Significant Reduction In Disease Severity Research Articles

Attrition from Care and Clinical Outcomes in a Cohort of Sickle Cell Disease Patients in a Tribal Area of Western India.

In a tribal area of western India, a non-governmental organization implemented a comprehensive sickle cell disease (SCD) program at a secondary level hospital. In a cohort of SCD patients registered during December 2015 to June 2017, we assessed rates of lost to follow-up (LTFU) during the follow-up period using routinely collected data. We compared the uptake of proven interventions and indicators of disease severity from one year prior to registration until the end of the study (June 2018). Of 404 patients, the total follow-up duration was 534 person-years (PY). The rate (95% CI) of LTFU was 21 (17.5–25.3) per 100 PY. The proportion of people who received the pneumococcal vaccine improved from 10% to 93%, and coverage of hydroxyurea improved from 3.5% to 88%. There was a statistically significant decrease in rates (per 100 PY) of pain crisis (277 vs 53.4), hospitalization (49.8 vs 42.2), and blood transfusion (27.4 vs 17.8) after enrollment in the SCD program. Although clinical intervention uptake was high, one quarter of the patients were LTFU. The study demonstrated significant reductions in disease severity in SCD patients.

The Virulence Function and Regulation of the Metalloprotease Gene prtA in the Plant-Pathogenic Bacterium Burkholderia glumae.

Bacterial panicle blight caused by Burkholderia glumae is a major bacterial disease of rice. Our preliminary RNA-seq study showed that a serine metalloprotease gene, prtA, is regulated in a similar manner to the genes for the biosynthesis and transport of toxoflavin, which is a known major virulence factor of B. glumae. prtA null mutants of the virulent strain B. glumae 336gr-1 did not show a detectable extracellular protease activity, indicating that prtA is the solely responsible gene for the extracellular protease activity detected from this bacterium. In addition, inoculation of rice panicles with the prtA mutants resulted in a significant reduction of disease severity compared with the wild-type parent strain, suggesting the requirement of prtA for the full virulence of B. glumae. A double mutant deficient in both serine metalloprotease and toxoflavin (ΔtoxA/prtA-) exhibited a further numeric but not statistically significant decrease of disease development compared with the ΔtoxA strain. Both the prtA-driven extracellular protease activity and the toxoflavin production were dependent on both the tofI/tofR quorum-sensing and the global regulatory gene qsmR, indicating the important roles of the two global regulatory factors for the bacterial pathogenesis by this pathogen.

Treatment of Adult Obstructive Sleep Apnea With Positive Airway Pressure: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment.

The purpose of this systematic review is to provide supporting evidence for the clinical practice guideline for the treatment of obstructive sleep apnea (OSA) in adults using positive airway pressure (PAP). The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of PAP with no treatment as well as studies that compared different PAP modalities. Meta-analyses were performed to determine the clinical significance of using PAP in several modalities (ie, continuous PAP, auto-adjusting PAP, and bilevel PAP), to treat OSA in adults. In addition, meta-analyses were performed to determine the clinical significance of using an in-laboratory versus ambulatory strategy for the initiation of PAP, educational and behavioral interventions, telemonitoring, humidification, different mask interfaces, and flexible or modified pressure profile PAP in conjunction with PAP to treat OSA in adults. Finally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations. The literature search resulted in 336 studies that met inclusion criteria; 184 studies provided data suitable for meta-analyses. The data demonstrated that PAP compared to no treatment results in a clinically significant reduction in disease severity, sleepiness, blood pressure, and motor vehicle accidents, and improvement in sleep-related quality of life in adults with OSA. In addition, the initiation of PAP in the home demonstrated equivalent effects on patient outcomes when compared to an in-laboratory titration approach. The data also demonstrated that the use of auto-adjusting or bilevel PAP did not result in clinically significant differences in patient outcomes compared with standard continuous PAP. Furthermore, data demonstrated a clinically significant improvement in PAP adherence with the use of educational, behavioral, troubleshooting, and telemonitoring interventions. Systematic reviews for specific PAP delivery method were also performed and suggested that nasal interfaces compared to oronasal interfaces have improved adherence and slightly greater reductions in OSA severity, heated humidification compared to no humidification reduces some continuous PAP-related side effects, and pressure profile PAP did not result in clinically significant differences in patient outcomes compared with standard continuous PAP.

Dithranol-loaded nanostructured lipid carrier-based gel ameliorate psoriasis in imiquimod-induced mice psoriatic plaque model

Objective: The aim of this study was to formulate nanostructured lipid carriers (NLCs) of dithranol-loaded in gel for ease of application and to evaluate its anti-psoriatic efficacy vis-a-vis conventional ointment formulation. Significance: This study will provide an insight about the use of nanocarriers, esp. NLCs loaded with dithranol for the effective treatment of psoriasis. Methods: Dithranol-loaded NLCs were prepared by hot melt homogenization method and characterized for particle size and percentage entrapment efficiency. The optimized NLCs were loaded into gel and evaluated for drug release, spreadability, rheological behavior, and staining. Anti-psoriatic efficacy of the NLC gel was evaluated in imiquimod (IMQ) induced psoriatic plaque model in comparison with prepared conventional ointment formulation (1.15% w/w dithranol). Results: NLCs were prepared with particle size below 300 nm, polydispersity index (PDI) below 0.3 and percentage entrapment efficiency of ∼100%. The prepared NLC gel was then compared with the ointment for drug release, staining property, and efficacy. Topical application of dithranol-loaded NLC gel on IMQ-induced psoriatic plaque model reduced the symptoms of psoriasis assessed by both Psoriasis area severity index (PASI) scoring and enzyme-linked immunosorbent assay. There was a significant reduction in disease severity and cytokines like Interleukins-17, 22, 23 and Tumor necrosis factor-α by the developed system in comparison to the negative control. Conclusions: To conclude dithranol-loaded NLCs in gel base was efficacious in management of psoriasis at the same drug concentration and also offer less cloth staining to that of the ointment product.

Zinc oxide nanostructures as a control strategy of bacterial speck of tomato caused by Pseudomonas syringae in Egypt.

This study was conducted to evaluate the ability of zinc oxide nanoparticles (ZONPs) with unique properties to protect tomato against the bacterial speck pathogen, caused by Pseudomonas syringae pv. tomato DC3000 (Pst). Protection of tomato against bacterial speck using ZONPS was evaluated by its direct antibacterial activity and its ability for inducing resistance in tomato plants. The results revealed that ZONPs showed significant direct antibacterial activity against Pseudomonas syringae pv. tomato under laboratory conditions. Moreover, tomato plants treated with ZONPs showed a significant reduction in disease severity and bacterial proliferation relative to non-treated plants. Furthermore, tomato plants treated with ZONPs showed higher self-defense enzyme activity relative to untreated plants. The regulatory and defense genes, LePR-1a and Lipoxygenase (LOX), involved in the salicylic acid (SA) and (JA) signaling pathways, respectively, were highly expressed in tomato plants treated with ZONPs compared to untreated plants. Growth characters of tomato plants treated with ZONPs were significantly enhanced relative to untreated plants. The control of bacterial speck pathogen of tomato using ZONPs through its direct antibacterial and by developing of systemic resistance in treated tomatoes against the pathogen is considered the first report.

Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis.

Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 (AEG-1) regulates NFκB activation, and germline knockout of AEG-1 in mice (AEG-1-/-) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell-specific AEG-1-/- mice (AEG-1ΔHEP and AEG-1ΔMAC, respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1ΔHEP mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1ΔMAC mice were profoundly resistant. In vitro, AEG-1-/- hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1-/- macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion, and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis.Significance: These findings distinguish a novel role of macrophage-derived oncogene AEG-1 from hepatocellular AEG-1 in promoting inflammation and driving tumorigenesis. Cancer Res; 78(22); 6436-46. ©2018 AACR.

Effect of methotrexate monotherapy on T‐cell subsets in the peripheral circulation in psoriasis

Psoriasis is a T-helper (Th)1/Th17-mediated chronic inflammatory disease. There is an increased population of Th cells in skin lesions and peripheral circulation of patients with psoriasis. Systemic methotrexate (MTX) is an effective treatment for moderate to severe psoriasis; however, its effect on different T-cell subsets is not yet clear. To study the effect of MTX monotherapy on the psoriatic T-cell profile in the peripheral circulation of patients with psoriasis. This was a follow-up study involving 50 patients with moderate to severe psoriasis treated with systemic MTX for 12 weeks. Blood samples (5 mL) were collected from participants, from which PBMCs were isolated, and T-cell phenotyping was performed by flow cytometry. Following 12 weeks of MTX treatment, there was an increase in the percentages of Th2/Treg cells, and a relative decrease in the percentages of Th1/Th17 cells, along with a significant reduction in the median Psoriasis Area and Severity Index (PASI). MTX helps in the restoration of the immune balance by decreasing the numbers of Th1 and Th17 cells and increasing the numbers of Th2 and Treg cells, thus resulting in a significant reduction in disease severity. MTX converts a proinflammatory T-cell phenotype to a protective anti-inflammatory phenotype, thus significantly suppressing the inflammation in psoriasis.

Salicylic Acid Induces Resistance in Rubber Tree against Phytophthora palmivora.

Induced resistance by elicitors is considered to be an eco-friendly strategy to stimulate plant defense against pathogen attack. In this study, we elucidated the effect of salicylic acid (SA) on induced resistance in rubber tree against Phytophthora palmivora and evaluated the possible defense mechanisms that were involved. For SA pretreatment, rubber tree exhibited a significant reduction in disease severity by 41%. Consistent with the occurrence of induced resistance, the pronounced increase in H2O2 level, catalase (CAT) and peroxidase (POD) activities were observed. For defense reactions, exogenous SA promoted the increases of H2O2, CAT, POD and phenylalanine ammonia lyase (PAL) activities, including lignin, endogenous SA and scopoletin (Scp) contents. However, SA had different effects on the activity of each CAT isoform in the particular rubber tree organs. Besides, three partial cDNAs encoding CAT (HbCAT1, HbCAT2 and HbCAT3) and a partial cDNA encoding PAL (HbPAL) were isolated from rubber tree. Moreover, the expressions of HbCAT1, HbPAL and HbPR1 were induced by SA. Our findings suggested that, upon SA priming, the elevated H2O2, CAT, POD and PAL activities, lignin, endogenous SA and Scp contents, including the up-regulated HbCAT1, HbPAL and HbPR1 expressions could potentiate the resistance in rubber tree against P. palmivora.

Evaluation of certain Penicillium frequentans isolates against Cercospora leaf spot disease of sugar beet

The impact of six local isolates of Penicillium frequentans recovered from healthy sugar beet (Beta vulgaris L.) leaves was evaluated against Cercospora beticola, the causal pathogen of Cercospora sugar beet leaf spot under laboratory and field conditions. In in vitro studies, all the six isolates were able to inhibit the mycelial growth of C. beticola with variation in their antagonistic capability. P. frequentans isolates produce pectinase and cellulase at different degrees. There was a correlation between enzyme activity and the antagonistic ability for each isolate. The high antagonistic ability isolates had the most enzyme activity. In field studies, some adhesives such as agar, starch flour, white glue, gum, and commercial adhesive (Triton Mok) were added to conidia spore suspensions of P. frequentans at 1% to improve conidial adhesion to sugar beet plant surface. Data also showed that all adhesives increased (P = 0.05) the efficiency of the spore suspension of P. frequentans to control the disease. The starch flour at 1% gave a significant reduction in disease severity from 43.23 to 10.42% pre-infection and from 43.23 to 10.52% post-infection. The application of P. frequentans led to improved root yield and the sugar percent of sugar beet crop in two tested seasons.

Small molecule modulators of prion protein (PrpC) in Dendritic cells regulate inflammatory responses in a model of Multiple Sclerosis

Abstract Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for human multiple sclerosis, an autoimmune disease driven by differentiated Th1 and Th17 cells, and inflammatory dendritic cells (DCs). Recent data show that EAE is worsened in mice lacking PrPC protein and disease exacerbation has been attributed to T cells, which would differentiate into more aggressive effectors, when deprived of PrPC. Novel compounds, modulating PrPC activity, have been recently developed, although not tested in EAE models yet. Interestingly, by specific gene array studies, we found that PrPC was highly expressed in DCs and differentially expressed among selected DC subsets. Moreover, by using a series of computational, and biochemical assays we identified novel small molecules, able to modulate PrPC function in specific cell lines overexpressing PrPC. By employing such tools, we studied the impact of PrPC modulation in promoting regulatory DC subsets. To this aim, DCs were treated either with novel PrPC modulators or a reference PrPC binding molecule Fe (III)-TMPyP. Then, they were co-cultured with sorted naïve CD4+ T cells in vitro. Notably, we found a significant expansion of FOXP3+CD4+ T regulatory (Treg) cells in cultures containing DC subsets, which were pre-treated with the specific PrPC modulators. Moreover, in a EAE model, we showed that systemic administration of such PrPC regulators, resulted in significant reduction of disease severity, compared to untreated controls. Overall, our results suggest that PrPC modulation in selected DC subsets may represent a novel means to restrain inflammatory T cell effectors, resulting in reduced inflammation, demyelination, and axonal injury in a model of EAE.

EFFECT OF BOTANICALS FOR MANAGEMENT OF LEAF BLAST AND ENHANCING YIELD TRAITS IN RICE

Field experiments were undertaken during kharif 2012 and 2013 under irrigated ecosystem to evaluate the efficacy of botanicals along with standard fungicides for assessing per cent disease incidence, plant height, number of tiller per plant, number of spikelet per panicle, panicle length, 100-grain weight and grain yield against blast of rice. Pooled data of two years suggest that neem based commercial biopesticides with azadiractin as active ingredients were found effective in reducing disease severity and improving the yield attribute of the crop and proves promising products when compared to standard fungicides. Among the botanicals the spraying of Achook, Neem Azal T/S, Neem gold and Tricure shows significant reduction in disease severity, along with improving yield attributes, increasing the 100-grain weight and grain yield.

EFFICIENCY OF ARBUSCULAR MYCORRHIZAL FUNGI AND SOME SPECIES OF PLANT GROWTH PROMOTING RHIZOBACTERIA TO CONTROL FUNGI Fusarium chlamydosporum CAUSING AGENT OF DECLINE DATE PALM OFF SHOOTS

The objective of this study was to evaluation the efficiency of Arbuscular mycorrhizal fungi and some species of Plant growth promoting rhizobacteria (PGPR) to control Fusarium chlamydosporum fungus causing agent of decline date palm off-shoots. The isolation and identification results showed presence of F. chlamydosporum fungus from infected roots of infected palm trees and its major causing agent of diseases. The results appeared Pseudomonas fluorescens , Azotobacter chroococcum and Azosperillium sp. have high antagonism of pathogen under laboratory conditions. The evaluation results of biocontrol factors Glomus intraradices, G. mosseae, Gigaspora, P. fluorescens, A. chroococcum and Azospirillum sp. indicated that all treatments caused significant reduction in disease severity of death palm off-shoots disease into13.3-60.0%. compared to control (pathogen only) 86.7%. The interaction between G. intraradices and P. flourescens caused significant reduction in disease severity to 13.3% and enhanced the growth of foliage and root of offshoots length to 39.0 and 36.3cm respectively and increased the fresh and dry weight of foliage and root, 1.7750, 0.4977, 1.764 and 0.339g this result was closed to Beltanol fungicide effect. Also all biocontrol agents which used in this study alone (without pathogen) enhancement of plant growth compared with control treatment. The results of the current study showed for the first time that Arbuscular mycorrhizal fungi and Azospirillum sp. Bactrium to control and have good inhibition of Fusarium chlamydosporum fungus causing agent of decline date palm off-shoots and increasing plant growth in Iraq.

Argx-113, a Novel Fc-Based Approach for Antibody-Induced Pathologies Such As Primary Immune Thrombocytopenia

The neonatal Fc Receptor (FcRn) is a key player in the maintenance of high serum levels of immunoglobulin G (IgG) antibodies. IgGs enter cells by pinocytic uptake and bind FcRn in acidic endosomal compartments. FcRn then recycles IgGs back to the cell surface where they are released into circulation at physiological pH. This half-life prolonging salvage pathway has obvious advantages in IgG-mediated pathogen clearance, but also leads to persistence of disease-causing autoantibodies present in various autoimmune indications like immune thrombocytopenia (ITP). Indeed, the principal characteristic of ITP is autoantibody-mediated peripheral platelet destruction and impaired platelet production in bone marrow which leads to an increased risk of bleeding. Functional inhibition of the FcRn receptor could therefore be a novel therapeutic modality in the treatment of ITP as standard treatment options, like immunomodulatory drugs, typically suffer from a high risk of comorbidities.ARGX-113 is a proprietary antibody Fc-fragment based on argenx’ ABDEG™ technology. ABDEG™ mutations dramatically increase the Fc/FcRn binding both at neutral and acidic pH. This results in constitutive blockage of FcRn function by ARGX-113, and concomitantly leads to fast clearance of pathogenic antibodies in an autoimmune setting.The ABDEG™ concept was validated in various mouse models for IgG-induced autoimmune indications. In all models, a significant reduction of disease severity is observed upon ARGX-113 administration, which parallels with markedly reduced disease-causing antibody levels. Follow-up studies in cynomolgus monkeys demonstrated a highly effective and rapid elimination of immunoglobulins, which outperformed by far the pharmacodynamic effects of a 50-fold higher dose of intravenous immunoglobulin (IVIg), a standard-of-care therapy in many IgG-driven autoimmune indications.A first-in-human Phase I study was initiated to evaluate safety, tolerability, efficacy (reduction in IgG levels), pharmacokinetics and immunogenicity of ARGX-113 following single or multiple intravenous administration(s). Up to 68 healthy volunteers will be enrolled in this double-blind placebo-controlled study (48 active, 20 placebo). At present, the compound showed favorable safety and tolerability across multiple doses and dosing regimens with promising pharmacodynamics effects relating to speed, depth and duration of IgG reduction. Upon multiple dosing, IgG reduction of up to 85% is observed and IgG levels slowly return to baseline when dosing is terminated. Full study results, covering all planned doses and dosing regimens, will be presented focusing on safety, PK/PD relationship, IgG subset response, anti-drug antibody formation and dose/dosing regimen selection for future studies.In addition, the study design and outcome measures of a Phase II study evaluating safety, tolerability and efficacy of ARGX-113 in an ITP setting is being prepared and will be presented. DisclosuresUlrichts:argenx: Employment. Cousin:argenx: Employment. Dreier:argenx: Employment. de Haard:argenx: Employment. Leupin:argenx: Employment.

Screening Potential of Some Bacterial Species and Trichoderma hrzianum Against Sclerotinia sclerotiorum on Cucumber.

Eight bacterial isolatesbelonged to 4 genera, i.e., Serratia sp.,(one isolate) Bacillus subtilis, (three isolates) Bacillus thuringiensis,(two isolates) Streptomyces sp.(one isolate)and Pseudumonas flourescens(one isolate) and one fungal isolate (T. harzianum) were isolated from cucumber rhizosphere to evaluate their potential as antagonists to Sclerotiniastem and root rot on cucumber. In vitro, all isolates resulted in a significant reduction in hyphal growth of pathogenic fungus, Streptomyces sp. was more significantly reduced mycelium growth followed by P. flourescens and Bacillus subtilis (Bs1) (72.22, 68.0 and 62.22 %); respectively. All isolates gave a significant reduction in disease severity on cucumber plants, B2, Bs1, Bs2 and Streptomyces sp. isolates gave best reduction in disease severity. All isolates resulted in significant increase in morphological parameters of cucumber plants (stem and root length, foliage and root dry weight) compared to control.

R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding.

The trafficking of T-lymphocytes to peripheral draining lymph nodes is crucial for mounting an adaptive immune response. The role of chemokines in the activation of integrins via Ras-related small GTPases has been well established. R-Ras is a member of the Ras-subfamily of small guanosine-5’-triphosphate-binding proteins and its role in T cell trafficking has been investigated in R-Ras null mice (Rras −/−). An examination of the lymphoid organs of Rras −/− mice revealed a 40% reduction in the cellularity of the peripheral lymph nodes. Morphologically, the high endothelial venules of Rras −/− mice were more disorganized and less mature than those of wild-type mice. Furthermore, CD4+ and CD8+ T cells from Rras −/− mice had approximately 42% lower surface expression of L-selectin/CD62L. These aberrant peripheral lymph node phenotypes were associated with proliferative and trafficking defects in Rras −/− T cells. Furthermore, R-Ras could be activated by the chemokine, CCL21. Indeed, Rras −/− T cells had approximately 14.5% attenuation in binding to intercellular adhesion molecule 1 upon CCL21 stimulation. Finally, in a graft-versus host disease model, recipient mice that were transfused with Rras −/− T cells showed a significant reduction in disease severity when compared with mice transplanted with wild-type T cells. These findings implicate a role for R-Ras in T cell trafficking in the high endothelial venules during an effective immune response.

The Role of Yeast in Atopic Dermatitis Revisited: a Critical Appraisal

Atopic dermatitis (AD) is the commonest chronic inflammatory skin disorder. In a subset of patients, particularly those with symptoms predominating on the head and neck, the yeast Malassezia is thought to be an important driver of AD of a more recalcitrant nature. Mechanistically, sensitization to Malassezia appears mediated by antigen-presenting cells in eczematous skin that promote cutaneous inflammation, partly through cross-reactivity with auto-antigens. This is consistent with evidence that patients with head and neck dermatitis (HND) have higher rates of sensitization to Malassezia versus healthy controls. However, to prove that Malassezia is a causative factor in HND, we should evaluate evidence on whether efforts to reduce Malassezia actually improve disease activity. We therefore performed a systematic review of randomized controlled trials (RCTs) investigating antifungal treatments in AD/HND. The majority of RCTs concluded that antifungals were superior to placebo or standard treatment in terms of reducing AD severity, supporting the notion that yeast can contribute to eczematous skin inflammation. Recognising and treating yeast colonization in AD patients can result in a significant reduction in disease severity, in addition to anti-inflammatory therapy alone.

Dengue virus requires the CC-chemokine receptor CCR5 for replication and infection development.

Dengue is a mosquito-borne disease that affects millions of people worldwide yearly. Currently, there is no vaccine or specific treatment available. Further investigation on dengue pathogenesis is required to better understand the disease and to identify potential therapeutic targets. The chemokine system has been implicated in dengue pathogenesis, although the specific role of chemokines and their receptors remains elusive. Here we describe the role of the CC-chemokine receptor CCR5 in Dengue virus (DENV-2) infection. In vitro experiments showed that CCR5 is a host factor required for DENV-2 replication in human and mouse macrophages. DENV-2 infection induces the expression of CCR5 ligands. Incubation with an antagonist prevents CCR5 activation and reduces DENV-2 positive-stranded (+) RNA inside macrophages. Using an immunocompetent mouse model of DENV-2 infection we found that CCR5(-/-) mice were resistant to lethal infection, presenting at least 100-fold reduction of viral load in target organs and significant reduction in disease severity. This phenotype was reproduced in wild-type mice treated with CCR5-blocking compounds. Therefore, CCR5 is a host factor required for DENV-2 replication and disease development. Targeting CCR5 might represent a therapeutic strategy for dengue fever. These data bring new insights on the association between viral infections and the chemokine receptor CCR5.

Impact of simulated rainfall on persistence of fungicides used against late blight (Phytophthora infestans) of tomato (Solanum lycopersicum)

Persistence of mancozeb 75%WP and metalaxyl 8%+mancozeb 64 %WP fungicides was studied on tomato (Solanum lycopersicum L.) leaves with respect to different simulated rain amounts (0, 5, 10 and 15mm) after different number of days (0, 2, 4, 6, 8 and 10) after fungicidal spray. Rainfall applied immediately after fungicidal spray removed fungicides from the leaf surface resulting in higher disease severity. As rain amount increased from 5 to 15 mm, disease was also increased in both the test fungicides. In case of metalaxyl 8%+mancozeb 64 %WP @ 0.25 per cent, disease severity was less as compared to the mancozeb 75%WP @ 0.25 per cent. The delaying of rainfall by 2 days after fungicidal spray resulted in significant reduction in disease severity in case of metalaxyl 8%+mancozeb 64%WP sprayed tomato plants. Metalaxyl 8%+mancozeb 64%WP being a systemic fungicide was absorbed into the system of the plant. However, this was not true in case of mancozeb 75%WP sprayed tomato plants. Since, mancozeb 75 %WP a non systemic fungicide was washed with the application of rain.

Management of leaf spot of wild rocket using fungicides, resistance inducers and a biocontrol agent, under greenhouse conditions

A new leaf spot of wild rocket (Diplotaxis tenuifolia), caused by the seed transmitted pathogen Plectosphaerella cucumerina, is causing severe losses on this crop. Disease management is complicated, as few chemicals are registered for use on rocket. Four experimental trials using fungicides, resistance inducers, and a biocontrol agent against P. cucumerina were carried out on two cultivars of wild rocket, under greenhouse conditions, in order to evaluate the efficacy of the different treatments. In the presence of a disease severity ranging from 5.8 to 26.6 in the control plots of wild rocket (cvs Grazia and Rucola selvatica), one foliar application of azoxystrobin, boscalid alone or combined with pyraclostrobin provided a significant reduction in disease severity, compared with the untreated control, at values ranging between 48.5% and 84.8%. The phosphites-based products and acibenzolar-S-methyl provided the most constant results when applied in three treatments, with a disease severity reduction ranging between 34%–82% and 45%–70.3%, respectively. The highest disease reduction in disease severity was observed by using two sprays of mandipropamid at 18.7 mL/100 L with an efficacy ranging between 64% and 92%. Among the copper-based products, the most effective treatments compared with the untreated control plants were the copper hydroxide and terpenic alcohols. Thiram provided a significant reduction in disease severity compared with the untreated control plants at values ranging from 53% to 78%; however, the plants generally did not improve in biomass compared with the untreated control. The most effective treatment in terms of disease severity reduction did not always provide a better response in plant biomass. Streptomyces griseoviridis provided only a partial, but consistent, reduction of leaf spot on wild rocket when applied in three treatments at seven day-intervals, with results statistically different from those observed in the untreated control plants. Considering the difficulty in reaching a complete disease management level against P. cucumerina, an integrated approach should be considered.

Discovery of an Oral Respiratory Syncytial Virus (RSV) Fusion Inhibitor (GS-5806) and Clinical Proof of Concept in a Human RSV Challenge Study

GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.