A transcriptomic snapshot of early molecular communication between Pasteuria penetrans and Meloidogyne incognita

© The Author(s). 2018Background: Southern root-knot nematode Meloidogyne incognita (Kofoid and White, 1919), Chitwood, 1949 is a key pest of agricultural crops. Pasteuria penetrans is a hyperparasitic bacterium capable of suppressing the nematode reproduction, and represents a typical coevolved pathogen-hyperparasite system. Attachment of Pasteuria endospores to the cuticle of second-stage nematode juveniles is the first and pivotal step in the bacterial infection. RNA-Seq was used to understand the early transcriptional response of the root-knot nematode at 8 h post Pasteuria endospore attachment. Results: A total of 52,485 transcripts were assembled from the high quality (HQ) reads, out of which 582 transcripts were found differentially expressed in the Pasteuria endospore encumbered J2 s, of which 229 were up-regulated and 353 were down-regulated. Pasteuria infection caused a suppression of the protein synthesis machinery of the nematode. Several of the differentially expressed transcripts were putatively involved in nematode innate immunity, signaling, stress responses, endospore attachment process and post-attachment behavioral modification of the juveniles. The expression profiles of fifteen selected transcripts were validated to be true by the qRT PCR. RNAi based silencing of transcripts coding for fructose bisphosphate aldolase and glucosyl transferase caused a reduction in endospore attachment as compared to the controls, whereas, silencing of aspartic protease and ubiquitin coding transcripts resulted in higher incidence of endospore attachment on the nematode cuticle. Conclusions: Here we provide evidence of an early transcriptional response by the nematode upon infection by Pasteuria prior to root invasion. We found that adhesion of Pasteuria endospores to the cuticle induced a down-regulated protein response in the nematode. In addition, we show that fructose bisphosphate aldolase, glucosyl transferase, aspartic protease and ubiquitin coding transcripts are involved in modulating the endospore attachment on the nematode cuticle. Our results add new and significant information to the existing knowledge on early molecular interaction between M. incognita and P. penetrans.Peer reviewedFinal Published versio

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

The effect of 17% EDTA and MTAD on smear layer removal and on erosion of root canal dentin when used as final rinse: An in vitro SEM study

Background: The aim of the present study was to evaluate and compare the ability of a mixture of tetracycline isomer, citric acid and detergent (MTAD) and ethylene diamine tetra-acetic acid (EDTA) in removing the smear layer along with their effects on peritubular and intertubular dentinal structures by scanning electron microscopic (SEM) examination. Materials and Methods: Thirty recently extracted maxillary and mandibular single-rooted human teeth were divided into 3 groups and prepared to an apical size of 30. In Group 1, 2, and 3, MTAD, EDTA, and distilled water were used, respectively, as a final rinse solution to remove the smear layer. The specimens were subjected to SEM evaluation for the presence or absence of the smear layer and degree of erosion using a scoring system. Results: The result showed that MTAD shows better smear layer removing ability and does not significantly change the structure of dentinal tubules. Conclusion: MTAD is an efficient solution for the removal of the smear layer, especially in the apical third of root canals, and does not significantly change the structure of the dentinal tubules

A National Perspective of Do-Not-Resuscitate Order Utilization Predictors in Intracerebral Hemorrhage

Nontraumatic intracerebral hemorrhage (ICH) is associated with substantial morbidity and mortality. Do-not-resuscitate (DNR) orders are linked to poorer outcomes in patients with ICH, possibly due to less active management. Demographic, regional, and social factors, not related to ICH severity, have not been adequately looked at as significant predictors of DNR utilization. We reviewed the Healthcare Cost and Utilization Project\u27s Nationwide Inpatient Sample (NIS) database in 2011 for adult ICH admissions and DNR status. We generated hierarchical 2-level multivariate regression models to estimate adjusted odds ratios. We analyzed 25 768 ICH hospitalizations, 18% of which (4620 hospitalizations) had DNR orders, corresponding to national estimates of 126 254 and 22 668, respectively. In multivariable regression, female gender, white or Hispanic/Latino ethnicity, no insurance coverage, and teaching hospitals were significantly associated with increased DNR utilization after adjusting for confounders. There was also significantly more interhospital variability in the lowest quartile of hospital volume. In conclusion, demographic factors and insurance status are significantly associated with increased DNR utilization, with more individual hospital variability in low-volume hospitals. The reasons for this are likely qualitative and linked to patient, provider, and hospital practices

A Nationwide Analysis of Outcomes of Weekend Admissions for Intracerebral Hemorrhage Shows Disparities Based on Hospital Teaching Status

BACKGROUND AND PURPOSE: With the weekend effect being well described, the Brain Attack Coalition released a set of best practice guidelines in 2005, with the goal to uniformly provide standard of care to patients with stroke. We attempted to define a weekend effect in outcomes among patients with intracranial hemorrhage (ICH) over the last decade, utilizing the Nationwide Inpatient Sample (NIS) data. We also attempted to analyze the trend of such an effect. MATERIALS AND METHODS: We determined the association of ICH weekend admissions with hospital outcomes including mortality, adverse discharge, length of stay, and cost compared to weekday admissions using multivariable logistic regression. We extracted our study cohort from the NIS, the largest all-payer data set in the United States. RESULTS: Of 485 329 ICH admissions from 2002 to 2011, 27.5% were weekend admissions. Overall, weekend admissions were associated with 11% higher odds of in-hospital mortality. When analyzed in 3-year groups, excess mortality of weekend admissions showed temporal decline. There was higher mortality with weekend admissions in nonteaching hospitals persisted (odds ratios 1.16, 1.13, and 1.09, respectively, for 3-year subgroups). Patients admitted during weekends were also 9% more likely to have an adverse discharge (odds ratio 1.09; 95% confidence interval: 1.07-1.11; P \u3c .001) with no variation by hospital status. There was no effect of a weekend admission on either length of stay or cost of care. CONCLUSION: Nontraumatic ICH admissions on weekends have higher in-hospital mortality and adverse discharge. This demonstrates need for in-depth review for elucidating this discrepancy and stricter adherence to standard-of-care guidelines to ensure uniform care

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50 &#60; 1 &#956;g/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer