Antibiot Khimioter, 1992 Apr, 37(4), 22 - 5 {Incorporation of an antineoplastic drug aclarubicin into liposomes in relation to the conditions of its encapsulation}; Griaznova NS et al.; The results of liposome drug encapsulation of aclarubicin (aclacinomycin A), an antitumor antibiotic, are presented . The method of flow detergent dialysis was applied . Conditions providing maximum encapsulation of aclarubicin (the ratio of lipid components and the lipid/detergent ratio), as well as conditions providing stability of liposomal emulsion (the presence of antioxidants, stearic acid and cholesterol) were defined. Antibiot Khimioter, 1992 Apr, 37(4), 19 - 22 {Use of analogs of primary metabolites in the selection of the producer of polymyxin B}; Vikhanskii IuD et al.; A number of amino acids were found to have effects on the growth of the polymyxin B-producing culture and biosynthesis of the antibiotic by it . Of special importance was the stimulating effect by methionine . Four selection stages were carried out with using structural analogs of purines and amino acids as selective factors . There were no stable variants with increased antibiotic productivity among the mutants resistant to the analogs of purines and leucine . The levels of polymyxin B accumulation by the variants resistant to 4-fluorophenylalanine were 30 to 50 per cent higher than those in the controls and the variants were characterized by low morphological and antibiotic production variation in the subcultures . The mechanisms of the methionine physiological effect and the prospects of using analogs of the primary metabolites in improvement of the culture producing polymyxin B are discussed. Hum Gene Ther, 1992 Apr, 3(2), 137 - 45 Use of cell-free retroviral vector preparations for transduction of cells from the marrow of chronic phase and blast crisis chronic myelogenous leukemia patients and from normal individuals; Etkin M et al.; Marrow cells were exposed to the LNL6 or G1N safety-modified variants of the N2 retrovirus, which contain the G418 bacterial resistance gene neo . The frequency of acquisition of the G418 resistance phenotype following exposure to LNL6 or G1N was compared among hematopoietic progenitor cells from the marrow of patients with chronic phase chronic myelogenous leukemia (CML), blast crisis CML, or from nonleukemic individuals . Under the conditions of our experiments, the myeloid committed progenitor cells from 3 of 6 nonleukemic individuals, 9 of 18 chronic-phase CML patients, and 2 of 4 blast crisis CML patients acquired resistance to at least 1 mg/ml G418 following incubation with cell-free supernatants from the PA317 LNL6 or PA317 G1N producer cell lines . Ten of the 32 colonies growing up in 0.8 mg/ml G418 from chronic-phase marrow exposed to LNL6 were shown to contain the neo gene by polymerase chain reaction (PCR) assay of DNA . These results were consistent with estimates of the transduction frequency based on acquisition of resistance to G418 as the number of colonies growing under G418 selection was always greater at 0.8 mg/ml G418 than at higher concentrations of G418 (1.0-1.4 mg/ml) . The average transduction frequency at each G418 concentration (1.0, 1.2, and 1.4 mg/ml) in cells from blast crisis CML cells ranged from 2 to 14%, as measured by acquisition of G418 resistance . Chronic-phase CML showed slightly lower average frequencies of transduction (0.6-2.8% of the colonies are G418 resistant) . The average transduction frequency of cells from nonleukemic marrow was as high as that seen from the marrow of chronic-phase CML individuals.(ABSTRACT TRUNCATED AT 250 WORDS) Hum Gene Ther, 1992 Apr, 3(2), 129 - 36 Retrovirus-mediated gene transfer as an approach to analyze neuroblastoma relapse after autologous bone marrow transplantation; Rill DR et al.; Disseminated neuroblastoma is a malignancy of children often treated by intensive chemotherapy/radiotherapy followed by autologous bone marrow transplantation (ABMT) . A high proportion of those treated subsequently relapse . It is unknown if relapse is a consequence of residual disease in the patient or of contaminating malignant cells remaining in the infused marrow, which, of necessity, is harvested and stored prior to ablative chemotherapy/radiotherapy . The assumption that residual cells in the infused marrow contribute to relapse has lead to the adoption of marrow purging prior to reinfusion . However, neither the necessity nor the efficacy of the procedure have been established . We now show how retroviral-mediated gene transfer using the LNL6 vector may resolve this issue . Clonogenic neuroblastoma cells in patient marrow can be transduced and the NEOR gene detected by observing individual neuroblastoma cell colony growth in G418, and by polymerase chain reaction (PCR) of individual colonies . Efficiency of transduction is between 0 and 13.5% . If marrow is exposed to LNL6 prior to infusion and marked cells are detected at the time of relapse, this would demonstrate that infused marrow contributed to disease recurrence . The technique could then be used to analyze the efficacy of marrow purging techniques . Since normal progenitor cells from these patients are also marked, the technique can be used to study factors that modify reconstitution and transducibility of infused marrow . Clinical studies using this approach have now begun. Semin Oncol, 1992 Apr, 19(2 Suppl 5), 64 - 70 Bleomycin pulmonary toxicity: current status and future directions; Comis RL; Bleomycin is a polypeptide antibiotic that has been used in clinical cancer chemotherapy for over 20 years . Risk factors associated with bleomycin include total dose of drug, age of patient, high-dose oxygen therapy during surgery, and prior and concomitant radiation therapy . Attempts at developing predictive and precise monitoring systems have not been completely successful; however, the combined use of clinical and laboratory tests, such as the DLCO test, can be used to permit safe administration of the drug . Recent work has emphasized the development of new analogues, such as liblomycin, that appear to possess less pulmonary toxicity than does bleomycin, and has focused on understanding the pathogenesis of pulmonary toxicity, particularly as it relates to the immune system. Semin Oncol, 1992 Apr, 19(2 Suppl 5), 3 - 8 Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics; Dorr RT; Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity . The drug binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide and by partial intercalation of the bithiazole rings . A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand . Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III) . The free radicals produce DNA single-strand breaks at 3'-4' bonds in deoxyribose . This yields free base propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase . In humans, bleomycin is rapidly eliminated primarily by renal excretion . This accounts for approximately half of a dose . In patients with renal compromise or extensive prior cisplatin therapy, the drug half-life can extend from 2 to 4 hours up to 21 hours . Thus, dose adjustments are needed when creatinine clearance is less than or equal to 3N mL/min . Finally, resistance to bleomycin in normal tissues can be correlated with the presence of a bleomycin hydrolase enzyme, which is in the cysteine proteinase family . The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and cytotoxic activity . The low concentration of enzyme in the skin and lung may explain the unique sensitivity of these tissues to bleomycin toxicity . However, correlation of hydrolase levels with tumor cell sensitivity has thus far been negative. Carcinogenesis, 1992 Apr, 13(4), 703 - 7 Initiation by bleomycin of hepatocellular foci in the rat; Kaufmann WK et al.; The antitumor antibiotic, bleomycin, was tested for activity as an initiator of hepatocellular foci and neoplasms in rats . The compound was administered in a single dose via the portal vein 4 h after the proliferative stimulus of a two-thirds partial hepatectomy . Rats were subsequently fed diet containing phenobarbital for up to 41 weeks to promote the development of initiated hepatocytes . Bleomycin-treated livers displayed significantly increased frequencies of basophilic hepatocellular foci and hepatocellular foci which retain glycogen during fasting . Foci that express glutathione-S-transferase (placental form) were not initiated by bleomycin . Hepatocellular neoplasms were infrequently seen in bleomycin-treated livers (5% incidence) . The results suggest that oxygen radical-mediated DNA damage may initiate, within populations of proliferating hepatocytes, new lineages of altered hepatocytes that form foci but have low probability of progressing to neoplasms during promotion with phenobarbital. Neurosurg Clin N Am, 1992 Apr, 3(2), 359 - 73 Nonoperative treatment of neurosurgical infections; Obana WG et al.; The indications for nonsurgical management of CNS infections manifested by collections of pus are very limited . In general, such management is restricted to neurologically intact patients who are unable to undergo the needed surgical procedure and in whom the organism can be identified presumptively from other cultures . In such circumstances, brain abscesses less than 1.5 cm in diameter, small subdural empyemas, some spinal epidural abscesses, and many cases of spinal osteomyelitis can be successfully treated with prolonged intravenous antibiotic therapy . In patients who are unable to tolerate a neurosurgical procedure, the presence of an infectious CNS mass lesion is not hopeless and vigorous medical therapy offers the possibility of cure. Bone Marrow Transplant, 1992 Apr, 9(4), 277 - 84 Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants; To LB et al.; The haematological recovery time, infection rate and supportive care requirements of patients receiving recovery phase autologous peripheral blood stem cell transplants (APBSCT) (n = 38), autologous bone marrow transplants (autoBMT) (n = 13) and allogeneic bone marrow transplants (alloBMT) (n = 14) were compared with respect to the time post-transplant to reach 0.1, 0.5 and 2.0 x 10(9) neutrophils/l and 50 and 150 x 10(9) platelets/l, the length of hospitalization, fever and antibiotic use, the incidence of documented infection and the number of red cell and platelet transfusions . The APBSCT group had a significantly more rapid recovery of neutrophils and platelets and their supportive care requirements were significantly less than the autoBMT and the alloBMT groups . There was no difference between the latter two groups . The most significant variables contributing to the differences in haematological recovery times were the granulocyte-macrophage progenitor (CFU-GM) dose infused and, to a lesser extent, patient age . The APBSCT group received a higher CFU-GM dose of 87 +/- 12 x 10(4)/kg BW compared with 12 +/- 5 and 17 +/- 3 x 10(4)/kg BW in the autoBMT and the alloBMT groups, respectively (p = 0.0001) . Patient age showed a negative correlation with the rate of recovery because the APBSCT group, which recovered faster was also older (48 +/- 2 years, compared with 33 +/- 3 and 31 +/- 2, respectively, p = 0.0001) . On multivariate analysis, CFU-GM dose was the only variable to show a significant correlation with all the haematological recovery endpoints studied in these 65 patients.(ABSTRACT TRUNCATED AT 250 WORDS) Eur J Med, 1992 Apr, 1(1), 52 - 4 Hip surgery skin cellulitis; Mainetti C et al.; Of 583 erysipelas/cellulitis seen in our Department between 1981 and 1991, six (1.04%) were localized to the buttock and hip . Five patients had had a dynamic hip screw implanted for coxarthritis on the side where the skin infection developed . This does not appear to be secondary to superinfection of the surgical wound as the erysipelas/cellulitis occurred weeks (7 to 520) after surgery . The possible surgical compromise of the venous/lymphatic circulation appears to be the causative factor . In all patients, the course was satisfactory upon systemic antibiotic therapy and no recurrence was seen after a mean follow up of 28 months. Am J Physiol, 1992 Apr, 262(4 Pt 1), C963 - 70 Plasma membrane Na(+)-H+ antiporter and H(+)-ATPase in the medullary thick ascending limb of rat kidney; Froissart M et al.; To characterize H+ transport mechanisms in a fresh suspension of rat medullary thick ascending limb (MTAL) tubules, we have monitored intracellular pH (pHi) with use of the fluorescent probe 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein . First, a Na(+)-H+ antiporter was identified in bicarbonate-free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered media at 25 degrees C . pHi recovery of Na-depleted acidified cells was dependent on extracellular sodium concentration, which was inhibited by amiloride in a manner consistent with simple competitive interaction with one external transport site (amiloride Ki = 1.5-2.1 x 10(-5) M); Na-induced pHi recovery of acidified cells was electroneutral since it was not affected by 5 or 100 mM extracellular potassium in the presence or absence of valinomycin . Second, at 37 degrees C, pHi recovery after acute intracellular acidification caused by 40 mM acetate addition to cell suspension was inhibited 36% by 200-400 nM bafilomycin A1, a macrolide antibiotic that specifically inhibits vacuolar-type H(+)-ATPase at submicromolar concentrations . In addition, amiloride-insensitive pHi recovery was inhibited by bafilomycin A1, 10(-3) M N-ethylmaleimide, and 10(-4) M preactivated omeprazole but not by 10(-5) M vanadate, 10(-4) M SCH 28080, or removal of extracellular potassium . Also, metabolic inhibition by absence of substrate, 10(-4) M KCN, or 5 x 10(-4) M iodoacetic acid inhibited amiloride-insensitive pHi recovery . The inhibitory effects of absence of metabolic substrate and iodoacetic acid were removed by reexposure to glucose and L-leucine and by exogenous ATP, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) Am J Physiol, 1992 Apr, 262(4 Pt 1), C1089 - 94 Basolateral Na-H antiporter: uncoupled Na transport produces an amiloride-sensitive conductance; Post MA et al.; An amiloride-inhibitable, Na(+)-H+ antiporter was identified in the basolateral membrane of turtle colon by measuring 22Na+ fluxes across isolated tissues apically permeabilized with the pore-forming antibiotic amphotericin B . In cells shrunken by exposure to Cl(-)-free (gluconate) solutions and treated with ouabain to block the Na-K-ATPase, Na+ movement across the basolateral membrane was due entirely to the antiporter . Elevation of cytosolic Na+ was associated with an amiloride-inhibitable outward current across the basolateral membrane . The sensitivity of the current to various amiloride analogues paralleled that of Na+ exchange rather than that of the apical Na+ channel . Furthermore, cell volume changes altered basolateral Na+ exchange and basolateral Na+ conductance in a parallel fashion . We propose that this amiloride-sensitive basolateral Na+ conductance represents an altered operating mode of a basolateral Na(+)-H+ exchanger. Arterioscler Thromb, 1992 Apr, 12(4), 503 - 11 Polymyxin B enhances low density lipoprotein catabolism in hepatic and extrahepatic cells; Liao W et al.; We investigated the effects of polymyxin B (PMB), an antibiotic that binds to endotoxins, on the uptake and degradation of low density lipoproteins (LDLs) in HepG2 cells, a highly differentiated human hepatoma cell line . The results showed that PMB very effectively enhanced the binding, internalization, and degradation of LDL in HepG2 cells . The PMB-mediated enhancement of LDL uptake was not dependent on the LDL receptor-mediated pathway, as blockage of the LDL receptor by use of a monoclonal anti-LDL receptor antibody had no effect on the PMB-mediated cellular processing of LDL and PMB-mediated enhancement of LDL uptake did not cause an increase in cholesterol esterification . In addition, chloroquine and colchicine, which inhibit lysosomal degradation and cellular endocytosis, respectively, diminished PMB-enhanced degradation of LDL, indicating that PMB mediates uptake through a pathway similar to the LDL receptor-mediated pathway . The PMB-mediated uptake of LDL was sensitive to treatment with phospholipase C and pronase and was dependent on the presence of Ca2+ . PMB caused similar changes in human skin fibroblasts, bovine smooth muscle cells, and bovine endothelial cells, which suggests that PMB-enhanced LDL uptake is a general cellular phenomenon . Our results thus indicate that PMB increases cellular catabolism of LDL through an endocytotic pathway not involving the LDL receptors. Biochemistry, 1992 Mar 24, 31(11), 2988 - 97 Role of magnesium ion in the interaction between chromomycin A3 and DNA: binding of chromomycin A3-Mg2+ complexes with DNA; Aich P et al.; Chromomycin A3 is an antitumor antibiotic which blocks macromolecular synthesis via reversible interaction with DNA template only in the presence of divalent metal ions such as Mg2+ . The role of Mg2+ in this antibiotic-DNA interaction is not well understood . We approached the problem in two steps via studies on the interaction of (i) chromomycin A3 and Mg2+ and (ii) chromomycin A3-Mg2+ complex(es) and DNA . Spectroscopic techniques such as absorption, fluorescence, and CD were employed for this purpose . The results could be summed up in two parts . Absorption, fluorescence, and CD spectra of the antibiotic change upon addition of Mg2+ due to complex formation between them . Analysis of the quantitative dependence of change in absorbance of chromomycin A3 (at 440 nm) upon input concentration of Mg2+ indicates formation of two types of complexes with different stoichiometries and formation constants . Trends in change of fluorescence and CD spectroscopic features of the antibiotic in the presence of Mg2+ at different concentrations further corroborate this result . The two complexes are referred to as complex I (with 1:1 stoichiometry in terms of chromomycin A3:Mg2+) and complex II (with 2:1 stoichiometry in terms of chromomycin A3:Mg2+), respectively, in future discussions . The interactions of these complexes with calf thymus DNA were examined to check whether they bind differently to the same DNA . Evaluation of binding parameters, intrinsic binding constants, and binding stoichiometry, by means of spectrophotometric and fluorescence titrations, shows that they are different . Distinctive spectroscopic features of complexes I and II, when they are bound to DNA, also support that they bind differently to the above DNA . Measurement of thermodynamic parameters characterizing their interactions with calf thymus DNA shows that complex I-DNA interaction is exothermic, in contrast to complex II-DNA interaction, which is endothermic . This feature implies a difference in the molecular nature of the interactions between the complexes and calf thymus DNA . These observations are novel and significant to understand the antitumor property of the antibiotic . They are also discussed to provide explanations for the earlier reports that in some cases appeared to be contradictory. FEBS Lett, 1992 Mar 23, 300(1), 25 - 9 Detection of elsamicin-DNA binding specificity by restriction enzyme cleavage; Parraga A et al.; The sequence specificity of elsamicin A, an anti-tumour antibiotic, binding to DNA was elucidated considering the inhibition of the rate of digestion of linearised pBR322 DNA by AatII, ClaI, EcoRI, HindIII and NruI restriction enzymes . Elsamicin A inhibits the rate of digestion by NruI (recognition sequence TCG/CGA) to a greater extent than it does for the other enzymes, thus evidencing the sequence-selective binding of elsamicin to CGC regions in DNA . Our results also show the important role of the neighbouring sequences in the elsamicin A-DNA interactions and their effects on the cleavage by restriction enzymes. BMJ, 1992 Mar 21, 304(6829), 737 - 9 Childhood deaths from intussusception in England and Wales, 1984-9; Stringer MD et al.; OBJECTIVE--To assess the incidence of potentially avoidable factors contributing to death of children with intussusception . DESIGN--Review of children who died with intussusception in England and Wales between 1984 and 1989 from data of the Office of Population Censuses and Surveys, case notes, coroners' records, and necropsy reports . MAIN OUTCOME MEASURES--Unambiguous objective criteria such as failure to diagnose intussusception within 24 hours of admission . RESULTS--33 children died of acute intussusception in England and Wales between 1984 and 1989 compared with 67 in the previous six years . Their median age was 7 months (range 2 months to 12 years), and two thirds were boys . Half of the deaths occurred at home or soon after arrival at hospital but 15 patients had surgery . Potentially avoidable factors contributing to death were identified in 20 (61%) children, all but three of whom had ileocolic intussusception . These factors were excessive delay in diagnosis, inadequate intravenous fluid and antibiotic therapy, delay in recognising recurrent or residual intussusception after hydrostatic reduction, and surgical complications . Of the 13 patients in whom no avoidable factors were identified, there were nine of 11 children with isolated small bowel intussusception, who tended to have atypical presentations . CONCLUSION--Although the mortality from intussusception has declined, there remains ample opportunity for improved management. Biochemistry, 1992 Mar 17, 31(10), 2822 - 9 Effect of the (+)-CC-1065-(N3-adenine)DNA adduct on in vitro DNA synthesis mediated by Escherichia coli DNA polymerase; Sun D et al.; (+)-CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis . Previous studies have shown that the potent cytotoxic and antitumor activities of (+)-CC-1065 are due to the ability of this compound to covalently modify DNA . (+)-CC-1065 reacts with duplex DNA to form an N3-adenine DNA adduct which lies in the minor groove of the DNA helix overlapping with a 5-base-pair region . As a consequence of covalent modification with (+)-CC-1065, the DNA helix bends into the minor groove and also undergoes winding and stiffening {Lee, C.-S., Sun, D., Kizu, R., & Hurley, L . H . (1991) Chem . Res . Toxicol . 4, 203-213} . In the studies described here, in which we have constructed site-directed DNA adducts on single-stranded DNA templates, we have shown that (+)-CC-1065 and select synthetic analogues, which have different levels of cytotoxicity, all show strong blocks against progression of Klenow fragment, E . coli DNA polymerase, and T4 DNA polymerase . The inhibition of bypass of drug lesions by polymerase could be partially alleviated by increasing the concentration of dNTPs and, to a small extent, by increasing polymerase levels . Klenow fragment binds equally well to a DNA template adjacent to a drug modification site and to unmodified DNA . These results taken together lead us to suspect that it is primarily inhibition of base pairing around the drug modification site and not prevention of polymerase binding that leads to blockage of DNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS) Gene, 1992 Mar 15, 112(2), 229 - 34 Use of the signal peptide of Pisum vicilin to translocate beta-glucuronidase in Nicotiana tabacum; Pang SZ et al.; A hybrid protein system was used for the study of protein transport in plant cells . A nucleotide sequence (vic) encoding a putative signal peptide of 15 amino acid residues, derived from the published aa sequence of one Pisum vicilin, was synthesized and fused in frame to the gus gene encoding a bacterial cytosolic beta-glucuronidase (GUS) . When the hybrid vic::gus gene was expressed in tobacco cells using the cauliflower mosaic virus 35S promoter, the hybrid GUS protein was targeted to, and glycosylated inside the rough endoplasmic reticulum . Glycosylation could be blocked with the antibiotic tunicamycin . The study of transient expression in protoplasts showed that extracellular secretion efficiency was low, which may be due to the nature of the GUS protein. Biochemistry, 1992 Mar 10, 31(9), 2502 - 8 Reversibility of the covalent reaction of CC-1065 and analogues with DNA; Warpehoski MA et al.; Covalent DNA adducts of the antitumor antibiotic CC-1065 and its analogues undergo a retrohomologous Michael reaction in aqueous/organic solvent mixtures to regenerate the initial cyclopropylpyrroloindole (CPI) structure and, presumably, intact DNA . This reaction, which at higher temperatures competes with depurination of the N3-alkylated adenine, also occurs to a significant extent at 37 degrees C in neutral aqueous solution . Tritium-labeled adozelesin, covalently bonded to a 3-kilobase DNA restriction fragment which was exhaustively extracted to remove unbonded drug, was efficiently transferred to a 1-kilobase fragment upon coincubation for 20 h at 37 degrees C in aqueous buffer . Covalent adducts of adozelesin, but not CC-1065, on calf thymus DNA were cytotoxic to L1210 cells after incubation for 3 days at 37 degrees C, indicating that reversal of DNA alkylation can mediate potent cellular effects for simplified CC-1065 analogues. Pharmacoeconomics, 1992 Apr, 1(4), 231 - 49 Recombinant granulocyte colony-stimulating factor (rG-CSF): pharmacoeconomic considerations in chemotherapy-induced neutropenia; Faulds D et al.; Recombinant granulocyte colony-stimulating factor (rG-CSF) therapy is associated with a dose-proportional reduction in the frequency, duration and severity of neutropenia associated with cytotoxic chemotherapy . This is associated with a decrease in the incidence of infection, with subsequent reductions in the number of hospitalisations, days of hospitalisation and antibiotic requirements . These effects produce marked reductions in costs, and could contribute substantially towards offsetting the costs of rG-CSF, although the magnitude of the savings will vary between institutions and with the chemotherapy regimen used . Other benefits include a reduction in the frequency and severity of mucositis, and an improved patient quality of life . However, further research is required to evaluate other potentially important considerations including the targeting of specific patient populations (e.g . those receiving regimens with a curative intent), and additional improvements in patient quality of life and, perhaps, mortality . Thus, although specific pharmacoeconomic analyses are limited, preliminary evidence indicates that rG-CSF, administered prior to the onset of neutropenia in patients receiving cytotoxic chemotherapy, can provide cost reductions both from an institutional and a payor perspective, with even greater potential savings from a societal viewpoint. Exp Parasitol, 1992 Mar, 74(2), 177 - 87 Leishmania donovani: antagonistic effect of S-adenosyl methionine on ultrastructural changes and growth inhibition induced by sinefungin; Phelouzat MA et al.; Sinefungin, an antifungal and antiparasitic nucleoside antibiotic, is a very potent antileishmanial agent in vitro and in vivo (Bachrach et al . 1980, FEBS Letters 121, 287-291; Neal et al . 1985, Transactions of the Royal Society of Tropical Medicine and Hygiene 79, 85-122) . It was previously shown that this molecule is a competitive inhibitor of AdoMet for transmethylases (Paolantonacci et al . 1986, Molecular and Biochemical Parasitology 21, 47-54; Avila et al . 1987, Molecular and Biochemical Parasitology 26, 69-76) and that it induces shape changes of Leishmania donovani promastigotes as observed by light microscopy (Lawrence and Robert-Gero 1990; Bulletin de la Societe Francaise de Parasitologie 8, 13-18) . In the present work the effect of the antibiotic on the ultrastructure was analyzed by electron microscopy . The main changes induced at sublethal concentrations (0.26 microM sinefungin for 16 hr) were progressive rounding, decreased motility, enlargement of the flagellar pocket, and shortening and loss of the external part of the flagellum . The comparison with control cells showed shorter Golgi saccules and fragmentation of the trans-Golgi network into vesicles, indicating a stimulated Golgi apparatus activity . This result, associated with the enlarged flagellar pocket, suggests an unbalanced cytoplasmic exchange between exocytosis and endocytosis . These effects are quite different from those induced by tunicamycin (Dagger et al . 1984, Biology of the Cell 50; 173-180) or paromomycin . In addition, other nucleoside and nonnucleoside growth inhibitors failed to induce similar changes . AdoMet antagonized the sinefungin-induced shape changes and ultrastructural modifications but had no effect with respect to other growth inhibitors . This suggests that the sinefungin activity at the cellular level is specifically related to competition with AdoMet . A comparative study of N-methylation and carboxylmethylation of proteins in sinefungin-treated promastigotes showed that the antibiotic preferentially inhibits the latter, catalyzed by protein-O-methyltransferases . These enzymes are known to regulate the function of various proteins involved in secretion . Overall the results suggest that one of the main targets of sinefungin in exponentially growing cells is the protein carboxylmethylation involved in membrane transport. Neurosurgery, 1992 Mar, 30(3), 426 - 31 Osteomyelitis of the skull base; Malone DG et al.; Three cases of osteomyelitis of the skull base with associated problems in diagnosis and therapy are discussed . Patients with atypical skull base osteomyelitis are difficult to diagnose as they have no ear abnormalities, but they often develop multiple cranial nerve deficits mimicking symptoms of a posterior fossa mass . We conclude that computed tomographic scans, magnetic resonance imaging studies, bone scans indium-labeled white blood cell scans, and gallium scans are useful in making the diagnosis . A biopsy of the bony lesion often is needed to identify the causative organism and to rule out a tumor . Intravenously administered antibiotics are the mainstay of therapy and should be continued until 1 week after the gallium scan shows no abnormalities . Follow-up gallium scans then are done at 1 week and 3 months after the cessation of antibiotic therapy to search for a recurrence. Am J Hosp Pharm, 1992 Mar, 49(3), 590 - 4 Pharmacoeconomic evaluation of treatment of penetrating abdominal trauma; Friedrich LV et al.; The hospital, pharmacy, and antibiotic costs for patients with penetrating abdominal trauma were compared with reimbursement received; these costs were also analyzed to assess the potential impact of a total prospective pricing system (PPS) . During a four-year period, 46 patients admitted solely for penetrating abdominal trauma were retrospectively evaluated: their discharge summaries indicated that, for 9 patients, reimbursement was based on diagnosis-related groups (DRGs) under the PPS; 9 patients had private insurance; and 28 were classified as "self-paying/no insurance." All costs, corrected for inflation, were reported in 1989 dollars . Antibiotics represented 22.5%, 1.7%, and 0.5% of pharmacy, hospital, and DRG reimbursement, respectively; pharmacy costs were 8.5% of hospital costs and 2.3% of DRG reimbursement . For all 46 patients, a net loss of $295 per patient was incurred . Four patients accounted for 43% of the hospital costs . If the hospital had been reimbursed for all of these patients by prospective pricing and DRGs, it would have had a median profit of $9730 in 42 of 46 patients . Costs exceeded DRG reimbursement in the remaining four patients by a median of $8210 . Antibiotic costs and pharmacy costs represent a small portion of hospital costs and DRG reimbursement for patients with penetrating abdominal trauma; thus, cost containment efforts in these patients should be directed at other ancillary services and length of stay. Early Hum Dev, 1992 Mar-Apr, 28(3), 223 - 9 Monocytosis in preterm infants; Rajadurai VS et al.; In sick preterm neonates receiving intensive care a spectacular rise in monocyte count has frequently been observed in sequential full blood examinations . The etiology of this has not previously been investigated and this study examines clinical factors that may contribute to this finding . Thirty (5.1%) of the 587 neonates who required intensive care during the study period had significant monocytosis (absolute count greater than 1700/mm3) . Their mean gestation was 29 weeks (range 26-32 weeks) . Monocytic response occurred at an age of 5.5 +/- 3 (mean +/- S.D.) days with 20% occurring at birth, 57% in the first week and 23% in the second week of life and lasted for 19.8 +/- 16 days (mean +/- S.D.) . Most reached peak levels within two weeks and these ranged between 2,170 and 7176 per mm3 . Analysis of the clinical variables against 37 controls revealed lower mean birth weight and gestational age, and higher incidence of leukocytosis, multiple transfusions, albumin infusions and theophylline therapy in the study group in comparison to the controls (P less than 0.001) . No significant difference was found in maternal risk factors (pre-eclampsia, diabetes and amnionitis), birth asphyxia, respiratory disease, parenteral nutrition, proven infection and antibiotic therapy . An unexpected association with maternal steroid therapy was demonstrated . It is speculated that monocytosis represents a physiological though immature response of the marrow of small premature infants to a variety of exogenous stimuli including drugs and foreign protein infusions. Adv Contracept, 1992 Mar, 8(1), 81 - 8 Self-induced abortion--the peril is still real; Weissman A et al.; A new immigrant from Romania tried to induce abortion by intrauterine self-administration of hypertonic sucrose at 7 weeks' gestation . Complete abortion did not occur and bleeding, infection and pregnancy residua persisted for 13 weeks . Evacuation by uterine curettage had failed, but a second curettage under real-time sonographic guidance was successful . Self-induced chemical abortions are rarely encountered in modern medicine . However, elevation of the iron curtain and mass immigration may increase the frequency of self-induced abortions in Western countries . Since the management, course, and outcome of each type of self-induced abortion are somewhat different, the pertinent differentiation is between chemical and mechanical and between various agents used for chemical-induced abortions . Mechanical abortions are best treated 12 to 24 hours after antibiotic therapy, while in chemically-induced abortion early evacuation of the uterus is indicated. Scand J Prim Health Care, 1992 Mar, 10(1), 60 - 5 Maternal cigarette smoking, breast-feeding, and respiratory tract infections in infancy . A population-based cohort study; Hakansson A et al.; This population-based study comprised 192 mothers and their infants; 58 mothers were smokers and 134 non-smokers . At the 18-month infant check-up at the child health clinic, mothers were questioned about the length of the breast-feeding period, both exclusively breast-feeding and overall breast-feeding time . The numbers of antibiotic-treated respiratory tract infections (RTIs) during the first year of life were noted during a scrutiny of records at the district physician's surgery and child health clinic of the Health Centre, and at the paediatric and ENT departments of the Central Hospital . We were unable to find any connection between the duration of breast-feeding and the number of antibiotic-treated RTIs in the infants . This applied to both exclusively breast-feeding period and overall breast-feeding period . Further, it was shown that infants of smokers were affected by RTIs more often than those of non-smokers, the incidence figures being 1.16 vs . 0.76 antibiotic courses per infant and year, respectively . Moreover, infants of smokers were breast-fed for a shorter period than those of non-smokers, the mean values being 3.3 vs . 4.3 months, respectively, for the period of exclusively breast-feeding, and 5.0 vs . 7.2 months, respectively, for the overall breast-feeding period. Int J Biomed Comput, 1992 Mar, 30(2), 125 - 35 Diffusion from gel in brain: modelisation and identification; Bellagoun A et al.; A mathematical model is proposed for describing the mechanism of diffusion from gel (Tissucol) into the extracellular space . After diffusion of the antibiotic in one dimension, the gradient concentration was determined with microvoltametric electrodes . These microelectrodes measure the free diffusible form of electroactive antibiotics in the extracellular brain space . The aim of this study was to find simultaneously the coefficient of diffusion and extraction of some antibiotics (in our case the Fotemustin) using the Alienor Algorithm . These coefficients are useful for predicting the concentration gradient into abscesses, fibrin, etc. Orthop Rev, 1992 Mar, 21(3), 367 - 9 The use of fibular grafts with anterior cervical fusion; Segal HD et al.; Anterior cervical fusion utilizing an iliac-crest graft is often associated with pain at the donor site and graft collapse or dislocation . These problems were overcome by a surgical technique using circular fresh-frozen fibular grafts . This provides the strongest possible graft, and affords an opportunity to combine autogenous with homologous bone . There is minimal risk of infection, and the grafts can be soaked in an antibiotic solution as an added precaution . The technique is relatively easy, and postoperative results with regard to graft integrity, restoration of function, and resolution of pain are excellent. Leukemia, 1992 Mar, 6(3), 220 - 3 Phase II trial of recombinant human interferon alpha in myelodysplastic syndromes; Nand S et al.; Twenty patients with myelodysplastic syndromes were treated with daily subcutaneous injections of interferon alpha 2a, at the initial dose of 3 x 10(6) U/m2 . Hemogram, chemistry profile, natural killer (NK) cell activity and lymphokine-activated killer (LAK) cell cytotoxicity were monitored serially . Bone marrow with cytogenetic analysis was done before therapy and every three months afterwards . Normalization to the complete blood count, and wherever applicable, decrease in blast count of 5% or less were defined as a complete response . Improvement in hemoglobin level to 12 g/dl, neutrophil count to 1000/mm3 and platelets to 100,000/mm3 was considered a partial response . The median age was 71 (range 59-83) years and 16 of the patients were males . Two patients withdrew from the treatment in the first week and were considered ineligible . Among the other 18, two had refractory anemia, two refractory anemia with ringed sideroblasts, four chronic myelomonocytic leukemia, eight refractory anemia with excess blasts, and two refractory anemia with excess blasts in transformation to acute leukemia . Twelve patients were treated for six months, the other six were taken off the treatment after six to eight weeks because of disease progression . Only one patient with chronic myelomonocytic leukemia had a partial response for two months . NK cell activity remained unchanged before (18.3 +/- 4.6 lytic units) and during interferon therapy (19.6 +/- 5.3 lytic units) . LAK cytotoxicity was not detected in any patient before therapy and was seen in only one patient (not the responder) during therapy (5.7 lytic units) . The toxicity of the interferon therapy was substantial . Seventeen patients required a dose reduction and fifteen lost greater than 10% of body weight . Eleven patients (61%) developed infections requiring antibiotic therapy, and eight (44%) required hospitalization . Seven patients developed neurologic toxicity . Interferon alpha 2a is an ineffective but toxic therapy in these elderly patients with myelodysplastic syndromes. Mol Gen Genet, 1992 Mar, 232(2), 262 - 70 Self cloning in Micromonospora olivasterospora of fms genes for fortimicin A (astromicin) biosynthesis; Dairi T et al.; We have cloned the seven genes that are responsible for biosynthesis of the antibiotic fortimicin A (FTM A) using a recently developed self-cloning system that employes the plasmid vector pMO116 for Micromonospora olivasterospora . Five chimeric plasmids that restored FTM A production in M . olivasterospora mutants blocked at different biosynthetic steps were isolated by shotgun cloning . Secondary transformation using other non-producing mutants showed that two additional FTM A biosynthetic genes were included on these plasmids, and that at least four of the genes were clustered . Interestingly AN38-1, a non-producing mutant that had a defect in dehydroxylation of a precursor of FTM A, was complemented by the DNA fragment containing a neomycin resistance gene that had been cloned from a neomycin-producing strain (Micromonospora sp . FTM A non-producing strain) in the course of constructing the plasmid vector pMO116 . These results clearly show that this novel gene cloning system in Micromonospora is of practical use. Semin Dermatol, 1992 Mar, 11(1), 31 - 6 Lyme disease in children: diagnosis, treatment, and prevention; Prose NS et al.; Lyme disease is a multisystem disorder that is caused by infection with Borrelia burgdorferi . In endemic areas, its occurrence is extremely common among children . The early diagnosis and treatment of Lyme disease may prevent the development of serious cardiac, rheumatological, and neurological sequelae . For this reason, a full understanding of the clinical manifestations, laboratory evaluation, and antibiotic therapy of Lyme disease is of vital importance. J Bacteriol, 1992 Mar, 174(6), 1810 - 20 Nucleotide sequence of the tcmII-tcmIV region of the tetracenomycin C biosynthetic gene cluster of Streptomyces glaucescens and evidence that the tcmN gene encodes a multifunctional cyclase-dehydratase-O-methyl transferase; Summers RG et al.; Mutations in the tcmII-tcmIV region of the Streptomyces glaucescens chromosome block the C-3 and C-8 O-methylations of the polyketide antibiotic tetracenomycin C (Tcm C) . The nucleotide sequence of this region reveals the presence of two genes, tcmN and tcmO, whose deduced protein products display similarity to the hydroxyindole O-methyl transferase of the bovine pineal gland, an enzyme that catalyzes a phenolic O-methylation analogous to those required for the biosynthesis of Tcm C . The deduced product of the tcmN gene also has an N-terminal domain that shows similarity to the putative ActVII and WhiE ORFVI proteins of Streptomyces coelicolor . The tcmN N-terminal domain can be separated from the remainder of the tcmN gene product, and when coupled on a plasmid with the Tcm C polyketide synthase genes (tcmKLM), this domain enables high-level production of an early, partially cyclized intermediate of Tcm C in a Tcm C- null mutant or in a heterologous host (Streptomyces lividans) . By analogy to fatty acid biosynthesis, the tcmKLM polyketide synthase gene products are probably sufficient to produce the linear decaketide precursor of Tcm C; thus, the tcmN N-terminal domain is most likely responsible for one or more of the early cyclizations and, perhaps, the attendant dehydrations that lead to the partially cyclized intermediate . The tcmN gene therefore appears to encode a multifunctional cyclase-dehydratase-3-O-methyl transferase . The tcmO gene encodes the 8-O-methyl transferase. Carcinogenesis, 1992 Mar, 13(3), 439 - 45 Spontaneous and mutagen-mediated amplification of a neo gene integrated at different genomic sites in rat 2 fibroblasts; Quinto H et al.; A promoterless neo gene was stably transfected in rodent fibroblasts to act as a reporter gene for rearrangements resulting in its expression at the different genomic integration sites . Nine clones were isolated which had integrated a varying copy number of neo at one or more genomic sites but still displayed a Neo- phenotype (G418-sensitive) . These clones were analyzed for their ability to become Neo+ (G418-resistant) either spontaneously or after mutagen treatment . They were all able to generate G418-resistant subclones spontaneously at frequencies ranging from 2 x 10(-8) to 6 x 10(-5) . The acquired G418-resistance was always associated with amplification and enhanced transcription of neo . No correlation was observed between the frequency of occurrence of G418-resistance and the number of copies or integration sites of neo . When treated with the mutagens mitomycin C or methylmethane sulfonate, only one clone, RH15, produced G418-resistant subclones in a dose-related fashion . In this mutagen-inducible clone, DNA lesions of a different nature (monoadducts or cross-links) were equally efficient in the induction of G418-resistance . Amplification and enhanced transcription of the neo gene were observed in both the spontaneous and mutagen-induced G418-resistant subclones of RH15 cell line . These findings indicate that the exogenous neo gene integrated at different genomic sites was acting as a reporter gene for amplification . Interestingly, while all nine integration sites were observed to amplify spontaneously, only one could be induced to amplify by mutagens . This suggests that different genomic regions display differing susceptibilities to mutagen-mediated amplification . This may be important in view of the major role played by mutagen-mediated gene amplification in carcinogenesis. Gan To Kagaku Ryoho, 1992 Mar, 19(3), 373 - 7 {A case of intracranial germinoma responsive to amphotericin B}; Okuno S et al.; A 20-year-old man was admitted to our institution complaining of gradually worsening motor weakness in the right extremities . On admission, the radiological examination revealed a mass located in the left parietal region . On April 4, 1988, a left fronto-parietal craniotomy was performed and the tumor was subtotally removed . The pathological findings of the surgical specimen confirmed no specific tumor, but the presence of a small mingled Candida glabrata supported the diagnosis of fungal granuloma . Amphotericin B (AmB) was administered intravenously for the later enlargement of the tumor . MRI 4 weeks after the beginning of this treatment demonstrated the tumor to be prominently decreased in size . At discharge 3 months later, there was no tumor except only a minimal one in the paraventricular region . However, the recurrence of the tumor was discovered again over the next 8 months . AmB was administered as before, but the tumor continued to be enlarged . In May, 1990, surgery was performed again, and the histological diagnosis was germinoma accompanied with considerable granulomatous reaction . Subsequently, local irradiation was given and complete remission was maintained up to the present time 8 months after irradiation . AmB is a polyene antifungal antibiotic, that has also been reported to enhance the response of antitumor drugs to some tumors on the basis of increased tumor cell permeability . Recent investigations revealed that AmB had immunoadjuvant properties mediated through activated lymphocytes and macrophages, which resulted in an increased host resistance against infectious diseases and even tumors in vivo or in vitro studies . We reported a rare case of intracranial germinoma which responded well to AmB probably through its own antitumor effect caused by immunoadjuvant properties . We discussed the possibility of AmB to be used as immunoadjuvant agent or in combination with other antitumor drugs for the effective treatment of some tumors. Ann Otol Rhinol Laryngol, 1992 Mar, 101(3), 261 - 4 Lepromatous leprosy: nasal manifestations and treatment with minocycline; Lalwani AK et al.; Nasal involvement in lepromatous leprosy is universal and occurs early in the course of the disease . Nasal symptoms include obstruction, crusting, bleeding, and hyposmia . Traditional therapy with dapsone, rifampin, and clofazimine is limited by its cost and toxicity . Minocycline hydrochloride, a tetracycline antibiotic with limited side effects, is promising as a new treatment for leprosy . A case is presented that highlights the clinical presentation, diagnosis, and treatment of lepromatous leprosy. Ann Otol Rhinol Laryngol, 1992 Mar, 101(3), 209 - 15 Conservative medical management of traumatic pharyngoesophageal perforations; Dolgin SR et al.; Traditionally, surgical treatment has been the acceptable management for perforation of the pharyngoesophageal tract secondary to blunt and penetrating trauma . From July 1983 to June 1990, we managed 10 patients with this type of lesion by a conservative medical management approach . Mirror or fiberoptic flexible laryngoscopy was performed in the majority of cases to ascertain the nature of the injury . An esophagogram is very helpful to locate and evaluate the extent of the injury . All patients were treated with broad-spectrum intravenous antibiotic therapy and no oral feeding . There were no complications or need for surgical treatment in any of the cases . The head and neck surgeon, in selected cases, should consider the possibility of using conservative management of pharyngoesophageal perforations . This approach has proven in our hands to be relatively safe and cost-effective, resulting in no disability or prolonged hospitalization of our patients . This study involves two institutions (two affiliated hospitals of Case Western Reserve University School of Medicine) with different surgeons selecting appropriate antibiotic therapy . It is a retrospective review . No controls were made by random selection of cases treated surgically . These cases, if not properly managed, may lead to fatal outcomes. Am Fam Physician, 1992 Mar, 45(3), 1321 - 30 Outpatient management of burns; Peate WF; Most of the 2.5 million Americans who seek medical attention for burns each year can be successfully managed as outpatients . Mainstays of treatment are proper wound cleaning, unroofing and debriding of most blisters, and topical chemoprophylaxis for all second- and third-degree burns . Early surgical evaluation for possible excision and grafting is necessary for third-degree burns, deep second-degree burns and infected burns . Systemic antibiotic therapy alone is insufficient for infected burns . Hospitalization is mandated for most fire-related inhalation injuries. J Nutr, 1992 Mar, 122(3 Suppl), 591 - 6 History of nutritional immunology: introduction and overview; Beisel WR; Nutritional immunology is a newly recognized subdiscipline of vast clinical and public health importance . Its history began in 1810 with recognition of lymphoid tissue atrophy due to malnutrition . Discovery of vitamins in the early 1900s was followed by reports on their contribution to immunity and other host defenses . A hiatus in immunonutritional progress occurred during World War II and the "antibiotic era," but a worldwide rebirth of interest began in the 1960s and early 1970s . The current logarithmic growth of nutritional immunology was triggered by increased medical interest, plus the introduction of new concepts and investigative research methodologies from both parent sciences. J Clin Invest, 1992 Mar, 89(3), 947 - 53 Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis; Tureen JH et al.; The effects of hydration status on cerebral blood flow (CBF) and development of cerebrospinal fluid (CSF) lactic acidosis were evaluated in rabbits with experimental pneumococcal meningitis . As loss of cerebrovascular autoregulation has been previously demonstrated in this model, we reasoned that compromise of intravascular volume might severely affect cerebral perfusion . Furthermore, as acute exacerbation of the inflammatory response in the subarachnoid space has been observed after antibiotic therapy, animals were studied not only while meningitis evolved, but also 4-6 h after treatment with antibiotics to determine whether there would also be an effect on CBF . To produce different levels of hydration, animals were given either 50 ml/kg per 24 h of normal saline ("low fluid") or 150 ml/kg 24 h ("high fluid") . After 16 h of infection, rabbits that were given the lower fluid regimen had lower mean arterial blood pressure (MABP), lower CBF, and higher CSF lactate compared with animals that received the higher fluid regimen . In the first 4-6 h after antibiotic administration, low fluid rabbits had a significant decrease in MABP and CBF compared with, and a significantly greater increase in CSF lactate concentration than, high fluid rabbits . This study suggests that intravascular volume status may be a critical variable in determining CBF and therefore the degree of cerebral ischemia in meningitis. J Bacteriol, 1992 Mar, 174(5), 1554 - 67 Suppression of insertions in the complex pdxJ operon of Escherichia coli K-12 by lon and other mutations; Lam HM et al.; Complementation analyses using minimal recombinant clones showed that all known pdx point mutations, which cause pyridoxine (vitamin B6) or pyridoxal auxotrophy, are located in the pdxA, pdxB, serC, pdxJ, and pdxH genes . Antibiotic enrichments for chromosomal transposon mutants that require pyridoxine (vitamin B6) or pyridoxal led to the isolation of insertions in pdxA, pdxB, and pdxH but not in pdxJ . This observation suggested that pdxJ, like pdxA, pdxB, and serC, might be in a complex operon . To test this hypothesis, we constructed stable insertion mutations in and around pdxJ in plasmids and forced them into the bacterial chromosome . Physiological properties of the resulting insertion mutants were characterized, and the DNA sequence of pdxJ and adjacent regions was determined . These combined approaches led to the following conclusions: (i) pdxJ is the first gene in a two-gene operon that contains a gene, temporarily designated dpj, essential for Escherichia coli growth; (ii) expression of the rnc-era-recO and pdxJ-dpj operons can occur independently, although the pdxJ-dpj promoter may lie within recO; (iii) pdxJ encodes a 26,384-Da polypeptide whose coding region is preceded by a PDX box, and dpj probably encodes a basic, 14,052-Da polypeptide; (iv) mini-Mud insertions in dpj and pdxJ, which are polar on dpj, severely limit E . coli growth; and (v) three classes of suppressors, including mutations in lon and suppressors of lon, that allow faster growth of pdxJ::mini-Mud mutants can be isolated . A model to account for the action of dpj suppressors is presented, and aspects of this genetic analysis are related to the pyridoxal 5'-phosphate biosynthetic pathway. Leber Magen Darm, 1992 Mar, 22(2), 79 - 82 {Tertiary gummatous syphilis of the liver--an unexpected disease today . Report of two cases}; Dammrich J et al.; Today the luetic hepatitis and gummata of liver are very rare manifestations of a tertiary syphilis because of the antibiotic therapy . Therefore a luetic involvement of liver is a most unexpected and at first mostly misinterpreted finding . In the both represented cases foci in the liver were present, which were suspicious for a metastasizing malignoma and set off the search for an unknown primary tumor . In liver biopsies no malignant process was seen, but necroses with a granulomatous reaction at the border were found which were classifiable definitively only after serological investigations as gummata of liver . Especially by the presence of an additionally reactive hepatitis in the remaining liver parenchyma, possibly with some sarcoid-like granulomas, a tertiary gummatous syphilis should be taken into consideration . The regression of gummata in sonography and computertomography as well as the return to normal of the laboratory findings are important parameters in the follow-up to confirm the diagnosis under antibiotic therapy . The described cases stress the importance that even today the tertiary lues should be taken into consideration by liver foci of unknown origin and should be excluded serologically. Antibiot Khimioter, 1992 Mar, 37(3), 18 - 20 {Study of general toxic and organotropic properties of clindamycin in long-term experiments}; Berezhinskaia VV et al.; The action of clindamycin monohydrate on the general state and weight rise, liver and kidney functions, peripheral blood count and pathomorphological state of the viscera was studied on rats in chronic experiments . Clindamycin was administered to laboratory animals orally in doses of 50, 100, 150 and 300 mg/kg . It was shown that some adverse reactions to the drug and in particular disorders in blood coagulation and morphological changes in the intestine did not depend on its dose and were due to duration of the drug use and probable development of dysbacteriosis . At the same time the disorders in the liver and kidney functions though transitory did depend, to a greater extent, on the dose and were evident after the antibiotic overdosage. Jpn J Antibiot, 1992 Mar, 45(3), 301 - 7 {Clinical evaluation of panipenem/betamipron in children}; Meguro H et al.; Panipenem/betamipron (PAPM/BP), a new injectable carbapenem antibiotic, was evaluated for its safety and efficacy in children . Ninety three percentage (14 in 15 cases) of various infections were cured with PAPM/BP therapy . Transient skin rash occurred in 1 case, probably due to the histamine-like effect of PAPM/BP . The plasma half life of panipenem was 0.85 +/- 0.07 hours . PAPM/BP was evaluated to be a less-epileptogenic carbapenem antibiotic. Wiad Lek, 1992 Mar, 45(5-6), 197 - 200 {Effectiveness of Cefobid in pediatric practice}; Roszkowska-Blaim M et al.; The sensitivity to Cefobid was evaluated in vitro in 37 bacterial strains obtained from 37 patients . Good effectiveness of the drug against the strains was found in 78.3%, moderate in 13.5%, none in 8.2% . The clinical examinations were carried out in 16 children and again a high clinical effectiveness of Cefobid was found, with cure in 14 cases (87.5%) . Cefobid was ineffective in 2 children with infection of Tenckhoff catheter, which required finally exchange of the catheter . No side effects of Cefobid were noted . Cefobid is a safe and effective antibiotic which may be given to small children and patients with renal failure . The broad spectrum and the possibility of drug use without dosage modification facilitate the treatment of patients with various grades of renal failure. J Membr Biol, 1992 Mar, 126(3), 265 - 75 Dimerization constant and single-channel conductance of gramicidin in thylakoid membranes; Schonknecht G et al.; The effect of the pore-forming antibiotic gramicidin on pure lipid membranes is well characterized . We studied its action in protein-rich thylakoid membranes that contain less than 25% (wt/wt) acyl lipids . A transmembrane voltage was induced by flashing light, and its decay was measured and interpreted to yield the distribution of gramicidin over thylakoids, its dimerization constant and its single-channel conductance in this membrane . The distribution of gramicidin over the ensemble of thylakoids was immediately homogeneous when the antibiotic was added under stirring, while it became homogeneous only after 20 min in a stirred suspension that was initially heterogeneous . The dimerization constant, 5 x 10(14) cm2/mol, was about 10 times larger than in pure lipid membranes . This was attributed to the up-concentration of gramicidin in the small fractional area of protein-free lipid bilayer and further by a preference of gramicidin for stacked portions of the membrane . The latter bears important consequences with regard to bioenergetic studies with this ionophore . As gramicidin was largely dimerized from a concentration of 1 nM (in the suspension) on, the membrane's conductance then increased linearly as a function of added gramicidin . When the negative surface potential at the thylakoid membrane was screened, the conductance of a single gramicidin dimer agreed well with figures reported for bilayers from neutral lipid (about 0.5 pS at 10 mM NaCl) . The modulation of the conductance by the surface potential in spinach versus pea thylakoids and between different preparations is discussed in detail. Pacing Clin Electrophysiol, 1992 Mar, 15(3), 252 - 5 Prospective evaluation of heart block complicating early Lyme disease; Rubin DA et al.; Lyme disease is a recognized cause of heart block/carditis . The incidence of heart block complicating early Lyme disease has not been prospectively evaluated . In this study, 61 patients with early Lyme disease documented by the rash of erythema migrans were prospectively evaluated for carditis . Fifty five of 61 patients had a repeat examination 3 to 4 weeks after initiation of antibiotic therapy . Only one of 61 patients (1.6%) presented with heart block, which resolved with antibiotics . None of the 54 patients without heart block on initial presentation had a change in any measured electrocardiographic parameter or progressed to heart block after antibiotics . Therefore, early Lyme disease appears to be infrequently complicated by heart block . Early administration of antibiotics may prevent the development of heart block/carditis. Acta Virol, 1992 Mar, 36(2), 166 - 72 On the antiviral activity of diffusomycin (oxazolomycin); Tonew E et al.; The effect of the beta-lactone antibiotic diffusomycin (oxazolomycin) was investigated against vaccinia (Lister), herpes simplex type 1 (Kupka), influenza A (WSN; H1N1), and Coxsackie A9 viruses . Diffusomycin reduced significantly the plaque formation of enveloped DNA and RNA viruses by more than 90% in the range of the maximally tolerated dose . As could be shown with vaccinia virus, the antiviral action was not caused by virucidal effect on virions or by interaction with virus adsorption and penetration . In one-step growth cycle assays diffusomycin prevented the replication of herpes simplex type 1, vaccinia and influenza A viruses in a dose-dependent manner . The replication of influenza A viruses was blocked immediately after addition of the compound during zero to six hr p.i . Partial reversibility of the antiviral action was established by washing off the antibiotic from chicken embryo cells (CEC) infected with influenza A virus . Finally, replication of Coxsackie A9 virus was not inhibited by diffusomycin . Electron-optical studies revealed a reduced synthesis of HSV-1 nucleocapsids in dependence on the concentration of the compound. Antibiot Khimioter, 1992 Mar, 37(3), 35 - 9 {Experience with using carminomycin in oncological clinical practice}; Gorbunova VA; Carminomycin is an original antitumor antibiotic from the anthracycline group isolated at the Institute of New Antibiotics (USSR) in 1973 . Pharmacological investigation of carminomycin revealed its satisfactory absorption from the gastrointestinal tract which proved to be a distinguishing property of the antibiotic as compared to other anthracyclines such as adriamycin and rubomycin . The clinical trials of carminomycin showed that it was mainly active against soft tissue sarcoma and breast cancer, lymphosarcoma, neuroblastoma, Wilms' tumor and Ewing's sarcoma in children, as well as acute leukemia . Various regimens for the antibiotic administration were applied: short-term, single and long-term . Suppression of hemopoiesis was considered as a limiting toxic effect . By the data available carminomycin had lower cardiotoxicity as compared with rubomycin and adriamycin . Development of oral carminomycin is believed promising. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi, 1992 Mar-Apr, 33(2), 112 - 8 Adenoviral pneumonia in children; Chiu NC et al.; This report reviews the manifestations in fifteen children of proved adenoviral pneumonia . Patients' ages ranged from 43 days to 4 years and 1 month . Twelve cases were younger than 2 years old . Adenoviral infections were proved by positive viral cultures or a four-fold increase of the complement fixation titer . Prolonged fever and cough were found in all cases . In 13 patients, respiratory distress occurred; 5 needed mechanical ventilation . Injected throats, conjunctivae and ear drums were common . Other clinical pictures included abdominal discomfort, hepatomegaly, skin rash, convulsion and bleeding tendency . Abnormal laboratory findings were mild anemia, leukopenia, thrombocytopenia, elevated erythrocyte sedimentation rate and C-reactive protein, impaired liver function test, and prolonged prothrombin time and partial thromboplastin time . Anemia (11 cases), leukopenia (7 cases) and elevated transaminases levels (7 cases) were more common than previously reported . All patients had para-hilar peribronchial infiltrates in chest roentgenography . Segmental atelectasis and compensated hyper-expansion were found frequently . Pleural effusion were noted in six of our cases . Air leak syndrome occurred in three patients who had received mechanical ventilation . Three of the 15 patients expired: one had a preceding measles infection, all had disseminated intravascular coagulopathy . For patients with antibiotic-resistant pneumonia, adenoviral studies should be done . Extrapulmonary manifestations, and some abnormal laboratory findings, i.e., mild anemia, leukopenia, impaired liver function are clues to adenoviral infections, while bleeding tendency can be regarded as a poor prognostic sign for children with adenoviral pneumonia. Curr Genet, 1992 Mar, 21(3), 255 - 60 The nature of extra-chromosomal maintenance of transforming plasmids in the filamentous basidiomycete Phanerochaete chrysosporium; Randall TA et al.; The nature of extra-chromosomal maintenance of the transforming plasmid p12-6 in Phanerochaete chrysosporium was studied . Our results indicate that the plasmid is maintained in the fungal transformants extra-chromosomally as part of a larger endogenous plasmid (designated pME) of P . chrysosporium . Using the total DNA of p12-6 fungal transformants, p12-6, as well as a larger plasmid, p511, were recovered in recA- E . coli strains while only p12-6 was recovered in recA+ E . coli strains . The results also showed that the cytosine methylation system has no apparent effect on the strain-dependent recovery of p12-6 and p511 in E . coli from the total DNA of fungal transformants. Chem Biol Interact, 1992 Mar, 82(1), 31 - 46 Calf thymus DNA binding/bonding properties of CC-1065 and analogs as related to their biological activities and toxicities; Krueger WC et al.; CC-1065 is a potent natural antitumor antibiotic that binds non-covalently and covalently (N-3 adenine adduct) in the minor groove of B-form DNA . Synthetic analogs of CC-1065 do not exhibit the delayed death toxicity of CC-1065 and are efficacious anticancer agents, some of them curative in murine tumor models . In an attempt to understand the different biological properties of CC-1065 and analogs, we have determined the following quantities for CC-1065, enantiomeric CC-1065, and three biologically active analogs and their enantiomers: the calf thymus DNA (CT-DNA) induced molar ellipticity of the adduct (or how rigidly the adduct is held in the right-hand conformation of the minor groove); the stability of the adduct with respect to long incubation times and to digestion by snake venom phosphodiesterase I (SVPD); the stabilizing effect on the CT-DNA helix of the covalently and non-covalently bound species with respect to thermal melting; and the CT-DNA binding/bonding (non-covalent/covalent) profiles at a low molar ratio of nucleotide to drug . The major observations from these studies are as follows: (i) molecules which show large DNA interaction parameters, stable adducts, and significant non-covalent binding exhibit delayed death toxicity; (ii) molecules which show intermediate DNA interaction parameters and stable adducts, but do not show significant non-covalent binding, do not exhibit delayed death toxicity and are biologically active; (iii) molecules which show small DNA interaction parameters and unstable DNA adducts are biologically inactive . The results suggest that a window exists in the affinity for the minor groove of DNA wherein an analog may possess the correct balance of toxicity and activity to make a useful anticancer agent . Outside of this window, the analog causes delayed deaths or has no significant biological activity. Biochemistry, 1992 Feb 25, 31(7), 1909 - 17 Influence of thiol structure on neocarzinostatin activation and expression of DNA damage; Dedon PC et al.; Neocarzinostatin (NCS) is an enediyne antitumor antibiotic that cleaves DNA following a thiol-induced electronic rearrangement to a diradical form . Structure-function studies with 11 thiol-containing compounds were undertaken to clarify the role of the thiol in NCS-mediated DNA damage . The rates of activation of NCS in the presence of DNA with the various thiols approximated a Bronsted relation (beta = 0.43, r2 = 0.86), which suggests that the basicity/nucleophilicity of the thiol is important to NCS activation . However, an additional contribution to NCS activation may arise from the affinity of the thiol for DNA, since there is a correlation between the concentration of thiol producing maximal DNA damage, assessed by quantitating the topologic forms of plasmid pBR322 following treatment with NCS, and the apparent ability of the thiol to bind to DNA by hydrophobic or electrostatic interactions . The overall second-order rate constants for the activation of NCS were found to be inversely correlated with the thiol optima; a plot of the former versus the reciprocal of the optimal thiol concentration revealed a first-order rate constant of activation of 0.013 s-1 in the presence of DNA . This indicates that maximal DNA damage occurs when NCS is activated with a half-life of 52 s, a relatively slow rate of activation that suggests that NCS binds to DNA before undergoing activation by thiol . Finally, an analysis of strand breaks in pBR322 shows that thiols possessing a carboxylate moiety produce larger quantities of bistranded DNA lesions than their esterified or non-carboxylate-containing counterparts. Eur J Biochem, 1992 Feb 15, 204(1), 69 - 74 Anthracycline binding to DNA . High-resolution structure of d(TGTACA) complexed with 4'-epiadriamycin; Leonard GA et al.; Crystallographic methods have been applied to determine the high-resolution structure of the complex formed between the self-complementary oligonucleotide d(TGTACA) and the anthracycline antibiotic 4'-epiadriamycin . The complex crystallises in the tetragonal system, space group P4(1)2(1)2 with a = 2.802 nm and c = 5.293 nm, and an asymmetric unit consisting of a single DNA strand, one drug molecule and 34 solvent molecules . The refinement converged with an R factor of 0.17 for the 2381 reflections with F greater than or equal to 3 sigma F in the resolution range 0.70-0.14 nm . Two asymmetric units associate such that a distorted B-DNA-type hexanucleotide duplex is formed incorporating two drug molecules that are intercalated at the TpG steps . The amino sugar of 4'-epiadriamycin binds in the minor groove of the duplex and displays different interactions from those observed in previously determined structures . Interactions between the hydrophilic groups of the amino sugar and the oligonucleotide are all mediated by solvent molecules . Ultraviolet melting measurements and comparison with other anthracycline-DNA complexes suggest that these indirect interactions have a powerful stabilising effect on the complex. Eur J Biochem, 1992 Feb 15, 204(1), 327 - 36 Evidence for a selective destabilization of an integral membrane protein, the cytochrome b6/f complex, during gametogenesis in Chlamydomonas reinhardtii; Bulte L et al.; We studied the process of photosynthetic inactivation during gametogenesis of the unicellular green alga Chlamydomonas reinhardtii . We show that it is caused by the selective destabilization of a single transmembrane protein complex, the cytochrome b6/f complex, which is initially accumulated in the thylakoid membranes of vegetative cells . This protein destabilization is controlled by the intracellular energy sources available in the gametes, i.e . the coupled electron flow in the mitochondria and the amount of starch accumulated in the chloroplast . It nevertheless requires the expression of gamete-specific proteins . The loss of cytochrome b6/f complexes during gametogenesis is prevented by the addition of cycloheximide, but is chloramphenicol insensitive . Therefore, it is likely to involve some translation product of nuclear origin, specifically expressed during gametogenesis . Among the new polypeptides specifically found in the gametes, we detected a soluble polypeptide M alpha (approximate molecular mass of 63 kDa), which shared common epitopes with cytochrome f . Its synthesis displays an antibiotic sensitivity typical of a nuclear-encoded polypeptide and is controlled by the same intracellular signals which control the destabilization of the cytochrome b6/f complexes in the thylakoid membranes. Eur J Biochem, 1992 Feb 15, 204(1), 179 - 85 Effects of ions on the intrinsic activities of c-H-ras protein p21 . A comparison with elongation factor Tu; Mistou MY et al.; The influence of the ionic environment on the intrinsic GTPase activity and the guanine-nucleotide interaction of Ha-ras protein p21 were studied in various experimental conditions and compared with the behaviour of elongation factor (EF) Tu . To this purpose, nucleotide-free p21 was prepared, which is much more stable than by any other reported method . Specific differences between p21 and EF-Tu were found in the action of divalent anions which strongly enhance the dissociation rate of p21.GDP without affecting that of EF-Tu . Unlike EF-Tu, the GTPase activity of p21 is only slightly dependent on the presence and concentration of monovalent cations . The concentrations of Mg2+ influencing the dissociation rate of the p21.GDP complex are much higher than for the intrinsic GTPase activity, an effect also observed for EF-Tu . These results point to two distinct roles of Mg2+: as a conformational regulator of the interaction with the substrate and as a key element for the hydrolysis of GTP . The GTPase activity of p21 is not affected by changes in pH over the range 6-9.2, different from that of EF-Tu . However, stabilization by kirromycin confers a pH independence to the GTPase of EF-Tu in the pH range 6.5-10, suggesting that the bell-shaped behaviour of this activity in the absence of the antibiotic is due to denaturation . This implies similar properties in the catalytic mechanism of these two guanine-nucleotide-binding proteins. Rheum Dis Clin North Am, 1992 Feb, 18(1), 67 - 79 Chlamydia and Reiter's syndrome (reactive arthritis); Rahman MU et al.; The etiology of RS is not clear, but there is a strong correlation with infectious episodes and some genetic factor(s) . Chlamydia have emerged as the most common pathogen associated with RS . We have presented evidence that chlamydia or its antigens may be present in the synovium and may be important in the pathogenesis of RS . The possibility of latent chlamydial infection has also been discussed . Although previous attempts to treat RS with antibiotics were not encouraging, recent reports suggest some favorable effects from antibiotic therapy . There is still a need to further assess the state of the infectious agent and to consider new, more effective regimens. J Pediatr Surg, 1992 Feb, 27(2), 209 - 12; discussion 212-4 Is there a role for laparoscopic appendectomy in pediatric surgery? Gilchrist BF, Lobe TE, Schropp KP, Kay GA, Hixson SD, Wrenn EL Jr, Philippe PG, Hollabaugh RS. Although laparoscopic procedures are currently in vogue in general surgery, the role of this approach in children has not been prospectively evaluated in the United States using the new instrumentation now available to us . To assess the value of laparoscopic appendectomy (LA) in childhood, we prospectively compared 14 LAs with 50 open appendectomies (OA) over 6 months in a single children's hospital . Antibiotic usage was at the discretion of the surgeon regardless of the procedure performed and was not different between groups . LA was performed under the direction of a single laparoscopy-trained surgeon and patient selection was based on parental consent . A three-puncture LA technique was used; children from this group were allowed to return to full activities as soon as they were comfortable . There were no significant differences between groups for severity of disease, age, weight, hospital cost, or complications . The types of complications that developed were comparable in both groups . The percent of complicated appendicitis (gangrene or perforation) was 32% in the OA group and 36% in the LA group . Patients in the LA group spent significantly fewer days in the hospital and returned to unrestricted activities (school, athletics, etc) faster than patients in the OA group . LA is approximately $1,000 more expensive than OA, the differences being easily explainable by the cost of the disposable supplies necessary for the procedure (laser fibers, trocars, etc), but because of the shorter hospital stay in the LA group the mean total cost for each group was comparable . These data suggest that although there appears to be no cost advantage, LA shortens the hospital stay and allows children to return to unrestricted activity sooner than OA.(ABSTRACT TRUNCATED AT 250 WORDS) J Chromatogr, 1992 Feb 7, 574(1), 65 - 70 Studies on cyclic peptides related to gratisin by reversed-phase high-performance liquid chromatography; Tamaki M et al.; The chromatographic behaviour of several synthetic peptides related to the antibiotic peptide gratisin was investigated using reversed-phase high-performance liquid chromatography . The influence of the concentration of the peptides, column temperature and flow-rate on the chromatographic separation was examined . Of these peptides, some analogues with the D-X-D-Y-L-Pro or L-Pro-D-X-D-Y sequences and strong activities gave double peaks in the chromatogram . The isomeric conformers were separated from each of the double peaks and were in equilibrium with each other at low temperatures . It is proposed that the presence of the sequences of D-X-D-Y-L-Pro and L-Pro-D-X-D-Y in these peptides gives rise to the stabilization and various degrees of hydrophobicity of their conformers. Br J Cancer, 1992 Feb, 65(2), 183 - 8 Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16; Nordenberg J et al.; The antibiotic drug novobiocin was evaluated for its anti-tumour properties in B16 melanoma cells . Novobiocin is shown to inhibit melanoma B16 cell proliferation . The anti-proliferative effect was gradually reversible upon removal of novobiocin from the culture medium . Growth inhibition by novobiocin was accompanied by phenotypic alterations, that included morphological changes, lipid accumulation and marked increases in the activities of NADPH cytochrome c reductase and gamma glutamyl transpeptidase . In vivo administration of repeated i.p . doses of novobiocin, to mice implanted with B16 melanoma cells resulted in growth retardation . The combined treatment of the B16 melanoma cells with novobiocin and other chemical inducers of differentiation was examined in a cell growth assay . Novobiocin and sodium butyrate inhibited cell growth in a near additive manner, while combination of novobiocin with the GTP-depleting agents, tiazofurin or mycophenolic acid resulted in a synergistic decrease in cell growth . Our results support the contention further that novobiocin and other differentiating agents might be of potential value in melanoma therapy. Arch Intern Med, 1992 Feb, 152(2), 406 - 8 Fluconazole in the treatment of hepatosplenic candidiasis; Flannery MT et al.; Hepatosplenic candidiasis has increased in frequency among immunocompromised hosts . Risk factors include hematologic malignancy, intensive chemotherapy, prolonged neutropenia, and treatment with broad-spectrum antibiotics . Patients most commonly present with abdominal pain, persistent fevers despite antibiotic therapy, and an elevated alkaline phosphatase level that is out of proportion to other hepatic enzyme levels . Gastrointestinal mucosal damage secondary to intensive chemotherapy may allow colonization with Candida species and subsequent seeding of the portal vein . Treatment has consisted of prolonged courses of amphotericin B, with mortality rates approaching 50% . We report a case of hepatosplenic candidiasis in a patient with acute myelogenous leukemia who had clinical and radiographic improvement during fluconazole therapy . Fluconazole may be an efficacious and less toxic alternative to amphotericin B. Am Fam Physician, 1992 Feb, 45(2), 579 - 82 Infection of fetal scalp electrode monitoring sites; Leatherman J et al.; Complications caused by placement of a fetal scalp electrode include trauma, hemorrhage and infection . Infections are usually localized and self-limited, but they can occasionally lead to serious complications, such as osteomyelitis, sepsis and death . The recommended treatment for a scalp abscess is incision and drainage, followed by appropriate antibiotic therapy . If a serious infection is suspected, the infant should be hospitalized, blood cultures obtained and intravenous antibiotic therapy initiated. Radiat Res, 1992 Feb, 129(2), 163 - 70 Leptomycin B-induced fixation of X-ray-related potentially lethal damage; Sasaki H et al.; Effects of an antifungal antibiotic, Leptomycin B (LMB), on X-ray cell killing were studied using cultured mammalian cells (BHK21) . LMB at concentrations from 0.05 to 2 ng/ml inhibited cell proliferation but enhanced cell killing without significant cytotoxic effect when added to cell cultures pre- and postirradiation . The degree of enhanced cell killing decreased as the interval between irradiation and LMB treatment was prolonged . Enhancement of cell killing was probably due to fixation of potentially lethal damage (PLD) to LMB . Radioresistant S-phase cells were more sensitive to LMB-induced PLD fixation than G1-phase cells . Furthermore, a preliminary study showed that LMB not only inhibited the repair of PLD which was induced by conditioned medium but also inhibited splitdose repair of sublethal damage . Although the target molecule of LMB has not been identified, we suggest that LMB inhibits repair processes by altering the structure of the nuclear scaffold, which is supposed to be a radiosensitive site. J Am Coll Cardiol, 1992 Feb, 19(2), 365 - 71 Severe mitral or aortic valve regurgitation, or both, requiring valve replacement for infective endocarditis complicating hypertrophic cardiomyopathy; Roberts WC et al.; Certain clinical and morphologic findings are described in 11 patients with hypertrophic cardiomyopathy complicated by infective endocarditis that produced severe mitral or aortic valve regurgitation, or both, necessitating valve replacement . All 11 patients had changes in the operatively excised valve or valves characteristic of healed infective endocarditis . The infection involved only the mitral valve in seven patients, only the aortic valve in three patients and both valves in one patient . Study of the operatively excised mitral valves indicated that the healed vegetations were located most commonly on the left ventricular aspects of the anterior mitral leaflet, indicating that vegetation had formed at contact points of this leaflet with mural endocardium of the left ventricular outflow tract . In all 11 patients, the infective endocarditis either worsened preexisting valve regurgitation or initiated valve regurgitation and led to worsened signs and symptoms of cardiac dysfunction, necessitating valve replacement . Functional class improved in the nine patients who survived 7 to 101 months after valve replacement . Hypertrophic cardiomyopathy appears to be a factor predisposing to infective endocarditis . Patients with hypertrophic cardiomyopathy should receive prophylactic antibiotic therapy during procedures that predispose to infective endocarditis. J Virol, 1992 Feb, 66(2), 685 - 93 Germiston virus transcriptase requires active 40S ribosomal subunits and utilizes capped cellular RNAs; Vialat P et al.; The transcriptase associated with Germiston virus was assayed in an in vitro reaction in which transcription was coupled to translation by adding reticulocyte lysate under the appropriate salt conditions . When analyzed in polyacrylamide gels, the major transcripts migrated like authentic S mRNAs and possessed 12- to 18-base-long nontemplated 5' extensions similar to the 5' end of viral mRNAs . These transcripts were functional for the synthesis of at least proteins N and NSS . When translation was inhibited by adding protein synthesis inhibitors such as puromycin, cycloheximide, and anisomycin, a drastic inhibitory effect was observed on the synthesis of the complete S mRNA transcripts . However, initiation and part of the elongation process were still active, since short and incomplete RNA molecules with RNA primers at their 5' ends were synthesized . On the other hand, we found that edeine, another inhibitor of protein synthesis, stimulated not only synthesis of S mRNAs but also that of the full-length S cRNAs . Taking into account the mode of action of this antibiotic, we discuss the results, which emphasize the crucial role of active ribosomes during bunyavirus transcription and confirm the observations reported on La Crosse virions . Moreover, we showed that the RNA transcripts synthesized in a transcription-translation reaction were capped and that most of them have acquired the 5' terminal sequences of the alpha- or beta-globin mRNA. J Infect Dis, 1992 Feb, 165(2), 218 - 23 Infectious disease manpower in the United States--1986 . 2 . Changes in practice patterns over time and training needs . Manpower and Training Committee, Infectious Diseases Society of America; Hamory BH et al.; Infectious disease-trained internal medicine physicians responding to a questionnaire survey (n = 1802) reported minor differences in time spent in patient care versus laboratory-based research whether they subsequently became practitioners or academicians . Both practitioners and academicians ranked hospital epidemiology first, followed by knowledge of hospital antibiotic policies in order of importance for new trainees to be taught . Internists with greater than 12 months of training in infectious diseases were divided into private practice versus academically based groups, and their distribution of time spent in various professional activities was analyzed by 5-year intervals for each cohort . These studies confirmed an increasing proportion of time spent in infectious disease-related patient care for new practitioners . Over time, patient care activities decreased and administrative activities increased in all groups . These data are important for estimating future manpower needs. Ann Intern Med, 1992 Feb 1, 116(3), 177 - 82 Granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjunct therapy in relapsed Hodgkin disease; Gulati SC et al.; OBJECTIVE: To determine the clinical and economic effects of granulocyte macrophage colony-stimulating factor (GM-CSF) as adjunct therapy in relapsed or refractory Hodgkin disease . DESIGN: A randomized, double-blind, phase III clinical trial . SETTING: A tertiary referral center . PATIENTS: Twenty-four patients (twelve of whom were controls) treated with high-dose chemotherapy and autologous bone marrow transplantation . MAIN RESULTS: The 12 patients treated with GM-CSF, when compared with placebo recipients, had shorter periods of neutropenia (median duration of an absolute neutrophil count of less than 1000 cells/mm3, 16 days compared with 27 days; P = 0.02), shorter periods of platelet-transfusion dependency (median duration, 13.5 days compared with 21 days; P = 0.03), and shorter hospitalizations (median hospital stay, 32 days compared with 40.5 days; P = 0.004) . Other clinical outcomes, such as frequency and severity of toxicities, development of pneumonia or infection, in-hospital death, and response rate were similar in the two groups . Actuarial long-term disease-free survival was 64% for patients treated with GM-CSF and 58% for patients who received placebo after 32 months of follow-up (P = 0.15) . The group treated with GM-CSF had lower total charges after infusion of autologous marrow than the placebo group (median in-hospital charges, $39,800 compared with $62,500; P = 0.005) because of lower post-infusion charges for room and board, antibiotic therapy, transfusions, laboratory tests, and physical therapy visits . CONCLUSIONS: Administration of GM-CSF was associated with acceleration of myeloid and platelet recovery and was cost effective in the treatment of patients with relapsed Hodgkin disease who received intensive chemotherapy. Jpn J Antibiot, 1992 Feb, 45(2), 155 - 9 {Investigation of panipenem/betamipron levels in sera and various tissues in patients of orthopedic surgery}; Kurata K; Panipenem/betamipron (PAPM/BP), a new parenteral carbapenem antibiotic, was investigated with regard to their levels in sera and various tissues collected from patients under orthopedic surgery . The subjects were 17 patients, complaining low back pain and hospitalized for surgical operations . PAPM/BP was administered by intravenous drip infusion for 30 minutes of a dose of 500 mg/500 mg . Serum and cerebrospinal fluid (CSF) specimens were taken from 8 patients at 15-70 minutes after administration and assayed for PAPM and BP levels . Serum, bone, and joint capsule samples where taken from the other 9 cases at 25-127 minutes after administration and assayed . PAPM levels in CSF were considerably lower than those in serum . They were 23.74-1.11 micrograms/ml in sera, 0.31-0.05 micrograms/ml in CSF's during 15 to 70 minutes after administration . PAPM levels were 27.85-2.97 micrograms/ml in sera, 2.54-0.20 micrograms/g in bones, 5.63 and 1.67 micrograms/g in joint capsules during 25 to 127 minutes after administration . BP levels in sera and various tissues were low compared to those of PAPM . These results showed that PAPM was detected at higher levels than 0.2 microgram/g in various tissues, except CSF during 20 to 120 minutes after drip infusion of PAPM/BP 500 mg/500 mg for 30 minutes. Nihon Kyobu Shikkan Gakkai Zasshi, 1992 Feb, 30(2), 352 - 7 {A case of allergic bronchopulmonary candidiasis treated with amphotericin B inhalation}; Inoue K et al.; A 77-year-old man underwent emergency admission for nocturnal asthmatic attack . Although his asthmatic attack improved within a few days with treatment including systemic corticosteroid, bilateral recurrent infiltrative shadows developed in his chest roentgenogram in association with a further exacerbation of dyspnea . Various antibiotic agents were given; however, the pulmonary infiltration did not improve . He was transferred to our department with the diagnosis of intractable pneumonia . C . albicans was detected in the sputum, and both IgE antibody and precipitating antibody specific for C . albicans were positive . Immediate cutaneous reactivity to C . albicans was positive even with a million-fold dilution of antigen extract C . albicans was also detected in bronchoalveolar lavage fluid . A diagnosis of allergic bronchopulmonary candidiasis was made . Chest roentgenographic findings as well as clinical symptoms improved with inhalation of 50 mg of amphotericin B. Aust N Z J Obstet Gynaecol, 1992 Feb, 32(1), 43 - 6 Endocervical Chlamydia trachomatis infection in pregnancy: direct test and clinico-sociodemographic survey of pregnant patients at the Port Moresby General Hospital antenatal clinic to determine prevalence and risk markers; Klufio CA et al.; The prevalence of endocervical C . trachomatis infection in 181 consecutive antenatal clinic patients at the first attendance and who had not received antibiotic therapy in the previous 4 weeks, was 17.7% . The direct fluorescent antibody test was used for diagnosis . There was no significant clinical or sociodemographic factor which distinguished patients who tested positive from those who tested negative. Int J Pancreatol, 1992 Feb, 11(1), 49 - 57 Role of bacterial infection in diet-induced acute pancreatitis in mice; Isaji S et al.; This study was performed to elucidate the role of bacterial infection in acute pancreatitis in young female mice fed a choline-deficient diet supplemented with 0.5% DL-ethionine (CDE diet) . Mice were randomly classified into two groups: one had been fed CDE diet alone (nonantibiotic group), the other was fed a CDE diet with oral administration of antibiotics (antibiotic group) . Survival rates at 96 and 144 h after introduction of the CDE diet were significantly improved in the antibiotic group, 25.0 and 19.4%, respectively, as compared with 3.6 and 0% in the nonantibiotic group (p, 0.05) . Aerobic and anaerobic bacterial cultures of blood, ascites, spleen, and pancreas were taken from living mice 72 h after introduction of the CDE diet . Positive bacterial growth from one or more of the specimens occurred in 29.4% of the nonantibiotic group, and in 10.0% of the antibiotic group . Mice with pancreatic necrosis had a higher positive culture rate, 62.5% in the nonantibiotic group vs 20.0% in the antibiotic group . These results suggest that reduction of intestinal flora in mice inhibits secondary infection caused by bacterial translocation and improves survival in diet-induced hemorrhagic pancreatitis . We believe the development of bacterial infection of gut origin may be a factor influencing mortality in severe pancreatitis. FEMS Microbiol Lett, 1992 Feb 1, 70(1), 43 - 7 Tunicamycin resistance in Saccharomyces cerevisiae: genetic studies; Alex L et al.; Tunicamycin is a nucleoside antibiotic complex produced by Streptomyces lysosuperficus which inhibits glycosylation . Several mutants have been isolated in this laboratory that are resistant to tunicamycin, of which the majority are recessive and a few are dominant . The mutations are possibly due to some loss of transport function or alteration in the membrane . These recessive mutations have been mapped to chromosome 1 by the 2 mu mapping method . Studies are underway to map the dominant mutations as well and to group these mutations into its complementation groups and to characterize them biochemically . Both mating types of these mutant strains have been generated in our laboratory. Scott Med J, 1992 Feb, 37(1), 11 - 7 Indications for and accuracy of magnetic resonance imaging and computed tomography in orbital disease; Ainsworth JR et al.; All patients referred for orbital imaging to the neuroradiology department of the Institute of Neurological Sciences in Glasgow over a three year period were enrolled in the study and were scheduled to undergo both magnetic resonance imaging and computed tomography . A total of 101 of the 110 referred patients were deemed suitable for analysis . Details of key presenting symptoms, signs, and a pre-imaging diagnosis were recorded prospectively . A final diagnosis was obtained by histology in 65% of cases with an orbital abnormality, by a minimum of one year of clinical review in 19.5%, by response to antibiotic or steroid therapy in 8.5%, or by conclusive investigations such as carotid angiography in in 7% of patients, 29% of the patients had no detectable orbital disease despite a minimum one years' follow-up, and so were regarded as a "normal" group . The images were interpreted prospectively by separate masked observers . The diagnostic accuracies of the two techniques were compared to the final diagnosis . The two imaging methods were shown to be comparable in overall diagnostic accuracy, with a small and statistically non-significant advantage held by magnetic resonance imaging . Interpretation of the two investigations gave more accurate information in different types of disease. Rev Port Cardiol, 1992 Feb, 11(2), 185 - 90 {Effects of cardiac and renal disease on clinical pharmacokinetics}; Soares Ade O; In this oral presentation, the author emphasized the need for individualization of drug treatment, reviewing the most known factors of variability in drug response . The importance of studies of clinical pharmacokinetics was focused . The main parameters for a judgement on the efficacy and virtual tolerability of a medicine, on the basis of its sequential concentrations in the blood after administration, were briefly outlined . The influence of congestive heart failure on the volume of distribution, systemic clearance, elimination half-life and bioavailability, was discussed . The changes that renal failure makes in drug elimination were equally presented, having been pointed the modification of protein binding, volume of distribution, and hepatic elimination . A selection of eight clinical cases was summarily presented, to illustrate the important contribute that can be afforded to practice by pharmacokinetics . The dosing of aminoglycosides and of other drugs with narrow therapeutic ranges was evaluated through some of the examples . A case of complex interferences of heart failure, renal failure and therapeutic hemoperfusion on the kinetics of an antibiotic drug was included . Two cases of intoxications (phenytoin and theophylline), whose management has been greatly improved by repeated drug dosing in blood, were discussed, too . A special call of attention was made to the need the currently practicing physician has of being aware of kinetic characteristics of the drugs he prescribes, and of how can disease modify the body fate of those medicines, and their therapeutic and nontherapeutic effects. Pharm Res, 1992 Feb, 9(2), 191 - 4 Enhanced bioavailability of cefoxitin using palmitoyl L-carnitine . I . Enhancer activity in different intestinal regions; Sutton SC et al.; The conditions under which the absorption enhancer palmitoyl L-carnitine chloride (PCC) improved the bioavailability of the poorly absorbed antibiotic cefoxitin throughout the rat intestine has been studied . Cefoxitin alone was appreciably absorbed only in the duodenum (31% vs less than 7% elsewhere) . PCC solutions (3 mg/rat, pH 4.0) enhanced cefoxitin bioavailability (F) by 0-, 22-, 16-, and greater than 32-fold in the duodenum, jejunum, ileum, and colon regions, respectively . The inability of PCC to improve F in the duodenum could not likely be attributed to enzymatic degradation of the enhancer, since coadministration with protease and esterase inhibitors produced similar results (F = 30%) . Coadministration of PCC solution with cefoxitin in the unligated or ligated colon, increased F to 33 and 76%, respectively . Qualitatively similar results were seen with PCC suspensions (3 mg/rat, pH 6.0) . Maintaining a high concentration of cefoxitin and PCC in a restricted region (i.e., by ligating a 2- to 3-cm section of the colon) afforded a two- to threefold advantage over an unligated colon section . The difference in cefoxitin bioavailability between ligated and unligated colon was probably due to sample spreading and subsequent/simultaneous dilution. Biotechnol Appl Biochem, 1992 Feb, 15(1), 80 - 9 Cloning, analysis, and heterologous expression of a polyketide synthase gene cluster of Streptomyces curacoi; Bergh S et al.; Streptomyces curacoi produces curamycin, an antibiotic based on a modified orsellinic acid skeleton that is synthesized by the polyketide pathway . We have cloned, characterized, and partly sequenced a polyketide synthase gene cluster of S . curacoi . The sequence data reveal an organization of open reading frames that is similar to those of other polyketide synthetic clusters, although the biosynthetic products differ considerably in size and structure . We propose that one of the predicted open reading frames (curA) encodes polykeptide synthase, on the basis of its homology with other enzymes with similar functions . Expression of the cloned chromosomal fragment in the heterologous host S . lividans leads to the production of a brown pigment in large quantities . The analysis and expression of the cur genes for detailed molecular studies of the mechanism of polyketide biosynthesis is discussed. Hautarzt, 1992 Feb, 43(2), 89 - 91 {Pigmented urticarial erythema with flaccid atrophy as expression of an unusual manifestation of Lyme borreliosis}; Merkle T et al.; Unusual courses of infections with borrelia burgdorferi can make diagnosis problematic, but early and adequate therapy is mandatory to avoid further complications . In this paper a patient is presented who developed urticarial erythemas and hyperpigmentation with slack skin atrophy . Positive serological findings and the regression of the skin eruptions under antibiotic therapy confirmed the diagnosis of an unusual manifestation of Lyme borreliosis. Mol Cell Endocrinol, 1992 Feb, 83(2-3), 211 - 8 Neomycin interacts with Ca2+ sensing of normal and adenomatous parathyroid cells; Ridefelt P et al.; Effects of the polyvalent cationic antibiotic neomycin on regulation of the cytoplasmic Ca2+ concentration ({Ca2+}i) were studied in normal and adenomatous human, and bovine parathyroid cells . Parathyroid hormone (PTH) release was also measured in the bovine cells . Elevation of extracellular Ca2+ from 0.5 to 3 mM caused biphasic increase of {Ca2+}i and inhibition of PTH release . In low external Ca2+ neomycin inhibited PTH release and virtually only triggered the {Ca2+}i transient . In contrast {Ca2+}i was lowered and PTH release stimulated by neomycin in the presence of 3.0 mM Ca2+ or 7 mM Mg2+ . These actions of Ca2+ and neomycin on {Ca2+}i were qualitatively similar but less pronounced in the adenomatous than normal human parathyroid cells . Some effects of neomycin were thus similar to those induced by other cationic agents interacting with the Ca2+ receptor mechanism on the parathyroid cell surface, whereas others may involve phospholipase C inhibition, protein kinase C activation or a direct reduction of the Ca2+ influx. Surg Neurol, 1992 Feb, 37(2), 142 - 6 Mycotic aneurysms of the intracavernous carotid artery: a case report and review of the literature; Hurst RW et al.; A case of mycotic aneurysm of the intracavernous carotid artery is reported and the literature is reviewed on this uncommon entity . Nineteen cases have been reported, most often occurring in the clinical setting of meningitis . Management recommendations include angiographic confirmation of aneurysm and follow-up with magnetic resonance imaging during antibiotic therapy . Evidence of aneurysm enlargement is an indication for endovascular trapping of the aneurysm or carotid occlusion. J Am Osteopath Assoc, 1992 Feb, 92(2), 226 - 30 Periorbital and orbital infections in children; Siddens JD et al.; Bacterial infections of the periorbital and orbital tissues range in severity from minor to life-threatening . Preseptal (periorbital) cellulitis is more common than orbital cellulitis and occurs quite frequently in children . A history of antecedent trauma or upper respiratory tract infection is present in more than half of all cases . Evaluation by computed tomography scans is an indispensable part of the diagnostic procedure . All cultures should be obtained before institution of antibiotic therapy . Initial therapy should begin with administration of broad-spectrum antibiotics with adjustments made in response to positive culture results . Response to antibiotics is usually prompt and the incidence of complications is low . If clinical improvement is slow, surgery should be performed early in the course of the disease to minimize the potential for significant complications such as cavernous sinus thrombosis. Anticancer Drug Des, 1992 Feb, 7(1), 15 - 36 Inhibition of T4 DNA ligase activity by (+)-CC-1065: demonstration of the importance of the stiffening and winding effects of (+)-CC-1065 on DNA; Sun D et al.; Non-denaturing gel electrophoresis analysis demonstrates that the stiffening and winding effects of (+)-CC-1065 produce unusual proximal and distal inhibition of T4 DNA ligase-catalysed ligation of covalently modified DNA . (+)-CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis . This drug selectively bonds through N3 of adenine in DNA and lies in the minor groove of DNA, reacting in a highly sequence-selective manner . Previous studies (Lee et al., 1991) have shown that (+)-CC-1065 produces bending and winding of DNA . The DNA bending and sequence specificity is mediated by the alkylating 'A' subunit of (+)-CC-1065, while the close van der Waals contacts between the non-alkylating B and C subunits of (+)-CC-1065 and the floor of the minor groove of DNA are responsible for the winding of DNA . Covalent modification of oligomers with (+)-CC-1065 and structurally related drugs leads to preferential inhibition of T4 DNA ligase on the non-covalently modified strand to the 5' side of the covalent adduct site, but enhanced ligation of the covalently modified strand . We speculate that the differential effect on proximal strand ligation is due to a drug-induced winding and helix-stabilizing effect which occurs predominantly to the 5' side of the adduct . In addition to the proximal inhibition of ligation, we also describe a distal inhibition of T4 DNA ligase activity which occurs exclusively with drug-modified oligomers and that, if successful, would result in 180 degrees out-of-phase bent DNA following ligation . In this case, two 25 mers or a 21 plus a 29 mer are inhibited from ligation when modified with (+)-CC-1065 . This distal ligation is unique to (+)-CC-1065 and its analogs that cause stiffening of the DNA helix . The (+)-CC-1065-induced stiffening effect was demonstrated using a circularization assay and was found to be associated with the close van der Waals contacts between the inside edge of (+)-CC-1065 and the floor of the minor groove, and also to the benzofuran moiety of (+)-ABC" (Adozelesin), a (+)-CC-1065 analog . We conclude from these studies that the DNA-winding and helix-stabilizing effects of these drug molecules can dramatically affect the efficiency of proximal ligation mediated by T4 DNA ligase, and the unusual helix-stiffening effect of (+)-CC-1065, (+)-AB'C' and (+)-ABC" can stabilize the structure of bent DNA formed by drug modification, which results in distal ligase inhibition. Arch Otolaryngol Head Neck Surg, 1992 Feb, 118(2), 201 - 4 Tobramycin-impregnated methylmethacrylate for mandible reconstruction; Goode RL et al.; Reconstruction of the mandible to restore continuity following resection is described in four cases using a tobramycin-impregnated methylmethacrylate implant fabricated at the time of surgery . Methylmethacrylate has excellent biocompatibility and strength and has been used in surgery for over 20 years . The technique uses readily available materials and is similar in concept to reconstruction with a metal plate . Potential advantages are: (1) the presence of a potent antibiotic within the implant that is released over a period of months to minimize postoperative infection and (2) the capability of the material to accurately fit any defect, either when used alone or in combination with a plate or rod . Three of the four patients whom we present are doing well; one implant became exposed following postoperative radiotherapy and had to be removed. Mol Pharmacol, 1992 Feb, 41(2), 427 - 33 Role of isozymes of rabbit microsomal cytochrome P-450 in the metabolism of retinoic acid, retinol, and retinal; Roberts ES et al.; The metabolism of retinoic acid, retinol, and retinal has been investigated with eight purified rabbit cytochrome P-450 (P-450) isozymes, including the major forms in nasal and liver microsomes . Retinoids hydroxylated at the 4-position were found to be major metabolites with each of the isozymes examined . Only two of the isozymes, polycyclic aromatic hydrocarbon-inducible P-450 1A2 and antibiotic-inducible P-450 3A6, also catalyze the oxidation of retinal to retinoic acid, a reaction not previously attributed to P-450 . P-450 1A2 showed high activities in both the 4-hydroxylation and aldehyde oxidation reactions . Phenobarbital-inducible P-450 2B4 also had high activity in the 4-hydroxylation reaction of retinoids, and cytochrome b5 was found to increase the activity of P-450 2B4 with each substrate but to increase the activity of P-450 1A2 only with retinoic acid . In microsomes, retinoic acid is converted in an NADPH-dependent manner to both 4-hydroxyretinoic acid and 4-oxoretinoic acid, but none of the isozymes investigated was found to convert the 4-hydroxy derivative to the 4-oxo derivative . Microsomes from animals treated with phenobarbital were more active than those from untreated animals in the 4-hydroxylation reaction and, consequently, showed an increase in the ratio of 4-hydroxy to 4-oxo derivatives produced . These results show that the individual forms of P-450 metabolize retinoic acid, retinol, and retinal to multiple products, and they indicate that the amounts formed may be dependent on the exposure of animals to various inducers of P-450. Mol Gen Genet, 1992 Feb, 231(3), 337 - 44 Characterization of a staurosporine- and temperature-sensitive mutant, stt1, of Saccharomyces cerevisiae: STT1 is allelic to PKC1; Yoshida S et al.; Staurosporine is an antibiotic that specifically inhibits protein kinase C . Fourteen staurosporine- and temperature-sensitive (stt) mutants of Saccharomyces cerevisiae were isolated and characterized . These mutants were divided into ten complementation groups, and characterized for their cross-sensitivity to K-252a, neomycin, or CaCl2 . The STT1 gene was cloned and sequenced . The nucleotide sequence of the STT1 gene revealed that STT1 is the same gene as PKC1 . The STT1 gene conferred resistance to staurosporine on wild-type cells, when present on a high copy number plasmid . STT1/stt1::HIS3 diploid cells were more sensitive to staurosporine than STT1/STT1 diploid cells . Analysis of temperature-sensitive stt1 mutants showed that the STT1 gene product functioned in S or G2/M phase . These results suggest that a protein kinase (the STT1 gene product) is one of the essential targets of staurosporine in yeast cells. Am J Obstet Gynecol, 1992 Feb, 166(2), 598 - 600 Postpartum paravaginal hematoma and lower-extremity infection; Chatwani A et al.; We report a case of infection of the lower extremity after a normal vaginal delivery . The infection originated in an occult obturator internus muscle hematoma, and diagnosis was based on a clinical suspicion and characteristic findings on computerized tomography scan . These findings permitted prompt surgical drainage, debridement, and antibiotic therapy and resulted in a successful outcome. Am J Obstet Gynecol, 1992 Feb, 166(2), 493 - 7 Angiographic embolization in the management of hemorrhagic complications of pregnancy; Gilbert WM et al.; Obstetric hemorrhage continues to be a major cause of maternal mortality and morbidity . Recent developments in percutaneous angiographic embolization techniques have afforded the ability to control persistent bleeding from pelvic vessels while avoiding the morbidity of surgical exploration . We report the use of angiographic embolization in 10 cases of pregnancy-related hemorrhage, including persistent postcesarean bleeding (three cases), vaginal wall hematomas (four cases), cervical ectopic pregnancies (two cases), and postpartum bleed