusion.

Food extrusion. Extrusion processing has become an important food process in the manufacture of pasta, ready-to-eat cereals, snacks, pet foods, and textured vegetable protein (TVP). An extruder consists of tightly fitting screw rotating within a stationary barrel. Preground and conditioned ingredients enter the screw where they are conveyed, mixed, and heated by a variety of processes. The product exits the extruder through a die where it usually puffs and changes texture from the release of steam and normal forces. Mathematical models for extruder flow and torque have been found useful in describing exclusion operations. Scale-up can be facilitated by the application of these models. A variety of food extruder designs have developed. The differences and similarity of design are discussed. Pertinent literature on the extrusion of cereal/snack products, full-fat soy, TVP, pet foods (dry and semi-moist), pasta, and beverage or other food bases are discussed. In many of these applications, the extruder is a high temperature, short time process which minimizes losses in vitamins and amino acids. Color, flavor, and product shape and texture are also affected by the extrusion process. Extrusion has been widely applied in the production of nutritious foods. Emphasis is placed on the use of extrusion to denature antinutritional factors and the improvement of protein quality and digestibility.


The antioxidant vitamins.

The antioxidant vitamins. This article is an attempt to study the metabolic functions of vitamin C and E together. Such a study must necessarily be imcomplete owing to the extreme richness of the literature. The increasing importance of the work on free radical reactions, their toxicity and carcinogenic action, and also their relation to the metabolism of metals, particularly iron, copper, selenium, and zinc, shows a number of metabolic pathways with which both vitamins interact. It is hoped that this article will indicate future research possibilities.


Ergot on cereal grains.

Ergot on cereal grains. Ergot is caused by a fungus (Claviceps species) which has been found on hundreds of plants in almost every country of the world. The fungus can adapt itself to form many different varieties. New species of the fungus and new hosts are still discovered today. The alkaloids in ergot have caused hundreds of thousands of deaths in the Middle Ages after consumption of contaminated cereal grains, but during the last two decades there has not been a recorded outbreak of ergotism. Grain standards in most countries are very strict and do not permit grain which contains ergot to reach commercial food channels. All involved in cereal grain production and ulilization should be cognizant of the potential danger, however, since ergot contamination at levels above those permitted by grain standards cannot necessarily be detected by the normal evaluation of a flour sample in the cereal chemistry laboratory. There always have been and always will be ergot infections and a possible danger to human health, but man has learned to minimize the potential problem by using proper agricultural practices. Futhermore, techniques for the removal of ergot from contaminated grains have been developed. While human ergotism is a disease of the past, ergotism in animals still occurs frequently. The problem is not a simple one because of many unanswered questions. What is the tolerance of different breeds or species of livestock to ergot? What are the effects of low-level long-term ingestion of ergot on livestock? What is the difference in toxicity to animals of ergot from different cereal ingestion of ergot on livestock? What is the difference in toxicity to animals of ergot from different cereal grain varieties? What is the effect of storage and processing of cereal grain products on the potential ergot toxicity? The last and most important chapter in the history of ergot concerns ergot as a source of pharmacologically useful alkaloids which have found applications in internal medicine and obstetrics. The future promises to bring some new ergot alkaloids and some new uses. Recent research data indicate the possibility of using ergot alkaloids in contraceptives, which would be truly remarkable.


Furans in foods.

Furans in foods. Furan represent a class of compounds that have been reported in a wide variety of foods. Normally, they result from thermal decomposition reactions, and, as such, are important in foods. They also possess unique sensory properties and, thus, can significantly contribute to food flavor. This review shall attempt to summarize their food occurrences, organoleptic properties, and formation pathways.


Low calorie bulking agents.

Low calorie bulking agents. Obesity, a common disorder causing excess mortality due to the development of cardiovascular disease, hypertension, respiratory illness, and diabetes, is difficult to control by simple dieting techniques. Low calorie foods, which can facilitate newer weight reduction approaches such as behavior modification, often lack adequate palatability due to the absence of carbohydrate or fat. Various low calorie bulking agents that can replace the traditionally used carbohydrates and fats are discussed in terms of caloric value, utility, and regulatory status. Methods of measuring caloric utilization of bulking agents in test animals and humans are evaluated. For fat, no really satisfactory replacement is currently available, although several promising are under development. Dietary fiber sources such as microcrystalline cellulose are receiving considerable attention as flour replacements. While the polyols have many desirable attributes, as sucrose replacements, their caloric utilization values generally prevent a significant caloric reduction when they are used in foods. Several experimental sucrose replacements are described.


Levodopa/benserazide ('Madopar') combination therapy in elderly patients with parkinsonism. A clinical evaluation was carried out in 20 elderly patients with parkinsonism to assess the effectiveness and acceptability of treatment with a combination preparation of levodopa and benserazide over a period of 9 months. Mean daily maintenance dosage was 612.5 mg levodopa and 140 mg benserazide. The effects of treatment on clinical features and activities of daily living were monitored at monthly intervals. Significant improvement occurred in the first month and optimal improvement was usually reached by the end of 3-months' treatment. Akinesia and rigidity were abolished or improved in the majority of patients but the effect on tremor was less satisfactory. The preparation was well tolerated and side-effects were not troublesome.


Intra-nasal flunisolide in the treatment of allergic rhinitis in general practice. An open trial was carried out in general practice to assess the effectiveness and acceptability of flunisolide nasal spray in relieving symptoms of allergic rhinitis. Eighty-eight patients were entered in the study, 82 of whom were hay fever sufferers. The spray was given as 2 insufflations into each nostril, using a metered pump, twice daily over a period of 1 month. This provided a daily dose of 200 microgram flunisolide. Patients' symptoms were assessed on entry and at 2-week intervals. Flunisolide produced statistically significant reductions in all symptoms and resulted in complete or good control in 73 patients.


Etomidate as an induction agent in minor operative procedures. Etomidate was compared to thiopentone sodium as an induction agent in 132 out-patients undergoing sterilization by laparoscopy and cauterization of the oviduct. Neither agent caused any significant effects on heart rate or blood pressure. Etomidate-induced patients had a statistically significantly quicker return of awareness post-operatively. In a further large series (164) of out-patients undergoing minor surgery, the average stay in hospital post-operatively was 1 hour 30 minutes. Side-effects were rare and did not include, with this technique, significant myoclonus or pain on injection.


Pimozide in the maintenance treatment of apathetic and emotionally withdrawn schizophrenics. An open pilot study was carried out to assess the effectiveness of pimozide as the sole maintenance therapy for chronic institutionalized schizophrenics who were withdrawn and apathetic. A total of 13 patients entered the study and, following withdrawal of all other neuroleptics for 1 month, patients then received pimozide in a dosage increased gradually from 8 mg to 20 mg per day. Patients were assessed using the Brief Psychiatric Rating Scale (BPRS) and the St. Wulston's Ward Behaviour Scale. There was a trend towards improvement when patients were assessed by both rating scales. This was only statistically significant between the pre-pimozide measurement and the 4 and 6-month's assessment on the BPRS. Other differences, including a slight reduction in side-effects, were not statistically significant.


The penetrability of cephazolin into the subcutaneous fat and skeletal muscle of ischaemic lower limbs with atherosclerotic disease. Seventeen patients with atherosclerotic disease, who were undergoing arterial reconstruction or amputation of the lower limb, had 2 g cephazolin injected per-operatively in two equal doses by intramuscular and intravenous routes. Samples of subcutaneous fat and skeletal muscle from the ischaemic leg, and serum were collected during the operation for assay of cephazolin content. The mean cephazolin levels in the serum, skeletal muscle and subcutaneous fat were found to be well above the minimum inhibitory concentrations required for most important Gram-positive and Gram-negative pathogens.


A multicentre study of twice daily acebutolol ('Sectral') in the treatment of hypertension in general practice. An open multicentre study was carried out under uncontrolled conditions in general practice to investigate the efficacy and acceptability of twice daily acebutolol in patients with mild to severe hypertension. Data from 1007 patients were analyzed. Most (901) had been treated previously with other hypertensive agents before starting on acebutolol. Oral dosages of acebutolol ranged from 200 mg to 1200 mg/day, according to individual requirements, and 331 patients received concomitant therapy, usually with a diuretic, either from the start of therapy or after 4 to 8 weeks. A significant reduction (p less than 0.001) was observed in mean diastolic blood pressure over the 12-week assessment period, and response increased with treatment duration. There were 280 reports of side-effects and 63 patients were withdrawn from the study for this reason.


Glipizide ('Glibenese') in maturity-onset diabetes mellitus. A clinical evaluation was carried out in 19 maturity-onset diabetics to assess the effectiveness of glipizide in the treatment of newly diagnosed patients (11) not responding to diet alone and of patients (8) who had been inadequately controlled on other oral antidiabetic agents. Patients were studied over a period of 6 months. All of the 11 newly diagnosed patients were adequately controlled with glipizide in a dose of 5 to 15 mg/day (mean 9.6 +/- 3.7 mg/day), as were 5 of the 8 previously treated patients with a dose of 10 to 25 mg/day (mean 18 +/- 6.7 mg/day). None of the patients became hypoglycaemic nor did the blood sugar levels indicate hypoglycaemia in the fasting state. Serum triglyceride levels did not change significantly during glipizide therapy, neither did the patients' weight. No side-effects were reported.


Comparison of over-the-counter agents for tinea pedis. To evaluate the relative effectiveness of the treatment of tinea pedis, we performed a double-blind study comparing undecylenic acid ointment, tolnaftate cream, and a placebo. Ninety patients with clinically and mycologically proven tinea pedis took part in this clinical trial. Our results showed both agents to be superior to the placebo, but there was no significant difference in effectiveness between the two active agents. We observed no side effects with the preparations used.


Thrombocytosis in chronic eosinophilic pneumonia. Thrombocytosis has not yet been described in chronic eosinophilic pneumonia. A typical patient with chronic eosinophilic pneumonia is described. The patient's thrombocyte count was up to 900,000 per cu mm, which returned to normal under steroid therapy. Thrombocytosis may be associated with chronic inflammation and should not require further investigations such as lung biopsy, in an otherwise usual case of chronic eosinophilic pneumonia.


In vitro additive effect of nitrofurantoin combined with trimethoprim-sulfamethoxazole against Serratia marcescens. The combination of nitrofurantoin (NF) plus trimethoprim-sulfamethoxazole (TMP-SMZ) was found to be additively effective against all of 12 clinical isolates of Serratia marcescens that represented 7 nosocomially significant strains, some of which were mulitple-drug-resistant. All isolates were resistant against NF; minimal inhibitory concentrations (MICs) ranged from 320 to 1,280 microgram NF/ml. The isolates were inhibited by TMP-SMZ concentrations ranging from 0.03 microgram TMP + 0.57 microgram SMZ/ml to 8 microgram TMP + 152 microgram SMZ/ml. Significantly, NF combined with TMP-SMZ proved effective against isolates with decreased susceptibility to TMP-SMZ as well. The observed in vitro additive effect of NF + TMP-SMZ might prove of clinical relevance with respect to the chemotherapy of hospital-acquired urinary tract infections due to multiple-drug-resistant strains of S. marcescens.


Effect of disodium phosphonoacetate and iododeoxyuridine on the multiplication of African swine fever virus in vitro. Disodium phosphonoacetate (PAA) was found to inhibit the replication of African swine fever virus (ASFV). The action of this compound has been compared with the inhibitory capacity of iododeoxyuridine (IDU) upon ASFV growing in Vero cells. The study was done by the immunofluorescence technique in order to detect formations of cytoplasmic virus antigens and inclusion bodies; both were found to be inhibited by IDU and PAA. At 100 microgram/ml, IDU blocked completely the multiplication of ASFV and with PAA, a few scattered cells showed positive fluorescence. The infectivity of the virus was reduced 1--5 log depending upon drug concentrations and time of exposure to the drugs. Inhibition of ASFV replication by PAA suggests that this virus, like other herpesviruses, involves a virus-specific DNA polymerase in its replication mechanism.


Double-blind multicenter trial of a rifampicin-trimethoprim combination and rifampicin alone in urinary tract infections. A double-blind multicenter trial was carried out in 146 patients with urinary tract infections in order to compare the combination of rifampicin and trimethoprim (450 mg plus 120 mg twice daily) with rifampicin alone (450 mg twice daily). The success rate on the day after a 10-day course of treatment was significantly higher after the combination than after rifampicin alone (72% of 60 cases vs. 45% of 55 cases). The difference was still significant, and of the same order of magnitude, 1 week after the end of the treatment (53% of 51 vs. 24% of 45 cases). The subgroups of patients with organisms sensitive to both rifampicin and trimethoprim before treatment was considered separately in each treatment group: rifampicin-resistant strains were isolated  after treatment in 27% of 26 patients treated with rifampicin alone, and in 7% of 27 patients in the other group. The tolerances of the two treatments were superimposable. The combination rifampicin-trimethoprim appears to overcome the problem of selection of rifampicin-resistant strains, with the concomitant therapeutic failures, in urinary tract infections.


Nonspecific resistance of Serratia marcescens against antimicrobial drugs. Resistance or decreased susceptibility of phenotypic variants against chloramphenicol, nalidixic acid, nitrofurantoin, sulfonamides and trimethoprim. Several clinical isolates and O-antigen reference strains of Serratia marcescens were shown to yield spontaneously phenotypic variants with nonspecific, combined resistance or decreased susceptibility for chloramphenicol, nalidixic acid, nitrofurantoin, sulfonamides, and trimethoprim, including cotrimoxazole. Additional presumptive evidence indicated that this resistance phenomenon is not mediated extrachromosomally, but rather chromosomally. The nature of this novel resistance mechanism remains to be elucidated.


Nonspecific aminoglycoside cross-resistance of Serratia marcescens. 10 of 11 clinical isolates of Serratia marcescens yielded small numbers (10(-7) to 10(-8)) of 'gray' colony-type variants after selection with either amikacin, gentamicin or kanamycin, of which most proved resistant against all of the following aminoglycoside antibiotics: amikacin, gentamicin, kanamycin, neomycin, netilmicin, sisomicin and streptomycin. The level of resistance was not absolute, but rather low-level to intermediate. All except two of these 'gray', resistant phenotypic variants yielded 'opaque' revertants which were essentially indistinguishable from the parent (wild type) strains in terms of colonial morphology and antibiotic susceptibility. The 'gray' variants kinetically were more susceptible to the bactericidal activity of fresh human serum than the 'opaque' variants. Preliminary evidence afforded the tentative conclusion that this nonspecific aminoglycoside-resistance mechanism was not plasmid-mediated.


Bacteriuria diagnosis and antibiotic susceptibility testing in a group practice by dipslide techniques. In group practice, screening for bacteriuria and antibacterial susceptibility testing of bacteria in urine specimens were performed by dipslide methods (Uricult and Sensicult, Orion Diagnostica) and the results were evaluated with respect to conventional cultivation of urine specimens and standardized susceptibility testing by the disc diffusion method at a bacteriological laboratory. Bacteriuria diagnosis by screening by the Uricult method seemed to be satisfactorily performed except for some streptococcal strains. In the case of direct susceptibility testing by the Sensicult dipslide method, however, the results obtained by personnel at the surgeries and by trained bacteriologists displayed unacceptable disparities, despite the fact that a continuously running training programme was established.


Clinical and experimental evaluation of cefoxitin therapy. 30 patients were treated with i.v. cefoxitin (4-8 g/day), of which 20 had documented infections which included endocarditis (5), lung abscess (4), empyema (4), liver and subhepatic abscess (3), osteomyelitis (3), and pancreatic abscess (1). 14 patients had infections caused by anaerobic bacteria and 5 had endocarditis due to aerobic organisms. All but 2 patients with osteomyelitis of the mandible were cured. Adverse reactions were noted in 7 patients, mostly due to drug fever and leukocytosis; one had Coombs'-positive hemolytic anemia. The average serum cefoxitin levels were 24, 16, 12, and 4 microgram/ml at 1, 2, 3 and 4 h, respectively, and the average serum/pleural fluid ratio was 1:0.5 +/- 0.25. All anaerobic and aerobic isolates except one strain of Bacteroides fragilis were susceptible to cefoxitin at less than or equal to 32 microgram/ml. The concentration of cefoxitin in the tissues was measured in 8 rabbits; it was 4 +/- 1 microgram/ml in the heart and 2 +/- 0.5 microgram/ml in the femur and mandibular tissue, suggesting that the lack of response in cases of osteomyelitis could be due to inadequate antibiotic concentration in the bone. Our study suggests that cefoxitin can be used in the treatment of anaerobic infections and endocarditis due to susceptible organisms.


Spinal lipomas in infancy and childhood. The clinical course of 42 children with lipomatous lesions of the lower spine is reviewed. Good neurological exam, IVP and myelography are considered essential components of the preoperative studies. The surgical aim is to free all intra- to extradural adhesions with dural grafting, if necessary. The results suggest that early corrective surgery within the first few weeks to months of life is the most satisfactory approach to preserving normal neurological and urological function in these children. 88% of children not operated on early developed progressive loss of neurological function and while delayed surgery frequently stopped progression of the disease it rarely returned the children to a normal state.


Effect of dantrolene sodium on the incidence of seizures in children with spasticity. In this two-phase study, 21 pediatric patients with epilepsy and spasticity were initially treated with dantrolene sodium suspension and, after a washout period, began a double-blind portion where one half received dantrolene sodium suspension and the other half received a placebo suspension. The frequency of seizures, serum anticonvulsant levels and electroencephalograms were compared with control values. On dantrolene sodium suspension, there was no persistent change in these parameters. Therefore, it is concluded that dantrolene sodium does not adversely affect the frequency of seizures in children with epilepsy and spasticity, who are being maintained on anticonvulsant medications.


[Blood vessel sutures with absorbable suture material: roentgenological, hemodynamic, light and electron microscopy findings. I]. Simple end-to-end anastomoses were performed in the common carotid and femoral arteries and in the jugular and femoral veins of dogs. In other dogs, lateral sutures (running) consisting of absorbable material made from polyglycolic acid were inserted. No occlusions, aneurysms, or infections occurred in the arteries. Without heparin, the patency rate after up to 234 days was 98%. In veins, the observation period was 60 days and a patency rate of 83% was found. All vessels were studied by angiography and by light and electron microscopy. Additionally, an original method of hemodynamic assessment was used (Turbulence Index). The alternating effect of morphological variations in the vessel wall and the degree of blood flow disturbance was evident.


[The significance of duodenal passage for insulin and gastrin secretion in patients following total gastrectomy]. After total gastrectomy and different forms of reconstruction as well as before and after B II-B I conversion, an oral glucose tolerance test was performed in 24 patients, and insulin and gastrin secretion were measured. The results in the patients with preserved or reestablished passage of the glucose through the duodenum demonstrate that (1) the glucose tolerance is significantly better, (2) the secretory capacity of the beta-cells is about twofold greater, and (3) the postprandial gastrin secretion is about threefold greater.


[Dye dilution test to determine leakage during regional perfusion in the treatment of malignant tumors of the extremities]. During regional perfusion of the extremity in the dog, the dye Evans blue (T 1824) was used as an indicator to control leakage from the isolated region into the systemic circulation. The rate of elimination of the dye was 10% +/- 2% per hour. A simulated leakage from the perfused region into the systemic circulation was determined with a sensitivity of 1,67%.


[Reaction of articular cartilage to subchondral defect filling with autologous cancelous bone, Kiel's bone chips and bone cement]. Equally sized subchondral osseous defects were produced in 30 adult rabbits. The defects were filled with autologous cancellous bone, bone cement, or macerated heterologous cancellous bone. Twelve weeks later those filled with autologous cancellous bone showed consolidation with preservation of the subchondral border line. There were no degenerative changes of the joint's cartilage. Filling with bone cement or heterologous cancellous bone, on the other hand, led to destruction of the joint's cartilage. The defects treated with heterologous cancellous bone had not reached osseous consolidation at that time. These results suggest that effective treatment of subchondral osseous defects can only be achieved by filling with autologous cancellous bone.


[Fluorescent microscopy studies of osteosynthesis and bony defect filling with cyanoacrylate]. Bone defects and osteotomies of the rabbit tibia were stabilized by a mixture of ethyl cyanoacrylate and bone meal. Healing of osteotomy or new bone formations growing through the defect could not be observed.


[Arguments for suturing of a gap in the flexor tendons of fingers]. 1. Tendon healing may originate from the vascularized epitenon of the tendon stumps. 2. This is dependent upon the gap between the tendon stumps being rather small. 3. In tendon sutures after Kessler the gap averaged only 2.5 mm, whereas the average after Bunnell suture was 6.7 mm and after Lengemann suture, 9.8 mm. 4. After isolated division of the deep flexor tendon (80% of cases) and division of both flexor tendons (65%), good results with a distance = 2.5 cm between the nail and the distal palmar crease could be obtained.


[Prevention and therapy of gastroduodenal stress hemorrhage in intensive care patients using the histamine H2-receptor antagonist cimetidine]. In our intensive care unit we were able to prevent almost all bleedings from stress ulcerations in patients with insufficiency of various organs by administering the H2-receptor blocker, cimetidine, in doses of 200 mg eight times per day. However, stres ulcer bleedings occurred in 14% of those patients also suffering from a sepsis. At lower doses of cimetidine, the rate of bleeding was comparable to that encountered in patients treated with antacids, i.e. 12.5% patients with multiple organ insufficiency and 42.7% with sepsis. Cimetidine did not show any therapeutic effect in case of bleeding which led to a significant fall in hemoglobin concentration.


Enhancement of local immune response in the treatment of experimental peritonitis. We conclude from these experiments that the host defense in peritoneal infections rests largely on the phagocytic cells attracted into the peritoneal cavity by the offending organism, and that an increase in the number of available phagocytes by pretreatment with chemotactic substances protects against lethal peritoneal infections. There seems to be a direct relationship between the number of available phagocytes in the peritoneal cavity at the time of inoculation and the reduction of mortality in experimental peritonitis (Fig. 1).


[Hypothermic storage under aerobic conditions--the effect of different flushing solutions on kidney functional recovery]. Canine kidneys (n = 17) were flushed with COLLINS (C2), SACKS II, LAMBOTTE (KMgS), ROSS (hypertonic citrate), or RINGER glucose-mannitol solution following a 30-min period of normothermic ischemia. After 24 h hypothermic preservation with retrograde oxygen persufflation (ROP) and autotransplantation, the immediate functional recovery was determined using inulin and PAH clearance methods and compared with the normal contralateral kidney. While a good functional recovery was found in the COLLINS group, significantly exceeding results from hypothermic ischemic storage preservation, in experiments using other flush solutions ROP preservation resulted in only a small immediate function. Thus the experiments indicate that COLLINS solution C2 is the optimal flush solution for ROP preservation.


[Effect of high-dosage prednisolone administration on interstitial transplantation edema following allogeneic kidney transplantation in rats]. To measure subcapsular pressure of rat kidneys and kidney allografts, microcatheters were implanted in the subcapsular space and the pressure was continuously recorded with a transducer. Subcapsular pressure was found to increase significantly during allograft rejection. After single bolus injection of prednisolone 300 mg/kg on the day of transplantation or on the fourth postoperative day, considerably lower subcapsular pressures were recorded. This steroid effect together with other immunosuppressive measures could have an important influence on graft function and prognosis.


[Clinical significance of immunological findings for the survival time of kidney transplants with antilymphocyte globulin therapy]. A balanced combination of immunosuppressive regimens like cortisone, azathioprine and ALG can not only reduce the frequency, but also the severity of rejection episodes in kidney transplant patients. Addition of ALG influences the lymphocyte populations, especially T-lymphocytes. The significant reduction produced obviously includes cytotoxic effector lymphocytes as well as socalled regulator cells (suppressor cells). It seems as if this beneficial function for the graft is not only reduced under immunosuppressive therapy and administration of ALG, but disappears during rejection crises. The results indicate, however, that these cell populations recover quickly after finishing the immunosuppressive regimen.