In vitro sensitivity of Plasmodium falciparum to amodiaquine compared with other major antimalarials in Madagascar

Chloroquine has been used in Madagascar since 1945 and remains the first-line treatment for uncomplicated cases of malaria. Low-grades of resistance type R1 and R2 have been reported. Thus, in vitro tests were performed in order to monitor the drug sensitivity of Plasmodium falciparum from different study sites, with the aim of identifying alternatives to chloroquine. Chloroquine IC50 values ranged from 0.2 nM to 283.4 nM (n = 190, mean IC50 = 52.6 nM; 95% CI = 46.1-59.1 nM). Fifteen isolates (7.9%) were chloroquine-resistant. One mefloquine-resistant isolate was detected (1/139). The test isolates were sensitive to amodiaquine (n = 118), quinine (n = 212), pyrimethamine (n = 86) and cycloguanil (n = 79). The median IC50 for amodiaquine was 12.3 nM (mean IC50 = 15.3 nM, 95% CI = 13.3-17.3 nM). Amodiaquine was 3.4 times as active as chloroquine in vitro and 7 times as active as quinine against P. falciparum. These results indicate that amodiaquine may be a potent alternative to chloroquine in Madagascar. There was positive correlation between tested quinoline-containing drugs activities, which suggests in vitro cross-susceptibility.     

A different path: Revealing the function of staphylococcal proteins in biofilm formation

Staphylococcus aureus and Staphylococcus epidermidis cause dangerous and difficult to treat medical device-related infections through their ability to form biofilms. Extracellular poly-N-acetylglucosamine (PNAG) facilitates biofilm formation and is a vaccination target, yet details of its biosynthesis by the icaADBC gene products is limited. IcaC is the proposed transporter for PNAG export, however a comparison of the Ica proteins to homologous exo-polysaccharide synthases suggests that the common IcaAD protein components both synthesise and transport the PNAG. The limited distribution of icaC to the Staphylococcaceae and its membership of a family of membrane-bound acyltransferases, leads us to suggest that IcaC is responsible for the known O-succinylation of PNAG that occurs in staphylococci, identifying a potentially new therapeutic target specific for these bacteria.     

Direct injection technique for gas chromatographic determination of ethanol and other volatiles in concentrated cell suspensions

Summary The accuracy of direct injection gas chromatography for the estimation of volatile components in concentrated, undisrupted cell suspensions was assessed. Quantitative recovery of intracellular and extracellular ethanol, butanol and acetone was obtained. The technique eliminates the requirement for a separate disruption step to release intracellular components and the need to measure the percentage of disrupted cells.     

Evaluation of plastic composite-supports for enhanced ethanol production in biofilm reactors

Biofilms are a natural form of cell immobilization that result from microbial attachment to solid supports. Biofilm reactors with polypropylene composite-supports containing up to 25% (w/w) of various agricultural materials (corn hulls, cellulose, oat hulls, soybean hulls or starch) and nutrients (soybean flour or zein) were used for ethanol production. Pure cultures ofZymomonas mobilis, ATCC 31821 orSaccharomyces cerevisiae ATCC 24859 and mixed cultures with either of these ethanol-producing microorganisms and the biofilm-formingStreptomyces viridosporus T7A ATCC 39115 were evaluated. An ethanol productivity of 374g L^–1 h^–1 (44% yield) was obtained on polypropylene composite-supports of soybean hull-zein-polypropylene by usingZ. mobilis, whereas mixed-culture fermentations withS. viridosporus resulted in ethanol productivity of 147.5 g L^–1 h^–1 when polypropylene composite-supports of corn starch-soybean flour were used. WithS. cerevisiae, maximum productivity of 40 g L^–1 h^–1 (47% yield) was obtained on polypropylene composite-supports of soybean hull-soybean flour, whereas mixed-culture fermentation withS. viridosporus resulted in ethanol productivity of 190g L^–1 h^–1 (35% yield) when polypropylene composite-supports of oat hull-polypropylene were used. The maximum productivities obtained without supports (suspension culture) were 124 g L^–1 h^–1 and 5 g L^–1 h^–1 withZ. mobilis andS. cerevisiae, respectively. Therefore, forZ. mobilis andS. cerevisiae, ethanol productivities in biofilm fermentations were three- and eight-fold higher than suspension culture fermentations, respectively. Biofilm formation on the chips was detected by weight change and Gram staining of the support material at the end of the fermentation. The ethanol production rate and concentrations were consistently greater in biofilm reactors than in suspension cultures.This is Journal Paper No. J-16356 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa. Project No. 3253     

Clinical study of the efficacy of staphylococcal anatoxin in relation to the phage group to which the staphylococcal strains--the causative agents of infection--belong]

In comparing the bacteriophage group reference of the strains of pathogenic staphylococci isolated in case of postoperative complications from children given staphylococcus toxoid for prophylactic purpose and from control group it was found that prophylactic vaccinations of staphylococcus toxoid created the most intense immunity against staphylococci of the I bacteriophage group. There was found no significant association between the efficacy of the therapy and bacteriophage reference of staphylococci--the causative agents of the infection.     

Stable free radical scavenging and antiperoxidative properties of resveratrol compared in vitro with some other bioflavonoids

Stable free radical scavenging and antiperoxidative activities of resveratrol, a component of grapes and red wine, were evaluated and compared with some other known bioflavonoids (quercetin, catechin, kaempferol, myricetin, fisetin, ellagic acid and naringenin) widely present in the plant kingdom. Free radical scavenging activity was measured in an in vitro chemical system (DPPH assay), while for antiperoxidative activity, biological system comprising of hepatic and pulmonary homogenates was employed. Antiradical activity assay showed quercetin and myricetin to be stronger antiradical agents than resveratrol. Structure-activity study revealed that O-dihydroxy group on ring B of flavonoid plays a crucial role. A double bond at 2-3 position conjugated with a 4-oxo function and hydroxy groups at positions 3 and 5 also contribute towards antiradical activity of flavonoids. Resveratrol exhibited stronger antiradical activity than kaempferol and naringenin and was also more efficient than alpha-tocopherol, a known strong endogenous non-flavonoid antioxidant, used for comparison. In vitro antiperoxidative assay showed fisetin as the strongest and kaempferol as the weakest antioxidant. Resveratrol was found to be stronger antioxidant than catechin, myricetin, kaempferol and naringenin, but was weaker than quercetin, fisetin and alpha-tocopherol. Antiradical and antiperoxidative activities of resveratrol may explain its beneficial effects in disease states. Assays exhibited no direct correlation between antiradical and antiperoxidative activities of the phenolics.     

Expression of liver peroxisomal proteins as compared to other organelle marker enzymes in rats treated with hypolipidemic agents

Peroxisome proliferation induced by 2 hypolipidemic agents (clofibrate and ciprofibrate) was studied in rats by complementary approaches, ie cell fractionation, electron microscopy, marker enzyme activities, immunoblotting and nucleic acid hybridization techniques. Administration of clofibrates for 2 and 52 weeks in doses of 500 ppm and 50 ppm respectively, or ciprofibrate for 2,28 and 52 weeks in doses of 250, 25 and 25 ppm respectively, did not alter the behavior of the peroxisomes after induction as shown by ultracentrifugation profiles. The peroxisome mass was increased as shown by the purification procedure. Specific enzymes (catalase and mostly cyanide insensitive palmitoyl CoA oxidase) were induced. A mechanism of peroxisome biogenesis might have been initiated ie cytosolic factor, ligand-receptor interaction and/or post-translational modification of the import. Increase in marker enzyme activities showed that the peroxisomes are the most responsive organelles in comparison to lysosomes, mitochondria and smooth endoplasmic reticulum (except for cytochrome P-450 LA omega-hydroxylase). Peroxisomal integral membrane proteins appeared to be differently induced: some of them were virtually absent in untreated rat liver but were strongly expressed in treated liver. Induction was sustained for 52 weeks, indicating that there was no compensatory mechanism.     

Production of monoclonal antibodies to staphylococcal alpha-toxin using the technique of in vitro immunization]

The aim of this study is production of monoclonal antibodies (MAB) to staphylococcal alpha-toxin (SAT). SAT was obtained from culture medium of S. aureus s. 0-15 with ion-exchange chromatography and chromatofocusing. SAT was conjugated with CH-sepharose 4B and used for in vitro immunization of spleen cells, extracted from intact BALB/c mouse.     

微生态制剂在儿童幽门螺杆菌根除治疗中应用效果的Meta分析

目的 系统评价微生态制剂联合标准三联疗法或贯序疗法在儿童幽门螺杆菌（H. pylori）治疗中应用的临床疗效及其对治疗中抗生素相关不良反应发生的改善情况。方法 计算机检索CNKI、VIP、Wan Fang Data、Pub Med、Web of science和The Cochrane Library数据库,搜集国内外公开发表的关于微生态制剂在治疗儿童H. pylori感染中应用的随机对照试验（RCT）,检索时限均为从建库至2017年10月,同时人工检索相关文献的参考文献,以补充获取研究文献。由2位研究员独立筛选文献、提取数据并对纳入研究进行质量评价,采用RevMan 5.3软件进行Meta分析。结果 共纳入17个RCT,共2 033例H. pylori 阳性的儿童患者。Meta分析结果显示,微生态制剂+标准三联或贯序疗法vs标准三联或贯序疗法：微生态制剂+标准三联或贯序疗法在儿童H. pylori根除率方面优于对照组[OR=2.66,95%CI（2.09,3.40）,P<0.00001];总不良反应发生率明显低于对照组[OR=0.28,95%CI（0.21,0.37）,P<0.00001],差异均有统计学意义。微生态制剂+标准三联或贯序疗法组的恶心呕吐（P<0.001）、腹痛（P=0.015）、腹泻（P<0.001）、便秘（P=0.023）、纳差（P<0.001）、味觉障碍或口腔炎（P<0.001）发生率明显低于对照组,差异有统计学意义。结论 与标准三联或贯序疗法相比,微生态制剂+标准三联或贯序疗法安全、有效,能提高儿童H. pylori的根除率,降低H. pylori治疗中抗生素相关不良反应的发生。受纳入研究质量的限制,上述结论尚需开展高质量的RCT 进一步验证。     

Binding of type-I and type-II collagens to Staphylococcus aureus strains isolated from patients with toxic shock syndrome compared to other staphylococcal infections

Abstract Toxic shock syndrome toxin-1 (TSST-1) producing strains of Staphylococcus aureus isolated from 18 patients with toxic shock syndrome (TSS) and from 56 patients with other diagnoses were compared for capacity to interact with various serum and connective tissue proteins. TSS associated isolates showed significantly stronger binding of Type-I collagen (Cn-I) and Cn-II than non-TSS strains, in a particle agglutination assay (PAA) as well as in ¹²⁵I labelled Cn uptake experiments. ¹²⁵I Cn-IV binding, was similar between the two groups, whereas in PAA, a stronger interaction was observed for non-TSS than TSS associated strains. The median binding of ¹²⁵I Cn to TSS-associated strains were 52.2 (Cn-I), 30.6 (Cn-II) and 20.0 (Cn-IV) compared to 20.0 (Cn-I), 14.4 (Cn-II) and 24.4 (Cn-IV) values of non-TSS strains. A saturation with ¹²⁵I Cn-I and Cn-II binding was established for TSS (30 min) and non-TSS (15 min) strains. ¹²⁵I Cn-IV binding reached a saturation in 10 min and 90 min with TSS and non-TSS strains respectively. Finally, the binding profiles of TSS associated and non-TSS strains to fibronectin, fibrinogen, laminin and IgG did not differ in both PAA and radioisotope assays. In scanning electron microscopy, cells of TSS associated strains bound to the reprecipitated native Cn-I fibrils. In contrast, most cells of non-TSS strains were localized to the distal end or were trapped between the Cn fibrils. The stronger interaction with Cn-I and II in particular, shown by TSS associated strains, might enhance submucosal localization, thereby facilitating entry of toxins into the blood and establishment of TSS.     

Binding of type-I and type-II collagens to Staphylococcus aureus strains isolated from patients with toxic shock syndrome compared to other staphylococcal infections

Toxic shock syndrome toxin-1 (TSST-1) producing strains of Staphylococcus aureus isolated from 18 patients with toxic shock syndrome (TSS) and from 56 patients with other diagnoses were compared for capacity to interact with various serum and connective tissue proteins. TSS associated isolates showed significantly stronger binding of Type-I collagen (Cn-I) and Cn-II than non-TSS strains, in a particle agglutination assay (PAA) as well as in 125I labelled Cn uptake experiments. 125I Cn-IV binding, was similar between the two groups, whereas in PAA, a stronger interaction was observed for non-TSS than TSS associated strains. The median binding of 125I Cn to TSS-associated strains were 52.2 (Cn-I), 30.6 (Cn-II) and 20.0 (Cn-IV) compared to 20.0 (Cn-I), 14.4 (Cn-II) and 24.4 (Cn-IV) values of non-TSS strains. A saturation with 125I Cn-I and Cn-II binding was established for TSS (30 min) and non-TSS (15 min) strains. 125I Cn-IV binding reached a saturation in 10 min and 90 min with TSS and non-TSS strains respectively. Finally, the binding profiles of TSS associated and non-TSS strains to fibronectin, fibrinogen, laminin and IgG did not differ in both PAA and radioisotope assays. In scanning electron microscopy, cells of TSS associated strains bound to the reprecipitated native Cn-I fibrils. In contrast, most cells of non-TSS strains were localized to the distal end or were trapped between the Cn fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the synergistic potential of vancomycin combined with other antimicrobial agents against methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus spp strains

Methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative Staphylococcus spp (CNS) are the most common pathogens that cause serious long term infections in patients. Despite the existence of new antimicrobial agents, such as linezolid, vancomycin (VAN) remains the standard therapy for the treatment of infections caused by these multidrug-resistant strains. However, the use of VAN has been associated with a high frequency of therapeutic failures in some clinical scenarios, mainly with decreasing concentration of VAN. This work aims to evaluate the synergic potential of VAN plus sulfamethoxazole/trimethoprim (SXT), VAN plus rifampin (RIF) and VAN plus imipenem (IPM) in sub-minimum inhibitory concentrations against 22 clinical strains of MRSA and CNS. The checkerboard method showed synergism of VAN/RIF and VAN/SXT against two and three of the 22 strains, respectively. The combination of VAN with IPM showed synergistic effects against 21 out of 22 strains by the E-test method. Four strains were analyzed by the time-kill curve method and synergistic activity was observed with VAN/SXT, VAN/RIF and especially VAN/IPM in sub-inhibitory concentrations. It would be interesting to determine if synergy occurs in vivo. Evidence of in vivo synergy could lead to a reduction of the standard VAN dosage or treatment time.     

The fate of sulphadimethoxine in primates compared with other species

1. The metabolism of sulphadimethoxine (2,4-dimethoxy-6-sulphanilamidopyrimidine) was examined in nine species of primates and nine species of non-primates. 2. The main metabolite of the drug in the urine in man, rhesus monkey, baboon, squirrel monkey, capuchin, bushbaby, slow loris and tree shrew was sulphadimethoxine N(1)-glucuronide. In the green monkey, although the main metabolite was N(4)-acetylsulphadimethoxine, the N(1)-glucuronide was also a major metabolite. 3. In the dog, rat, mouse, guinea pig, Indian fruit bat and hen the N(1)-glucuronide was a minor metabolite in the urine, whereas in the cat, ferret and rabbit this glucuronide was not found in the urine. 4. All the species examined except the dog excreted some N(4)-acetylsulphadimethoxine, which was the major metabolite in the green monkey, rabbit and guinea pig. 5. In the tree shrew, a doubtful primate, N(1)-glucuronide formation was similar to that in the other primates. 6. It is suggested that the slow excretion of the drug by the rat may be due partly to strong binding of the drug to tissue proteins and that the strength of binding may vary with species. 7. In the rat the amount of N(1)-glucuronide found in the urine is not a true indication of the extent of this conjugation since much more of the conjugate was found in the bile (7% of the dose) than in the urine (1%). In the rabbit, no N(1)-glucuronide was found in the bile or urine, but a small amount of sulphadimethoxine N(4)-glucuronide was found in the bile of the rat (0.5% of dose) and rabbit (0.8%).     

Pharmacology, in vitro activity, and in vivo efficacy of new antifungal agents

Invasive fungal infections remain significant clinical challenges and are associated with high morbidity and mortality in immunocompromised patients. Despite the availability of new antifungal agents, response rates against many of these infections remain suboptimal. In addition, many of the clinically available agents have limited oral bioavailability, are associated with adverse effects due to similarities between fungal and mammalian cells, or have significant drug-drug interactions. For these reasons, there is great interest in developing new antifungal drugs, including those with novel mechanisms of action. This article reviews the pharmacology, in vitro activity, and in vivo effectiveness of new antifungal agents, including members of new classes with novel mechanisms of action and at various stages of preclinical and clinical development. These agents include the triazole isavuconazole, the echinocandin aminocandin, the histone deacetylase inhibitor MGCD290, and the sordarin derivative FR290581.     

Action of ethanol and other solvents on the nerve tissue under in vitro conditions.

Explants and cells of nervous tissue were cultivated in the presence of aethanol, tween 80, dimethylformamid (DMF) and dimethylsulfoxid (DMSO) and the influence upon the index of area, the growth rate and fiber index was observed. They are important to solutions of drugs for tests in vitro. At the beginning of the cultivation aethanol in vitro influenced the regeneration of nerve fibers from explants and cells. A significant increase of the index of growth was observed. After a long term influence of tween 80, DMF and DMSO an inhibition of differentiation of neurons in vitro was observed.     

TLR4, ethanol, and lipid rafts: a new mechanism of ethanol action with implications for other receptor-mediated effects

Ethanol (EtOH) is the most widely abused substance in the United States, and it contributes to well-documented harmful (at high dosages) and beneficial (at low dosages) changes in inflammatory and immune responses. Lipid rafts have been implicated in the regulation and activation of several important receptor complexes in the immune system, including the TLR4 complex. Many questions remain about the precise mechanisms by which rafts regulate the assembly of these receptor complexes. Results summarized in this review indicate that EtOH acts by altering the LPS-induced redistribution of components of the TLR4 complex within the lipid raft and that this is related to changes in actin cytoskeleton rearrangement, receptor clustering, and subsequent signaling. EtOH provides an example of an immunomodulatory drug that acts at least in part by modifying lipid rafts, and it could represent a model to probe the relationships between rafts, receptor complexes, and signaling.     

Combination of microtubule targeting agents with other antineoplastics for cancer treatment

Microtubule targeting agents (MTAs) have attracted extensive attention for cancer treatment. However, their clinical efficacies are limited by intolerable toxicities, inadequate efficacy and acquired multidrug resistance. The combination of MTAs with other antineoplastics has become an efficient strategy to lower the toxicities, overcome resistance and improve the efficacies for cancer treatment. In this article, we review the combinations of MTAs with some other anticancer drugs, such as cytotoxic agents, kinases inhibitors, histone deacetylase inhibitors, immune checkpoints inhibitors, to overcome these obstacles. We strongly believe that this review will provide helpful information for combination therapy based on MTAs.