Genomic Assemblies of Members of Burkholderia and Related Genera as a Resource for Natural Product Discovery.

The genomes of 450 members of Burkholderiaceae, isolated from clinical and environmental sources, were sequenced and assembled as a resource for genome mining. Genomic analysis of the collection has enabled the identification of multiple metabolites and their biosynthetic gene clusters, including the antibiotics gladiolin, icosalide A, enacyloxin, and cepacin A

A Case of Portal Vein Thrombosis by Protein C and S Deficiency Completely Recanalized by Anticoagulation Therapy

Portal vein thrombosis (PVT) is a rare form of venous thrombosis that affects the hepatic portal vein flow, which can lead to portal hypertension. Treatment of PVT includes anticoagulants, thrombolysis, insertion of shunts, bypass surgery, and liver transplantation. Single anticoagulation therapy is not regarded as a curative treatment but can be associated with a reduction in new thrombotic episodes. We experienced a case of acute total occlusion of PVT provoked by protein C and S deficiency syndrome. PVT was completely recanalized with oral anticoagulant therapy following low molecular weight heparin therapy

Genome mining identifies cepacin as a plant-protective metabolite of the biopesticidal bacterium Burkholderia ambifaria.

Beneficial microorganisms are widely used in agriculture for control of plant pathogens, but a lack of efficacy and safety information has limited the exploitation of multiple promising biopesticides. We applied phylogeny-led genome mining, metabolite analyses and biological control assays to define the efficacy of Burkholderia ambifaria, a naturally beneficial bacterium with proven biocontrol properties but potential pathogenic risk. A panel of 64 B. ambifaria strains demonstrated significant antimicrobial activity against priority plant pathogens. Genome sequencing, specialized metabolite biosynthetic gene cluster mining and metabolite analysis revealed an armoury of known and unknown pathways within B. ambifaria. The biosynthetic gene cluster responsible for the production of the metabolite cepacin was identified and directly shown to mediate protection of germinating crops against Pythium damping-off disease. B. ambifaria maintained biopesticidal protection and overall fitness in the soil after deletion of its third replicon, a non-essential plasmid associated with virulence in Burkholderia cepacia complex bacteria. Removal of the third replicon reduced B. ambifaria persistence in a murine respiratory infection model. Here, we show that by using interdisciplinary phylogenomic, metabolomic and functional approaches, the mode of action of natural biological control agents related to pathogens can be systematically established to facilitate their future exploitation.A.J.M. is funded by a Biotechnology and Biological Sciences Research Council (BBSRC) South West doctoral training partnership award (BY1910 7007). E.M., G.L.C., T.R.C. and J.P. acknowledge additional support for genome mining from BBSRC award BB/L021692/1; C.J. and M.J. were funded by this award. M.J. is currently the recipient of a BBSRC Future Leader Fellowship (BB/R01212/1). The Bruker maXis II UHPLC-ESI-Q-TOF-MS system used in this research was funded by the BBSRC (BB/M017982/1). G.W. was supported by awards to E.M. from the Life Sciences Bridging Fund and Wellcome Trust Institutional Strategic Support Fund held at Cardiff University. T.R.C. and M.J.B. acknowledge funding support from the Medical Research Council’s Cloud Infrastructure for Microbial Bioinformatics (MR/L015080/1), which provided the computational resources to undertake the analyses for this work. D.R.N. and A.E.G. acknowledge funding from a Wellcome Trust and Royal Society Sir Henry Dale Fellowship awarded to D.R.N. (grant number 204457/Z/16/Z). G.L.C. is the recipient of a Wolfson Research Merit Award from the Royal Society (WM130033)

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(–/– and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg−1. Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration–time curve of doxorubicin in it>mdr1a(–/–) mice were 1.6- and 1.2-fold higher respectively.The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(–/–) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(–/–) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of oxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(–/–) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin. © 1999 Cancer Research Campaig

Diagnostic accuracy of placental growth factor and ultrasound parameters to predict the small-for-gestational-age infant in women presenting with reduced symphysis-fundus height.

OBJECTIVES: To assess the diagnostic accuracy of placental growth factor (PlGF) and ultrasound parameters to predict delivery of a small-for-gestational-age (SGA) infant in women presenting with reduced symphysis-fundus height (SFH). METHODS: This was a multicenter prospective observational study recruiting 601 women with a singleton pregnancy and reduced SFH between 24 and 37 weeks' gestation across 11 sites in the UK and Canada. Plasma PlGF concentration  95(th) centile and oligohydramnios (amniotic fluid index < 5 cm) were compared as predictors for a SGA infant < 3(rd) customized birth-weight centile and adverse perinatal outcome. Test performance statistics were calculated for all parameters in isolation and in combination. RESULTS: Of the 601 women recruited, 592 were analyzed. For predicting delivery of SGA < 3(rd) centile (n = 78), EFW < 10(th) centile had 58% sensitivity (95% CI, 46-69%) and 93% negative predictive value (NPV) (95% CI, 90-95%), PlGF had 37% sensitivity (95% CI, 27-49%) and 90% NPV (95% CI, 87-93%); in combination, PlGF and EFW < 10(th) centile had 69% sensitivity (95% CI, 55-81%) and 93% NPV (95% CI, 89-96%). The equivalent receiver-operating characteristics (ROC) curve areas were 0.79 (95% CI, 0.74-0.84) for EFW < 10(th) centile, 0.70 (95% CI, 0.63-0.77) for low PlGF and 0.82 (95% CI, 0.77-0.86) in combination. CONCLUSIONS: For women presenting with reduced SFH, ultrasound parameters had modest test performance for predicting delivery of SGA < 3(rd) centile. PlGF performed no better than EFW < 10(th) centile in determining delivery of a SGA infant

Microbial contributions to the persistence of coral reefs

On contemplating the adaptive capacity of reef organisms to a rapidly changing environment, the microbiome offers significant and greatly unrecognised potential. Microbial symbionts contribute to the physiology, development, immunity and behaviour of their hosts, and can respond very rapidly to changing environmental conditions, providing a powerful mechanism for acclimatisation and also possibly rapid evolution of coral reef holobionts. Environmentally acquired fluctuations in the microbiome can have significant functional consequences for the holobiont phenotype upon which selection can act. Environmentally induced changes in microbial abundance may be analogous to host gene duplication, symbiont switching / shuffling as a result of environmental change can either remove or introduce raw genetic material into the holobiont; and horizontal gene transfer can facilitate rapid evolution within microbial strains. Vertical transmission of symbionts is a key feature of many reef holobionts and this would enable environmentally acquired microbial traits to be faithfully passed to future generations, ultimately facilitating microbiome-mediated transgenerational acclimatisation (MMTA) and potentially even adaptation of reef species in a rapidly changing climate. In this commentary, we highlight the capacity and mechanisms for MMTA in reef species, propose a modified Price equation as a framework for assessing MMTA and recommend future areas of research to better understand how microorganisms contribute to the transgenerational acclimatisation of reef organisms, which is essential if we are to reliably predict the consequences of global change for reef ecosystems

The DUNDRUM Quartet: validation of structured professional judgement instruments DUNDRUM-3 assessment of programme completion and DUNDRUM-4 assessment of recovery in forensic mental health services

<p>Abstract</p> <p>Background</p> <p>Moving a forensic mental health patient from one level of therapeutic security to a lower level or to the community is influenced by more than risk assessment and risk management. We set out to construct and validate structured professional judgement instruments for consistency and transparency in decision making</p> <p>Methods</p> <p>Two instruments were developed, the seven-item DUNDRUM-3 programme completion instrument and the six item DUNDRUM-4 recovery instrument. These were assessed for all 95 forensic patients at Ireland's only forensic mental health hospital.</p> <p>Results</p> <p>The two instruments had good internal consistency (Cronbach's alpha 0.911 and 0.887). Scores distinguished those allowed no leave or accompanied leave from those with unaccompanied leave (ANOVA F = 38.1 and 50.3 respectively, p < 0.001). Scores also distinguished those in acute/high security units from those in medium or in low secure/pre-discharge units. Each individual item distinguished these levels of need significantly. The DUNDRUM-3 and DUNDRUM-4 correlated moderately with measures of dynamic risk and with the CANFOR staff rated unmet need (Spearman r = 0.5, p < 0.001).</p> <p>Conclusions</p> <p>The DUNDRUM-3 programme completion items distinguished significantly between levels of therapeutic security while the DUNDRUM-4 recovery items consistently distinguished those given unaccompanied leave outside the hospital and those in the lowest levels of therapeutic security. This data forms the basis for a prospective study of outcomes now underway.</p

Crustose Coralline Algae and a Cnidarian Neuropeptide Trigger Larval Settlement in Two Coral Reef Sponges

In sessile marine invertebrates, larval settlement is fundamental to population maintenance and persistence. Cues contributing to the settlement choices and metamorphosis of larvae have important implications for the success of individuals and populations, but cues mediating larval settlement for many marine invertebrates are largely unknown. This study assessed larval settlement in two common Great Barrier Reef sponges, Coscinoderma matthewsi and Rhopaloeides odorabile, to cues that enhance settlement and metamorphosis in various species of scleractinian coral larvae. Methanol extracts of the crustose coralline algae (CCA), Porolithon onkodes, corresponding to a range of concentrations, were used to determine the settlement responses of sponge larvae. Cnidarian neuropeptides (GLW-amide neuropeptides) were also tested as a settlement cue. Settlement in both sponge species was approximately two-fold higher in response to live chips of CCA and optimum concentrations of CCA extract compared to 0.2 µm filtered sea water controls. Metamorphosis also increased when larvae were exposed to GLW-amide neuropeptides; R. odorabile mean metamorphosis reached 42.0±5.8% compared to 16.0±2.4% in seawater controls and in C. matthewsi mean metamorphosis reached 68.3±5.4% compared to 36.7±3.3% in seawater controls. These results demonstrate the contributing role chemosensory communication plays in the ability of sponge larvae to identify suitable habitat for successful recruitment. It also raises the possibility that larvae from distinct phyla may share signal transduction pathways involved in metamorphosis

Abdominal Wound Dehiscence in Adults: Development and Validation of a Risk Model

Background: Several studies have been performed to identify risk factors for abdominal wound dehiscence. No risk model had yet been developed for the general surgical population. The objective of the present study was to identify independent risk factors for abdominal wound dehiscence and to develop a risk model to recognize high-risk patients. Identification of high-risk patients offers opportunities for intervention strategies. Methods: Medical registers from January 1985 to December 2005 were searched. Patients who had primarily undergone appendectomies or nonsurgical (e.g., urological) operations were excluded. Each patient with abdominal wound dehiscence was matched with three controls by systematic random sampling. Putative relevant patient-related, operation-related, and postoperative variables were evaluated in univariate analysis and subsequently entered in multivariate stepwise logistic regression models to delineate major independent predictors of abdominal wound dehiscence. A risk model was developed, which was validated in a population of patients who had undergone operation between January and December 2006. Results: A total of 363 cases and 1,089 controls were analyzed. Major independent risk factors were age, gender, chronic pulmonary disease, ascites, jaundice, anemia, emergency surgery, type of surgery, postoperative coughing, and wound infection. In the validation population, risk scores were significantly higher (P < 0.001) for patients with abdominal wound dehiscence (n = 19) compared to those without (n = 677). Resulting scores ranged from 0 to 8.5, and the risk for abdominal wound dehiscence over this range increased exponentially from 0.02% to 70.1%. Conclusions: The validated risk model shows high predictive value for abdominal wound dehiscence and may help to identify patients at increased risk