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An ozone-generating system and chamber for testing injury to cultured cells.

A system was constructed which alternately exposed cultured cells to specific concentrations of ozone in the gas phase and then to cell culture medium. It was designed to produce a constant mass transfer between the gas phase and the exposed cell phase. Monolayers of neonatal rat lung fibroblasts cultured in miniature glass dishes were used to test for ozone toxicity. The cells were alternately exposed to ozone (0.05, 0.15, 0.45, 1.35, and 4.05 ppm) for 30 sec and then to culture medium for 30 sec over a 1-hr period. Toxicity was measured as inhibition of cell growth 4 days after exposure to ozone. Growth was significantly inhibited at all concentrations with a 50% inhibitory concentration of 0.8 ppm. The system described was effective for quantifying ozone toxicity for cultured lung cells.

Animals↗
PubMed1978

Deoxyadenosine antagonism of the antiviral activity of 9-beta-D-arabinofuranosyladenine and 9-beta-D-arabinofuranosylhypoxanthine.

Deoxyadenosine but not adenosine reversed the antiviral activity of 9-beta-D-arabinofuranosyladenine (ara-A) and 9-beta-D-arabinofuranosylhypoxanthine (ara-H) when used in the presence of coformycin, an inhibitor of adenosine deaminase. In suspension cultures of KB cells, 10 muM ara-A inhibited the replication of herpes simplex virus type 1 by 80%. Concomitant addition of 50 muM deoxyadenosine reduced the antiviral activity of 10 muM ara-A to only 40% inhibition. Adenosine failed to antagonize the antiviral activity. In monolayer cultures of KB cells, the 50% inhibitory concentration of ara-A was increased from 1.5 to 2.9 muM by 2 muM deoxyadenosine and to 8.5 muM by 10 muM deoxyadenosine. Analysis of the dose-response data by a double reciprocal plot method indicated that the antagonism was competitive. The antiviral activity of ara-H also was antagonized by deoxyadenosine. The 50% inhibitory concentration of ara-H was increased from 42 muM to 70, 91, or 121 muM by the concurrent addition of 5, 10, or 20 muM deoxyadenosine. Competitive antagonism could not be demonstrated. In the absence of the adenosine deaminase inhibitor, neither ara-A nor ara-H was antagonized by deoxyadenosine. Since such inhibitors were not available unitl recently, previous investigators were unable to observe the antagonistic capacity of deoxyadenosine.

Adenosine↗
PubMed1979

Inhibitory action of 6-ethyl-3-(1H-tetrazol-5-YL)chromone (AA-344) on IgE, IgGa- or chemical agent-induced histamine release from isolated rat mast cells.

The antiallergic action of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) was studied on isolated rat peritoneal mast cells. AA-344 clearly inhibited the IgE-mediated release of histamine caused by various concentrations of antigen and the 50% inhibitory concentration was 0.1 microM. On the IgGa-mediated release of histamine, a peak inhibition of AA-344 was observed at 10 microM. The histamine release induced by chemical agents such as concanavalin A, dextran and compound 48/80 was depressed by AA-344 at the range of 0.1--1 mM. The results obtained in this study indicate that the antiallergic action of AA-344 is due to selective inhibition on the immunological release of the chemical mediator from mast cells.

Animals↗
PubMed1977

Suppression of human T-cell mitogenesis by prostaglandin. Existence of a prostaglandin-producing suppressor cell.

Small amounts of PGE inhibit mitogen-induced [3H]thymidine incorporation in human peripheral lymphocytes. The 50% inhibitory concentration is approximately 10(-7) M, and this is reduced to approximately 10(-8) M when endogenous PGE production is blocked. PGE inhibits PHA- and Con A-stimulated cultures much better than PWM cultures, suggesting a differential effect of PGE on T-cell vs. B-cell function. In vitro blockade of PG synthesis results in approximately 50% increase in [3H]thymidine incorporation in PHA cultures. PGE is produced endogenously in PHA cultures by glass adherent suppressor cells.

Cyclooxygenase Inhibitors↗
PubMed1977

Analysis of the systemic corticosteroid sensitivity of patients with primary open-angle glaucoma.

Patients with primary open-angle glaucoma have an ocular and systemic sensitivity to corticosteroids. We adapted a cellular assay that used peripheral blood lymphocytes to detect this corticosteroid sensitivity in vitro in a microtiter assay. It reduced the time, cost, and amount of blood required to examine a patient. We examined ten subjects on three separate days and demonstrated that the reliability of one 50% inhibitory concentration was about 76%. We then studied 25 patients with primary open-angle glaucoma and 25 control subjects using this in vitro assay. The patients with primary open-angle glaucoma were significantly more sensitive to corticosteroids than the control subjects (P less than .001).

Administration, Topical↗
PubMed2026

Artemether-lumefantrine for the treatment of Plasmodium falciparum malaria in Laos: a therapeutic efficacy study coupled with genomic and in vitro phenotypic analyses.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have played a crucial role in decreasing the impact of malaria worldwide. Since 2005, artemether-lumefantrine (AL) has been the main first-line treatment for uncomplicated Plasmodium falciparum malaria in Laos. Herein, we aimed to study the efficacy of AL in the context of malaria elimination in Laos. METHODS: Between Aug 1, 2019, and June 11, 2023, AL efficacy was evaluated in four provinces of southern Laos: Attapeu, Champassack, Salavan, and Savannakhet. Adults and children (aged 1-60 years) with microscopically confirmed P falciparum malaria received oral AL twice a day for 3 days, with follow-up on days 7, 14, 21, and 28. The primary outcome was PCR-adjusted adequate clinical and parasitological response (ACPR) by day 28. Resistance to dihydroartemisinin (DHA) and lumefantrine (LM) was assessed by an in vitro phenotypic analysis, and mutations in P falciparum kelch13 (pfkelch13), P falciparum multidrug resistance 1 (pfmdr1), P falciparum plasmepsin 2 (pfpm2), and P falciparum chloroquine resistant transporter (pfcrt) were characterised in parasites collected from enrolled patients. Safety outcomes included the frequency and nature of adverse events and serious adverse events. FINDINGS: A total of 198 patients (median age 16 years [IQR 10-28]; 124 [63%] male and 74 [37%] female) were initially enrolled, of whom three were lost to follow-up, resulting in 195 patients who received the 3-day AL regimen. At day 28, the PCR-adjusted ACPR was 96% (95% CI 92-98), with a treatment failure rate of 2% (1-5) and a reinfection rate of 2% (1-5). Among the four PCR-confirmed recrudescent isolates, one showed markedly reduced LM susceptibility (LM 50% inhibitory concentration [IC50] 59·9 nM, 2·5 times higher than the median IC50 of other isolates) and high artemisinin resistance in vitro (ring-stage survival survival rate 35·8%), which was associated with the pfkelch13 R539T mutation and day-3 microscopy-positive parasitaemia. Among 190 isolates with successfully determined pfkelch13 sequencing, nine (5%) carried the pfkelch13 mutation R539T and 43 (23%) carried the C580Y mutation, and both were associated with day-3 microscopy-positive parasitaemia (p=0·044). No amplification of pfmdr1 or pfpm2, nor any mutations in pfmdr1 and pfcrt, were associated with treatment failure. INTERPRETATION: Our findings indicate the potential emergence of LM resistance in Laos. Although AL remains efficacious, vigilance for decreasing efficacy and close monitoring of LM efficacy should be considered to support the country's goal of eliminating malaria by 2030. Importantly, none of the known pfmdr1 or pfcrt haplotypes were uniquely associated with treatment failure, including the isolate with the highest LM IC50, underscoring the need to identify reliable molecular markers for LM resistance. FUNDING: Bill and Melinda Gates Foundation and The Global Fund.

Humans↗
PubMed1977

Effect of combinations of penicillin and aminoglycosides on Streptococcus faecalis: a comparative study of seven aminoglycoside antibiotics.

The 50% inhibitory concentrations (IC50) of benzylpenicillin, streptomycin, sisomicin, gentamicin, tobramycin, kanamycin, amikacin, and butirosin were determined for 58 clinical isolates of Streptococcus faecalis, 28 of which were recovered from cultures of blood samples from patients with endocarditis. The IC50 of streptomycin was less than 100 microng/ml for 42 strains, 192-10,000 microng/ml for eight, and larger than or equal to 10,000 micron/ml for eight. One isolate that was highly resistant to streptomycin was also highly resistant to kanamycin and butirosin. Extraordinarily high resistance to the other aminoglycosides was not observed. The bactericidal effects of combinations of penicillin and aminoglycosides were studied in 20 strains of S. faecalis that represented different levels of resistance to streptomycin. Significant enhancement of the effect of the combination of penicillin and streptomycin was found only in strains with an IC50 of smaller than or equal to 190 microng/ml. Combinations of penicillin and sisomicin, gentamicin, or tobramycin were effective even against strains that were highly resistant to streptomycin and kanamycin.

Amikacin↗
PubMed1979

Penetrability of the outer membrane of Neisseria gonorrhoeae in relation to acquired resistance to penicillin and other antibiotics.

Acquired antibiotic resistance in Neisseria gonorrhoeae is principally associated with three genetic markers, penA, mtr, and penB. penA is a specific marker for penicillin resistance, whereas mtr and penB are nonspecific in conferring resistance to penicillin and several other antibiotics as well. It has been suggested that the nonspecific markers may cause a general decrease in the penetrability of the gonococcal outer membrane. To investigate this, antibiotic penetration of the outer membrane was studied in two isogenic strains-FA19 (susceptible parent) and FA140 (containing penA, mtr, and penB)-and also in a clinical isolate with multiple resistance. The method involved brief treatment of exponential cells with ethylenediaminetetraacetic acid at 5 degrees C to disrupt the outer membrane barrier. The 50% inhibitory concentrations of antibiotics for treated and normal cells were measured turbidimetrically, and from their ratios outer membrane penetration barriers were calculated. Small barriers were observed for actinomycin D and benzylpenicillin, and these were very similar in the susceptible and resistant strains. Also, in FA140 no significant barriers for rifampin, erythromycin, and tetracycline were detected. These results suggest that mechanism(s) other than reduced outer membrane penetrability underlie acquired resistance due to penA, mtr, and penB.

Anti-Bacterial Agents↗
PubMed2025

Viral hijacking of host DDX60 promotes Crimean-Congo haemorrhagic fever virus replication via G-quadruplex unwinding.

Crimean-Congo haemorrhagic fever virus (CCHFV) is the most prevalent tick-borne zoonotic bunyavirus, causing severe hemorrhagic fever and fatality in humans. Currently, the absence of approved vaccines or therapeutics for CCHFV infection necessitates the development of innovative therapeutic strategies. Here, we identify a guanine (G)-rich sequence located within the mRNA of the glycoprotein precursor in the medium (M) segment of the CCHFV genome, designated as M-PQS-1664(+). M-PQS-1664(+) can form stable G-quadruplex (G4) structure and functions as a negative regulatory element for viral replication. Host DDX60 is up-regulated in response to CCHFV infection, thereby it is hijacked to unwind M-PQS-1664(+) G4 for facilitating viral replication. The FDA-approved drug Cepharanthine (CEP), which competes with DDX60 to specifically stabilize M-PQS-1664(+) G4 without a global induction of host cellular G4s formation, exhibits remarkable antiviral activity in vitro and in vivo. More importantly, CEP possesses antiviral activity (50% inhibitory concentration ~ 0.2 μM) that having ~ 88 × the potency of ribavirin. Our findings underscore the CCHFV G4s as a promising target for drug development and highlight the significant potential of CEP in combating CCHFV.

Hemorrhagic Fever Virus, Crimean-Congo↗
PubMed1977

Immunoregulatory properties of fractions from human pregnancy urine: evidence that human chorionic gonadotropin is not responsible.

The immunologically privileged position of the histoin-compatible fetus and placenta is a striking example of a physiologic immunoregulatory mechanism. This study was designed to examine the effects of human chorionic gonadotropin (HCG) on the recognitive proliferative phase and the cytotoxic effector phase of in vitro cell-mediated immune responsiveness, since HCG has previously been reported to be immunosuppressive in vitro and in vivo. Commercial preparations of HCG were found to be potent inhibitors of lymphocyte proliferative responses to nonspecific mitogens like phytohemagglutinin (PHA), specific antigens such as streptolysin-O (SLO), and allogeneic cells as measured in the one-way mixed leukocyte response. Cytotoxic effector function of lymphocytes as measured by antibody-dependent cellular cytotoxicity (ADCC) and mitogen-induced cellular cytotoxicity were also markedly inhibited by these preparations. However, the 50% inhibitory concentration varied widely from lot to lot of these commercial materials. After dialysis, a portion of the inhibitory activity was lost from some but not all HCG lots. The dialysate from those lots with diminished activity was found to be immunosuppressive in vitro but contained no HCG detectable by radioimmunoassay. Following dialysis, the immunosuppressive activity of the various HCG lots remained variable and correlated poorly with values for HCG obtained by a double antibody radioimmunoassay. HCG preparations purified to a homogeneity sufficient for amino acid sequence were found to be only minimally immunosuppressive to the in vitro PHA response and had almost no effect on proliferative responses to antigens and allogeneic cells. These data do not support the concept of a primary immunoregulatory role for HCG, but they suggest that other uncharacterized compounds partially co-purified from pregnant urine along with HCG may have such immunoregulatory activity. Further characterization and identification of this immunoregulatory material(s) is essential, since it appears to have many of the properties of an ideal immunosuppressive compound: a) nontoxicity, b) ready reversibility, c) activity at very low concentration, and d) activity on a broad range of cellular immune functions.

Chorionic Gonadotropin↗
PubMed1977

Two distinct types of trimethoprim-resistant dihydrofolate reductase specified by R-plasmids of different compatibility groups.

R-Plasmids from a number of trimethoprim-resistant Escherichia coli and Citrobacter sp. were studied after transfer to E. coli K12 hosts. Each was found to specify a dihydrofolate reductase which was resistant to trimethoprim and Methotrexate, and which could be completely separated from the host chromosomal enzyme by gel filtration. Two distinct types of R-plasmid dihydrofolate reductases were identified. Type I enzymes, typified by the R483 enzyme previously described (Sköld, O., and Widh, A. (1974) J. Biol. Chem. 249, 4324-4325), are synthesized in amounts severalfold higher than the chromosomal enzyme. The 50% inhibitory concentrations (I50) of trimethoprim, Methotrexate, and aminopterin are increased several thousandfold over the corresponding values for the chromosomal enzyme. Type II R-plasmid dihydrofolate reductases are synthesized in about the same amount, or less, as the chromosomal enzyme, but are practically several hundredfold higher than those for the type I enzymes. Both types of R-plasmid dihydrofolate reductase showed little difference from the chromosomal enzyme in the binding of dihydrofolate, NADPH, folic acid, and 2,4-diaminopyrimidine.

Chromosomes, Bacterial↗
PubMed1979

Electron microscopic evidence of Phosfon D-induced alterations in the membranes of the dermatophytic fungus Microsporum cookei.

The dermatophytic fungus Microsporum cookei was cultivated for 24 h in the presence of subinhibitory and inhibitory concentrations (50 and 100 micrograms/ml) of Phosfon D, a growth retardant for higher plants also affecting fungal development, and its toxic effects were examined at the ultrastructural level. In both treatments, Phosfon D attacked the membranes, whose structural integrity was clearly compromised with damage of particular severity to mitochondria, nuclei and endoplasmic reticulum. In the instance of fungal growth suppression, the compound also caused plasmolytic and autolytic phenomena, sometimes accompanied by plasma membrane breakages. The submicroscopic effects observed confirm that Prosfon D is an antifungal compound which displays its toxic effects in the area of lipid metabolism, probably preventing the synthesis of fundamental components of the cellular membranes, such as unsaturated fatty acids and sterols.

Antifungal Agents↗
PubMed1979

Pharmacokinetics of cephradine suspension infants and children.

The pharmacokinetics of cephradine suspension were studied in 16 infants and children who were 13 months to 8 years and 3 months of age (means age, 3.5 years). Mean peak concentrations of 21.3 and 9.9 mug/ml were achieved at 30 min after administration of 60-mg/kg doses to fasting and nonfasting patients. The area under the serum concentration-time curve was 26% larger in fasting than in fed subjects. The half-life of cephradine in serum was 0.8 and 1.0 h in fasting and fed groups, respectively. Antimicrobial activity was detected in 49% of all salivary samples; in 75% of specimens, the concentrations were less than the 50% minimum inhibitory concentration for most pneumococci and group A streptococci. Urinary concentrations of cephradine ranged from 28 to 8,760 mug/ml and were independent of feeding status.

Administration, Oral↗
PubMed1978

Anaerobic resistance of clinical isolates of Staphylococcus aureus to aminoglycosides.

The anaerobic minimum inhibitory concentration of six aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, sisomicin, and tobramycin) averaged over 10-fold greater than the aerobic minimum inhibitory concentration for 50 clinical isolates of Staphylococcus aureus. Cultures from osteomyelitis and blood generally showed a somewhat greater increase in minimum inhibitory concentration due to anaerobiosis than did cultures from abscesses and wounds, and amikacin activity was most affected by anaerobiosis.

Aminoglycosides↗
PubMed2025

Antiviral Activity of the MEK1/2 Inhibitor Trametinib Against Lymphocytic Choriomeningitis Virus.

The lymphocytic choriomeningitis virus (LCMV) is a widespread pathogen that causes mild-to-severe infections to severe outcomes. In this study, we explored the potential of trametinib, a mitogen-activated protein kinase (MAPK) inhibitor, as an antiviral agent against LCMV. Trametinib demonstrated significant antiviral activity against two distinct LCMV strains, Armstrong and Cl13, with promising half-maximal inhibitory concentrations (IC50) and selectivity indices (SI) indicating its potency and safety profile. Mechanistic investigations revealed that trametinib interfered with multiple stages of the LCMV life cycle, including membrane fusion and genomic replication, leading to the robust inhibition of viral proliferation. Furthermore, trametinib disrupted the MEK/ERK signaling pathway, which is crucial for LCMV infection. In both in vitro and in vivo experiments, trametinib effectively reduced viral loads and mitigated pathological damage to the spleen and liver tissues. Overall, our findings suggest that trametinib is a promising novel therapeutic option for combating LCMV infection by targeting key stages of the viral life cycle and disrupting host cellular signaling pathways. Further exploration of the antiviral properties of trametinib is likely to pave the way for its clinical development as a treatment for LCMV infections.

Pyridones↗
PubMed1976

Studies on (Na+ plus K+)-activated ATPase. XXXVII. Stabilization by cations of the enzyme-ouabain complex formed with Mg1+ and inorganic phosphate.

Dissociation of the (Na+ + K+)-ATPase ouabain complex, formed in the presence of Mg2+ and inorganic phosphate (Complex II), is inhibited by Mg2+ (21-45%) and the alkali cations Na+ (25-59%) and K+ (27-75%) when kidney cortex tissue (bovine, rabbit, guinea pig) is the enzyme source. Choline chloride at 200 mM, equivalent to the highest concentration of NaCl tested, does not inhibit. Dissociation of Complex II from brain cortex (bovine, rat, rabbit) or heart muscle (rabbit) is much less inhibited: 0-11% by Na+ and 11-19% by K+. The degree of inhibition is not directly related to the size of the dissociation rate constant (k-) of the various complexes, but rather to the extent of interaction between the cation and ouabain binding sites for these tissues. Inhibition curves for Na+ and K+ are sigmoidal. Half-maximal inhibition for rabbit brain and kidney cortex is at 30-40 mM Na+ and 6-10 mM K+, and the maximally inhibitory concentrations are 50-150 and 15-20 mM, respectively. Maximal inhibition by Na+ or K+ for these tissues is the same. For guinea pig kidney cortex Na+ and K+ are almost equally effective, but 150 mM K+ or 200 mM Na+ are still not saturating, and inhibition curves indicate high- and low-affinity binding sites for the alkali cations. The inhibition curve for Mg2+ is not sigmoidal. In the kidney preparations Mg2+ inhibits half-maximally at 0.4-0.5 mM, maximally at 1-3 mM. Maximal inhibition by Mg2+ is higher than by Na+ or K+ for rabbit kidney cortex and lower for guinea pig kidney cortex. There is no competition or additivity among the cations, indicating the existence of different binding sites for Mg2+ and the alkali cations. Complex II differs in stability in the extent of inhibition, in the dependence of inhibition on the cation concentration and in the absence of antagonism between Na+ and K+, from the ouabain complex formed via phosphorylation by ATP (Complex I). This indicates that the phosphorylation states for the complexes are clearly different.

Adenosine Triphosphatases↗
PubMed1975

Haemophilus influenzae type B resistant to tetracycline isolated from children with meningitis.

During a three-year-period, 1971-73 inclusive, haemophili isolated from 96 children with severe infections, of whom 73 had meningitis and 19 acute epiglottitis, were serotyped and tested for sensitivity to antibacterial drugs. All strains were identified as Haemophilus influezae type b, and were sensitive to ampicillin, chloramphenicol, and trimethoprim. However, 3 isolates--from a boy aged 11 months and a girl aged 1 year with meningitis, and a girl aged 2 years with epiglottitis--were highly resistant to tetracycline, with a median minimal inhibitory concentration of 50 mug tetracycline hydrochloride per ml (resistance ratio greater than or equal to 50). Resistance was also demonstrated to doxycycline, oxytetracycline, and rolitetracycline and, in one strain, to minocycline. No evidence was obtained that the resistant organisms were capable of inactivating tetracyclines.

Acute Disease↗
PubMed1976

Comparison of the in vitro activity of several cephalosporin antibiotics against gram-negative and gram-positive bacteria resistant to cephaloridine.

The in vitro activity of each of two oral [cefatrizine (BL-S640), cephalexin] and three parenteral (cefamandole, cefazolin, cephapirin) cephalosporin antibiotics was compared with that of cephalothin against 168 clinical isolates of gram-negative and gram-positive bacteria selected as resistant to 20 mug of cephaloridine per ml on the basis of agar dilution susceptibility test data. Each of the five other cephalosporins inhibited a greater percentage of gram-negative bacillary isolates than did cephalothin or cephaloridine, with minimal inhibitory concentration values ranging 2- to 50-fold lower. Significant differences between minimal inhibitory concentrations of the compounds tested were also observed in tests against strains of Streptococcus faecalis and of methicillin-resistant Staphylococcus aureus. Potential advantages of including more than a single cephalosporin antibiotic in the panel of antibiotics used for routine susceptibility testing, suggested by these observations, are discussed.

Bacteria↗