Functional response of U.S. grasslands to the early 21st-century drought

Grasslands across the United States play a key role in regional livelihood and national food security. Yet, it is still unclear how this important resource will respond to the prolonged warm droughts and more intense rainfall events predicted with climate change. The early 21st-century drought in the southwestern United States resulted in hydroclimatic conditions that are similar to those expected with future climate change. We investigated the impact of the early 21st-century drought on aboveground net primary production (ANPP) of six desert and plains grasslands dominated by C4 (warm season) grasses in terms of significant deviations between observed and expected ANPP. In desert grasslands, drought-induced grass mortality led to shifts in the functional response to annual total precipitation (PT), and in some cases, new species assemblages occurred that included invasive species. In contrast, the ANPP in plains grasslands exhibited a strong linear function of the current-year PT and the previous-year ANPP, despite prolonged warm drought. We used these results to disentangle the impacts of interannual total precipitation, intra-annual precipitation patterns, and grassland abundance on ANPP, and thus generalize the functional response of C4 grasslands to predicted climate change. This will allow managers to plan for predictable shifts in resources associated with climate change related to fire risk, loss of forage, and ecosystem services. © 2014 by the Ecological Society of America

New Insights into Fluoroquinolone Resistance in Mycobacterium tuberculosis: Functional Genetic Analysis of gyrA and gyrB Mutations

Fluoroquinolone antibiotics are among the most potent second-line drugs used for treatment of multidrug-resistant tuberculosis (MDR TB), and resistance to this class of antibiotics is one criterion for defining extensively drug resistant tuberculosis (XDR TB). Fluoroquinolone resistance in Mycobacterium tuberculosis has been associated with modification of the quinolone resistance determining region (QRDR) of gyrA. Recent studies suggest that amino acid substitutions in gyrB may also play a crucial role in resistance, but functional genetic studies of these mutations in M. tuberculosis are lacking. In this study, we examined twenty six mutations in gyrase genes gyrA (seven) and gyrB (nineteen) to determine the clinical relevance and role of these mutations in fluoroquinolone resistance. Transductants or clinical isolates harboring T80A, T80A+A90G, A90G, G247S and A384V gyrA mutations were susceptible to all fluoroquinolones tested. The A74S mutation conferred low-level resistance to moxifloxacin but susceptibility to ciprofloxacin, levofloxacin and ofloxacin, and the A74S+D94G double mutation conferred cross resistance to all the fluoroquinolones tested. Functional genetic analysis and structural modeling of gyrB suggest that M330I, V340L, R485C, D500A, D533A, A543T, A543V and T546M mutations are not sufficient to confer resistance as determined by agar proportion. Only three mutations, N538D, E540V and R485C+T539N, conferred resistance to all four fluoroquinolones in at least one genetic background. The D500H and D500N mutations conferred resistance only to levofloxacin and ofloxacin while N538K and E540D consistently conferred resistance to moxifloxacin only. Transductants and clinical isolates harboring T539N, T539P or N538T+T546M mutations exhibited low-level resistance to moxifloxacin only but not consistently. These findings indicate that certain mutations in gyrB confer fluoroquinolone resistance, but the level and pattern of resistance varies among the different mutations. The results from this study provide support for the inclusion of the QRDR of gyrB in molecular assays used to detect fluoroquinolone resistance in M. tuberculosis

Detection of Atherosclerotic Inflammation by 68^{68}Ga-DOTATATE PET Compared to [18^{18}F]FDG PET Imaging

$\textbf{Background}$ Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([$^{18}$F]FDG PET), [$^{18}$F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. $\textbf{Objectives}$ Objectives This study tested the efficacy of gallium-68-labeled DOTATATE ($^{68}$Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. $\textbf{Methods}$ We confirmed $^{68}$Ga-DOTATATE binding in macrophages and excised carotid plaques. $^{68}$Ga-DOTATATE PET imaging was compared to [$^{18}$F]FDG PET imaging in 42 patients with atherosclerosis. $\textbf{Results}$ Target $\textit{SSTR2}$ gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific $^{68}$Ga-DOTATATE ligand binding to SST$_{2}$ receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid $\textit{SSTR2}$ mRNA was highly correlated with in vivo $^{68}$Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). $^{68}$Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBR$_{max}$) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). $^{68}$Ga-DOTATATE mTBR$_{max}$ predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [$^{18}$F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [$^{18}$F]FDG mTBR$_{max}$ differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [$^{18}$F]FDG spillover rendered coronary [$^{18}$F]FDG scans uninterpretable in 27 patients (64%). Coronary $^{68}$Ga-DOTATATE PET scans were readable in all patients. $\textbf{Conclusions}$ We validated $^{68}$Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that $^{68}$Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [$^{18}$F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)This study was funded by the Wellcome Trust and supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit. Dr. Tarkin is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). Dr. Evans is supported by a Dunhill Medical Trust fellowship (RTF44/0114). Dr. Chowdhury is supported by Royal College of Surgeons of England and British Heart Foundation (BHF) fellowships (FS/16/29/31957). Drs. Manavaki and Warburton are supported by the NIHR Biomedical Research Centres. Drs. Yu and Frontini are supported by the BHF (RE/13/6/30180). Dr. Fryer is supported by Higher Education Funding Council for England (HEFCE). Dr. Groves is supported by the University College London Hospital NIHR Biomedical Research Centre; and has received grant support from GlaxoSmithKline. Dr. Ouwehand’s laboratory is funded by EU-FP7 project Blueprint (Health-F5-2011-282510), BHF (PG-0310-1002 and RG/09/12/28096), and National Health Service Blood and Transplant. Dr. Bennett is supported by NIHR and BHF. Dr. Davenport is supported by research grants from Wellcome Trust (107715/Z/15/Z), Medical Research Council (MC_PC_14116), and BHF (RE-13-6-3180). Dr. Rudd is supported by the NIHR, BHF, Wellcome Trust, and HEFCE

Pyrosequencing-Based Comparative Genome Analysis of Vibrio vulnificus Environmental Isolates

Between 1996 and 2006, the US Centers for Disease Control reported that the only category of food-borne infections increasing in frequency were those caused by members of the genus Vibrio. The Gram-negative bacterium Vibrio vulnificus is a ubiquitous inhabitant of estuarine waters, and is the number one cause of seafood-related deaths in the US. Many V. vulnificus isolates have been studied, and it has been shown that two genetically distinct subtypes, distinguished by 16S rDNA and other gene polymorphisms, are associated predominantly with either environmental or clinical isolation. While local genetic differences between the subtypes have been probed, only the genomes of clinical isolates have so far been completely sequenced. In order to better understand V. vulnificus as an agent of disease and to identify the molecular components of its virulence mechanisms, we have completed whole genome shotgun sequencing of three diverse environmental genotypes using a pyrosequencing approach. V. vulnificus strain JY1305 was sequenced to a depth of 33×, and strains E64MW and JY1701 were sequenced to lesser depth, covering approximately 99.9% of each genome. We have performed a comparative analysis of these sequences against the previously published sequences of three V. vulnificus clinical isolates. We find that the genome of V. vulnificus is dynamic, with 1.27% of genes in the C-genotype genomes not found in the E- genotype genomes. We identified key genes that differentiate between the genomes of the clinical and environmental genotypes. 167 genes were found to be specifically associated with environmental genotypes and 278 genes with clinical genotypes. Genes specific to the clinical strains include components of sialic acid catabolism, mannitol fermentation, and a component of a Type IV secretory pathway VirB4, as well as several other genes with potential significance for human virulence. Genes specific to environmental strains included several that may have implications for the balance between self-preservation under stress and nutritional competence

Early temperature and mortality in critically ill patients with acute neurological diseases: trauma and stroke differ from infection

BACKGROUND: Fever suppression may be beneficial for patients with traumatic brain injury (TBI) and stroke, but for patients with meningitis or encephalitis [central nervous system (CNS) infection], the febrile response may be advantageous. OBJECTIVE: To evaluate the relationship between peak temperature in the first 24 h of intensive care unit (ICU) admission and all-cause hospital mortality for acute neurological diseases. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort design from 2005 to 2013, including 934,159 admissions to 148 ICUs in Australia and New Zealand (ANZ) and 908,775 admissions to 236 ICUs in the UK. RESULTS: There were 53,942 (5.8 %) patients in ANZ and 56,696 (6.2 %) patients in the UK with a diagnosis of TBI, stroke or CNS infection. For both the ANZ (P = 0.02) and UK (P < 0.0001) cohorts there was a significant interaction between early peak temperature and CNS infection, indicating that the nature of the relationship between in-hospital mortality and peak temperature differed between TBI/stroke and CNS infection. For patients with CNS infection, elevated peak temperature was not associated with an increased risk of death, relative to the risk at 37–37.4 °C (normothermia). For patients with stroke and TBI, peak temperature below 37 °C and above 39 °C was associated with an increased risk of death, compared to normothermia. CONCLUSIONS: The relationship between peak temperature in the first 24 h after ICU admission and in-hospital mortality differs for TBI/stroke compared to CNS infection. For CNS infection, increased temperature is not associated with increased risk of death. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-015-3676-6) contains supplementary material, which is available to authorized users