Potent Biological Agents Research Articles

Growth inhibitory properties of Bacillus subtilis strains and their metabolites against the green mold pathogen ( Penicillium digitatum Sacc.) of citrus fruit

Twenty three strains of Bacillus spp. screened from 205 Bacillus spp. isolated from soil, showed antagonistic activities in vitro towards the Penicillium digitatum pathogen, a cause of citrus fruit rot disease. Culture supernatants from nine strains caused >80% inhibition of P. digitatum growth when they were serially diluted to 1:32. Volatile compounds produced by these strains also caused 30–70% inhibition of fungal growth. An ethanol extract from a Bacillus subtilis 155 cell-free supernatant referred to as secondary metabolites (SMs) produced the best inhibitory effect on mycelial growth and spore germination of the fungus with EC 50 values of 77.26 and 82.10 μgm L −1, respectively. Inhibitory compounds, separated from the SMs by preparative thin-layer chromatography (CHCl 3/MeOH/H 2O: 65/25/4, v/v/v), had R f values of 0.14, 0.28, 0.31, 0.49, and 0.64 with EC 50 values of 95.73, 14.07, 15.19, 108.59, and 99.98 μg mL −1, respectively. Protein precipitated with 80% saturated ammonium sulphate, from the culture supernatant, had an EC 50 of 288 μg mL −1. After native polyacrylamide gel electrophoresis of this protein the antifungal protein activity was detected only in the lowest band. Inoculation of a suspension of P. digitatum conidia (10 4 conidia mL −1) onto wounded citrus fruit induced disease symptoms at day 3 and decay at day 5. Inoculation with 20 μL of a 10 8 CFU mL −1 B. subtilis endospore suspension 24 h prior to fungal spore inoculation decreased disease incidences by 86.7%, and disease symptoms were delayed by 6 days and decay symptoms to day 9. Addition of the SMs (10 mg mL −1), simultaneously with the fungus decreased disease incidence by 72.5%, delayed disease symptoms up to 5 days after inoculation, and no sign of decay was observed up to 9 days. The average lesion diameters observed from treatments with bacterial endospores, SMs and a control fungicide, imazalil were significantly different from the size of the wounds in the control set treated only with fungal conidia. B. subtilis 155 and its antibiotics are considered to be potent biological control agents to suppress growth of P. digitatum in the postharvest protection of citrus.

Anti-tumor necrosis factor therapy does not diminish the immune response to influenza vaccine in Japanese patients with rheumatoid arthritis

The recent widespread employing of potent biologic agents targeting tumor necrosis factor (TNF) for the therapy of rheumatoid arthritis (RA) raises the question as to whether patients treated in this way respond normally to the infl uenza vaccine. To the best of our knowledge, there are only a few articles in the English language literature discussing this issue, and no data have been reported from Japan. We therefore studied the humoral immune response to infl uenza vaccination in Japanese patients with RA who were treated/not treated with anti-TNF biologics in comparison with healthy controls.

Corticosteroid Therapy in the Age of Infliximab: Acute and 1-Year Outcomes in Newly Diagnosed Children With Crohn’s Disease

The aim of this study was to describe 3-month and 1-year outcomes of children with Crohn's disease (CD) treated with corticosteroids within 30 days of diagnosis, with particular emphasis on the influence of infliximab on these outcomes. We also aimed to determine whether there are clinical or laboratory characteristics associated with corticosteroid therapy outcomes. Data from 109 children were drawn from a multicenter observational registry that was started in 2002. Clinical characteristics and data on corticosteroid and other therapies were recorded prospectively. Corticosteroid therapy outcomes at 3 months were defined as complete acute response, partial response, or corticosteroid resistance. At 1 year, corticosteroid responsiveness, dependence, and surgical rates were determined. Infliximab's influence on short- and long-term outcomes also was investigated. At 3 months, 65 of 109 (60%) patients had a complete acute response to corticosteroids, 26 (24%) had a partial response, and 18 (17%) were corticosteroid resistant. At 1 year, 61% were corticosteroid responsive, 31% were corticosteroid dependent, and 8% required surgery. Irrespective of the duration of corticosteroid treatment, 16 of 24 of corticosteroid-dependent/resistant patients rapidly discontinued corticosteroids after starting infliximab. No clinical or laboratory characteristics at diagnosis predicted short-term outcome. Growth impairment at diagnosis increased risk for corticosteroid dependence or surgery at 1 year. At 3 months, 84% of children had a complete or partial response to corticosteroids. However, despite concomitant immunomodulators, at 1 year 31% were corticosteroid dependent and 8% required surgery. Infliximab improves outcomes of corticosteroid-dependent/resistant patients because the duration of corticosteroid use can be controlled by initiating treatment with infliximab.

Facile Synthesis of Some New Azetidinones (VI) and Acetyl Oxadiazoles (VIII) Bearing Benzo[b]thiophene Nucleus as a Potent Biological Active Agent.

Facile Synthesis of Some New Azetidinones (VI) and Acetyl Oxadiazoles (VIII) Bearing Benzo[b]thiophene Nucleus as a Potent Biological Active Agent.

Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow

Hydroxyapatite is a synthetic bone graft, which is used for the treatment of bone defects and nonunions. However, it is a rather inert material with no or little intrinsic osteoinductive activity. Recombinant human osteogenic protein-1 (rhOP-1) is a very potent biological agent, that enhances osteogenesis during bone repair. Bone marrow contains mesenchymal stem cells, which are capable of new bone formation. Biosynthetic bone grafts were created by the addition of rhOP-1 or bone marrow to granular porous hydroxyapatite. The performance of these grafts was tested in a sheep model and compared to the results of autograft, which is clinically the standard treatment of bone defects and nonunions. A 3 cm segmental bone defect was made in the tibia and fixed with an interlocking intramedullary nail. There were five treatment groups: no implant ( n=6), autograft ( n=8), hydroxyapatite alone ( n=8), hydroxyapatite loaded with rhOP-1 ( n=8), and hydroxyapatite loaded with autologous bone marrow ( n=8). At 12 weeks, healing of the defect was evaluated with radiographs, a torsional test to failure, and histological examination of longitudinal sections through the defect. Torsional strength and stiffness of the healing tibiae were about two to three times higher for autograft and hydroxyapatite plus rhOP-1 or bone marrow compared to hydroxyapatite alone and empty defects. The mean values of both combination groups were comparable to those of autograft. There were more unions in defects with hydroxyapatite plus rhOP-1 than in defects with hydroxyapatite alone. Although the differences were not significant, histological examination revealed that there was more often bony bridging of the defect in both combination groups and the autograft group than in the group with hydroxyapatite alone. Healing of bone defects, treated with porous hydroxyapatite, can be enhanced by the addition of rhOP-1 or autologous bone marrow. The results of these composite biosynthetic grafts are equivalent to those of autograft.

Where the boys aren't: dioxin and the sex ratio

Dioxins have the well-deserved reputation of being the most potent man-made biological agents and, along with their biological/chemical cousins, the coplanar poly-chlorinated biphenyl and polychlorinated dibenzofurans, they are ubiquitous in the environment, although usually at low concentrations. The low concentrations can become biologically magnified in the food chain as these lipophilic and hydrophobic substances get concentrated during their move from soil and sediment to fish or animal feed, to dairy and meat products, and eventually to the top of the food chain, human beings. Two Research Letters in today's Lancet show how contamination of the oceans, and of animal feed, can produce significant exposure of human beings to dioxins. Also in this issue of The Lancet is an article, by Paolo Mocarelli and colleagues, which provides intriguing and worrying results of how exposure to dioxins might affect people who consume dioxin-contaminated food. High fish-specific dioxin concentrations in FinlandDioxin concentrations in a population that frequently eat fish from the Baltic Sea are comparable to those seen in inhabitants of Seveso, Italy, after the accidental release of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 1976. Individual variations in the congener patterns in human beings are similar to congener patterns in the fish species consumed. Full-Text PDF Dioxin contamination of feed and foodA preventive action limit for dioxins in feed for broiler chickens and pigs was set to 2 pg toxic equivalents/g feed in Austria. This limit was effective in the detection of feed contamination from an imported mineral additive, and in the prevention of food contamination according to WHO tolerable daily intake. Full-Text PDF Paternal concentrations of dioxin and sex ratio of offspringExposure of men to TCDD is linked to a lowered male/female sex ratio in their offspring, which may persist for years after exposure. The median concentration of dioxin in fathers in this study is similar to doses that induce epididymal impairments in rats and is about 20 times the estimated average concentration of TCDD currently found in human beings in industrialised countries. These observations could have important public-health implications. Full-Text PDF

Neuropsychiatric toxicity associated with cytokine therapies.

The cytokines interleukin-2 and interferon-alpha are potent biological agents used to treat malignancy, infectious diseases, and neurodegenerative disorders. While these medications show substantial therapeutic promise, the neuropsychiatric toxicity associated with these agents is often treatment-limiting. The pathophysiology of this toxicity is not well delineated, and adverse effects to the central nervous system are often misdiagnosed by clinicians. This report reviews the preclinical and clinical literature describing the morbidity associated with these agents and suggests appropriate clinical management strategies and future directions for research.

Growth factors and wound healing.

Over the last decade, there has been an exponential increase in our knowledge of the biology of growth factors. The hope has been and remains that these potent biologic agents will effect a fundamental improvement in the way we treat wounds. We will discuss the biology of growth factors and the dramatic effects these proteins have on cell proliferation, cell chemotaxis, and on the formation of extracellular matrix molecules. Growth factors are extremely potent biologic agents that show promise in accelerating wound repair in both animal and human studies. They improve granulation tissue, enhance tensile strength, and promote reepithelialization. Cosmetic effects are also to be expected by antagonizing and blocking the action of these peptides. Growth factors are likely to become an important therapeutic tool for the dermatologic surgeon.

1,3-Dialkyl-3-acyltriazenes, a novel class of antineoplastic alkylating agents

Aliphatic triazenes, such as 1,3-dimethyltriazene, are potent biological alkylating agents because they form alkyldiazonium ions. They are also subject to very rapid proteolytic decomposition, even at physiological pH. The acylated analogues 1,3-dialkyl-3-acyltrizenes are much more stable in aqueous solution, but they also give rise to alkyldiazonium ions. Four acylated 1,3-dimethyltriazenes, where the acyl groups were diethylphosphoryl (DMP), carbethoxy (DMC), acetyl (DMA), and N-methylcarbamoyl (DMM), were studied kinetically. Rate-pH profiles indicated that the acyl group had a profound effect on the mechanism of decomposition. The cytotoxic potential of all four compounds was studied in vitro by using the MTT-tetrazolium assay. The compounds had fair-to-good activity against some cell lines, particularly those deficient in methylation repair. In vivo assays of DMC and DMM against several tumor xenografts in nude mice showed promising activity for some cancers, particularly in the case of DMM. In vitro assays were also carried out on three 1-(2-chloroethyl)-3-methyl-3-acyltriazenes. The acyl groups were carbethoxy (CMC), acetyl (CMA), and N-methylcarbamoyl (CMM). The activity of these compounds largely paralleled that of bis(2-chloroethyl)-N-nitrosourea (BCNU), except for those cell lines which exhibited the Rem phenotype; triazenes were more active in those lines than BCNU. The in vivo activity of CMC, CMA, and CMM was tested in the P388 leukemia assay. All three were active but CMC and CMA proved to be rather toxic. CMM was well tolerated and was examined in several tumor xenografts in nude mice. Significant activity was found against MX-1 mammary carcinoma, against LX-1 small cell lung carcinoma, and particularly against LOX amelanotic melanoma, where complete cures were effected. The antineoplastic activity of the acyltriazenes is well-correlated with their chemical behavior.

Characterization of Nocardia amarae as a Potent Biological Coalescing Agent of Water-Oil Emulsions

Nocardia amarae grown in a liquid medium induced coalescence of emulsions which differed in type, composition of the organic phase, and structure of stabilizing emulsifiers. De-emulsifying activity varied with the type of growth medium, culture age, and postharvest treatment. Based on extraction and degradation studies, it was concluded that de-emulsifying properties are due to the bacterial cell surface. Thus, bacteria may provide a new source of de-emulsifying agents.