Phytochemicals as antibiotic alternatives to promote growth and enhance host health

There are heightened concerns globally on emerging drug-resistant superbugs and the lack of new antibiotics for treating human and animal diseases. For the agricultural industry, there is an urgent need to develop strategies to replace antibiotics for food-producing animals, especially poultry and livestock. The 2nd International Symposium on Alternatives to Antibiotics was held at the World Organization for Animal Health in Paris, France, December 12-15, 2016 to discuss recent scientific developments on strategic antibiotic-free management plans, to evaluate regional differences in policies regarding the reduction of antibiotics in animal agriculture and to develop antibiotic alternatives to combat the global increase in antibiotic resistance. More than 270 participants from academia, government research institutions, regulatory agencies, and private animal industries from >25 different countries came together to discuss recent research and promising novel technologies that could provide alternatives to antibiotics for use in animal health and production; assess challenges associated with their commercialization; and devise actionable strategies to facilitate the development of alternatives to antibiotic growth promoters (AGPs) without hampering animal production. The 3-day meeting consisted of four scientific sessions including vaccines, microbial products, phytochemicals, immune-related products, and innovative drugs, chemicals and enzymes, followed by the last session on regulation and funding. Each session was followed by an expert panel discussion that included industry representatives and session speakers. The session on phytochemicals included talks describing recent research achievements, with examples of successful agricultural use of various phytochemicals as antibiotic alternatives and their mode of action in major agricultural animals (poultry, swine and ruminants). Scientists from industry and academia and government research institutes shared their experience in developing and applying potential antibiotic-alternative phytochemicals commercially to reduce AGPs and to develop a sustainable animal production system in the absence of antibiotics.Fil: Lillehoj, Hyun. United States Department of Agriculture. Agricultural Research Service; ArgentinaFil: Liu, Yanhong. University of California; Estados UnidosFil: Calsamiglia, Sergio. Universitat Autònoma de Barcelona; EspañaFil: Fernandez Miyakawa, Mariano Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Patobiología; ArgentinaFil: Chi, Fang. Amlan International; Estados UnidosFil: Cravens, Ron L.. Amlan International; Estados UnidosFil: Oh, Sungtaek. United States Department of Agriculture. Agricultural Research Service; ArgentinaFil: Gay, Cyril G.. United States Department of Agriculture. Agricultural Research Service; Argentin

Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation. The role of the heparan sulfate proteoglycans in cellular signaling and endocytic uptake pathways is also discussed.Proteoglicanos de heparam sulfato são encontrados tanto superfície celular quanto na matriz extracelular em todas as espécies animais. Esta revisão tem enfoque nas características estruturais dos proteoglicanos de heparam sulfato e nas interações destes proteoglicanos com proteínas que levam à sinalização celular. As cadeias de heparam sulfato, devido a sua variedade estrutural, são capazes de se ligar e interagir com ampla gama de proteínas, como fatores de crescimento, quimiocinas, morfógenos, componentes da matriz extracelular, enzimas, entreoutros. Existe uma especificidade estrutural que direciona as interações dos heparam sulfatos e proteínas alvo. Esta especificidade está relacionada com a estrutura da cadeia do polissacarídeo e os motivos conservados da cadeia polipeptídica das proteínas envolvidas nesta interação. Os heparam sulfatos possuem papel na sinalização celular como receptores ou coreceptores para diferentes ligantes. Esta ligação dispara vias de sinalização celular levam à fosforilação de diversas proteínas citosólicas ou com ou sem interações diretas com o citoesqueleto, culminando na regulação gênica. O papel dos proteoglicanos de heparam sulfato na sinalização celular e vias de captação endocítica também são discutidas nesta revisão.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP) Departamento de BioquímicaUniversidade Federal de São Paulo (UNIFESP) Departamento de OftalmologiaUNIFESP, Depto. de BioquímicaUNIFESP, Depto. de OftalmologiaSciEL

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

The Intensive Diet and Exercise for Arthritis (IDEA) trial: design and rationale

Background: Obesity is the most modifiable risk factor, and dietary induced weight loss potentially the best nonpharmacologic intervention to prevent or to slow osteoarthritis (OA) disease progression. We are currently conducting a study to test the hypothesis that intensive weight loss will reduce inflammation and joint loads sufficiently to alter disease progression, either with or without exercise. This article describes the intervention, the empirical evidence to support it, and test-retest reliability data. Methods/Design: This is a prospective, single-blind, randomized controlled trial. The study population consists of 450 overweight and obese (BMI = 27-40.5 kg/m2) older (age greater than or equal to 55 yrs) adults with tibiofemoral osteoarthritis. Participants are randomized to one of three 18-month interventions: intensive dietary restriction-plus-exercise; exercise-only; or intensive dietary restriction-only. The primary aims are to compare the effects of these interventions on inflammatory biomarkers and knee joint loads. Secondary aims will examine the effects of these interventions on function, pain, and mobility; the dose response to weight loss on disease progression; if inflammatory biomarkers and knee joint loads are mediators of the interventions; and the association between quadriceps strength and disease progression. Results: Test-retest reliability results indicated that the ICCs for knee joint load variables were excellent, ranging from 0.86 - 0.98. Knee flexion/extension moments were most affected by BMI, with lower reliability with the highest tertile of BMI. The reliability of the semi-quantitative scoring of the knee joint using MRI exceeded previously reported results, ranging from a low of 0.66 for synovitis to a high of 0.99 for bone marrow lesion size. Discussion: The IDEA trial has the potential to enhance our understanding of the OA disease process, refine weight loss and exercise recommendations in this prevalent disease, and reduce the burden of disability. Originally published BMC Musculoskeletal Disorders, Vol. 10, No. 93, July 200

A1C as a Diagnostic Criteria for Diabetes in Low- and Middle-Income Settings: Evidence from Peru

OBJECTIVES: To determine the prevalence of type 2 diabetes mellitus, in three groups of Peruvian adults, using fasting glucose and glycosylated hemoglobin (A1C). METHODOLOGY/PRINCIPAL FINDINGS: This study included adults from the PERU MIGRANT Study who had fasted ≥ 8 h. Fasting glucose ≥ 126 mg/dL and A1C ≥ 6.5% were used, separately, to define diabetes. Subjects with a current diagnosis of diabetes were excluded. 964 of 988 subjects were included in this analysis. Overall, 0.9% (95%CI 0.3-1.5) and 3.5% (95%CI 2.4-4.7) had diabetes using fasting glucose and A1C criteria, respectively. Compared to those classified as having diabetes using fasting glucose, newly classified subjects with diabetes using A1C (n = 25), were older, poorer, thinner and more likely to come from rural areas. Of these, 40% (10/25) had impaired fasting glucose (IFG). CONCLUSIONS: This study shows that the use of A1C as diagnostic criteria for type 2 diabetes mellitus identifies people of different characteristics than fasting glucose. In the PERU MIGRANT population using A1C to define diabetes tripled the prevalence; the increase was more marked among poorer and rural populations. More than half the newly diagnosed people with diabetes using A1C had normal fasting glucose

Physicians perceived usefulness of high-cost diagnostic imaging studies: results of a referral study in a German medical quality network

BACKGROUND: Medical and technological progress has led to increased numbers of diagnostic tests, some of them inducing high financial costs. In Germany, high-cost diagnostic imaging is performed by a medical specialist after referral by a general practitioner (GP) or specialist in primary care. The aim of this study was to evaluate the physicians' perceived usefulness of high-cost diagnostic imaging in patients with different clinical conditions. METHODS: Thirty-four GPs, one neurologist and one orthopaedic specialist in ambulatory care from a Medical Quality Network documented 234 referrals concerning 97 MRIs, 96 CTs-scan and 41 intracardiac catheters in a three month period. After having received the test results, they indicated if these were useful for diagnosis and treatment of the patient. RESULTS: The physicians' perceived usefulness of tests was lowest in suspected cerebral disease (40% of test results were seen as useful), cervical spine problems (64%) and unexplained abdominal complaints (67%). The perceived usefulness was highest in musculoskeletal symptoms (94%) and second best in cardiological diseases (82%). CONCLUSION: The perceived usefulness of high-cost diagnostic imaging was lower in unexplained complaints than in specific diseases. Interventions to improve the effectiveness and efficiency of test ordering should focus on clinical decision making in conditions where GPs perceived low usefulness

Potentials of leaves of Aspilia africana (Compositae) in wound care: an experimental evaluation

<p>Abstract</p> <p>Background</p> <p>The potentials of the leaves of the haemorrhage plant, <it>Aspilia africana </it>C. D Adams (Compositae) in wound care was evaluated using experimental models. <it>A. africana</it>, which is widespread in Africa, is used in traditional medicine to stop bleeding from wounds, clean the surfaces of sores, in the treatment of rheumatic pains, bee and scorpion stings and for removal of opacities and foreign bodies from the eyes. The present study was undertaken to evaluate the potentials for use of leaves of this plant in wound care.</p> <p>Methods</p> <p>The effect of the methanol extract (ME) and the hexane (HF) and methanol (MF) fractions (obtained by cold maceration and graded solvent extraction respectively) on bleeding/clotting time of fresh experimentally-induced wounds in rats, coagulation time of whole rat blood, growth of microbial wound contaminants and rate of healing of experimentally-induced wounds in rats were studied as well as the acute toxicity and lethality (LD₅₀) of the methanol extract and phytochemical analysis of the extract and fractions.</p> <p>Results</p> <p>The extract and fractions significantly (<it>P </it>< 0.05) reduced bleeding/clotting time in rats and decreased coagulation time of whole rat blood in order of magnitude of effect: MF>ME>HF. Also, the extract and fractions caused varying degrees of inhibition of the growth of clinical isolates of <it>Pseudomonas fluorescens </it>and <it>Staphylococcus aureus</it>, as well as typed strains of <it>Ps. aeruginosa </it>(ATCC 10145) and <it>Staph. aureus </it>(ATCC 12600), and reduced epithelialisation period of wounds experimentally-induced in rats. Acute toxicity and lethality (LD₅₀) test in mice established an i.p LD₅₀of 894 mg/kg for the methanol extract (ME). Phytochemical analysis revealed the presence of alkaloids, saponins, tannins, flavonoids, resins, sterols, terpenoids and carbohydrates.</p> <p>Conclusion</p> <p>The leaves of <it>A. africana </it>possess constituents capable of arresting wound bleeding, inhibiting the growth of microbial wound contaminants and accelerating wound healing which suggest good potentials for use in wound care.</p

Laminin-332 alters connexin profile, dye coupling and intercellular Ca(2+ )waves in ciliated tracheal epithelial cells

BACKGROUND: Tracheal epithelial cells are anchored to a dynamic basement membrane that contains a variety of extracellular matrix proteins including collagens and laminins. During development, wound repair and disease of the airway epithelium, significant changes in extracellular matrix proteins may directly affect cell migration, differentiation and events mediated by intercellular communication. We hypothesized that alterations in cell matrix, specifically type I collagen and laminin α3β3γ2 (LM-332) proteins within the matrix, directly affect intercellular communication in ciliated rabbit tracheal epithelial cells (RTEC). METHODS: Functional coupling of RTEC was monitored by microinjection of the negatively charged fluorescent dyes, Lucifer Yellow and Alexa 350, into ciliated RTEC grown on either a LM-332/collagen or collagen matrix. Coupling of physiologically significant molecules was evaluated by the mechanism and extent of propagated intercellular Ca(2+ )waves. Expression of connexin (Cx) mRNA and proteins were assayed by reverse transcriptase – polymerase chain reaction and immunocytochemistry, respectively. RESULTS: When compared to RTEC grown on collagen alone, RTEC grown on LM-332/collagen displayed a significant increase in dye transfer. Although mechanical stimulation of RTEC grown on either LM-332/collagen or collagen alone resulted in intercellular Ca(2+ )waves, the mechanism of transfer was dependent on matrix: RTEC grown on LM-332/collagen propagated Ca(2+)waves via extracellular purinergic signaling whereas RTEC grown on collagen used gap junctions. Comparison of RTEC grown on collagen or LM-332/collagen matrices revealed a reorganization of Cx26, Cx43 and Cx46 proteins. CONCLUSION: Alterations in airway basement membrane proteins such as LM-332 can induce connexin reorganizations and result in altered cellular communication mechanisms that could contribute to airway tissue function

Formation, evolution and multiplicity of brown dwarfs and giant exoplanets

This proceeding summarises the talk of the awardee of the Spanish Astronomical Society award to the the best Spanish thesis in Astronomy and Astrophysics in the two-year period 2006-2007. The thesis required a tremendous observational effort and covered many different topics related to brown dwarfs and exoplanets, such as the study of the mass function in the substellar domain of the young sigma Orionis cluster down to a few Jupiter masses, the relation between the cluster stellar and substellar populations, the accretion discs in cluster brown dwarfs, the frequency of very low-mass companions to nearby young stars at intermediate and wide separations, or the detectability of Earth-like planets in habitable zones around ultracool (L- and T-type) dwarfs in the solar neighbourhood.Comment: "Highlights of Spanish Astrophysics V", Proceedings of the VIII Scientific Meeting of the Spanish Astronomical Society (SEA) held in Santander, 7-11 July, 2008. Edited by J. Gorgas, L. J. Goicoechea, J. I. Gonzalez-Serrano, J. M. Diego. Invited oral contribution to plenary sessio