Is There a Role for Enterohormones in the Gastroparesis of Critically Ill Patients?.

Objectives: Delayed gastric emptying occurs in critically ill patients and impairs the delivery, digestion, and absorption of enteral feeding. A pathophysiologic role of the enterohormones peptide YY and ghrelin is supported by preclinical data. To compare the circulating plasma levels of peptide YY and ghrelin in control subjects and in critically ill patients, during feeding and fasting, and to search for a correlation with gastric emptying. Design: A prospective observational trial. Settings: Mixed ICU of an academic hospital. Subjects: Healthy volunteers and patients expected to stay in ICU for at least 3 days in whom enteral nutrition was indicated. Interventions: None. Measurements and Main Results: Plasma peptide YY and ghrelin (enzyme-linked immunosorbent assay) were measured once in 10 fasting volunteers (controls) and daily from admission until day 5 of the ICU stay in 30 critically ill patients (median [interquartile range] age 63 [57-67] yr, median [interquartile range] Acute Physiology and Chronic Health Evaluation II score 21 [14-24]). Eight patients could not be fed (fasting group). In fed patients, 13 never had a gastric residual volume higher than 250 mL (low gastric residual volume group), in contrast to the high gastric residual volume group (n = 9). The plasma levels of peptide YY did not differ between patients (6.4 [0-18.1] pg/mL) and controls (4.8 [0.3-17.7] pg/mL). Ghrelin levels were lower in patients than in control (213 [54.4-522.7] vs 1,435 [1,321.9-1,869.3] pg/mL; p

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Diabetes Is Not Associated With Increased 90-Day Mortality Risk in Critically Ill Patients With Sepsis.

Objectives: To determine the association of pre-existing diabetes, hyperglycemia, and hypoglycemia during the first 24 hours of ICU admissions with 90-day mortality in patients with sepsis admitted to the ICU. Design: We used mixed effects logistic regression to analyze the association of diabetes, hyperglycemia, and hypoglycemia with 90-day mortality (n = 128,222). Setting: All ICUs in the Netherlands between January 2009 and 2014 that participated in the Dutch National Intensive Care Evaluation registry. Patients: All unplanned ICU admissions in patients with sepsis. Interventions: The association between 90-day mortality and pre-existing diabetes, hyperglycemia, and hypoglycemia, corrected for other factors, was analyzed using a generalized linear mixed effect model. Measurements and Main Results: In a multivariable analysis, diabetes was not associated with increased 90-day mortality. In diabetes patients, only severe hypoglycemia in the absence of hyperglycemia was associated with increased 90-day mortality (odds ratio, 2.95; 95% CI, 1.19-7.32), whereas in patients without pre-existing diabetes, several combinations of abnormal glucose levels were associated with increased 90-day mortality. Conclusions: In the current retrospective large database review, diabetes was not associated with adjusted 90-day mortality risk in critically ill patients admitted with sepsis. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Investigating the Impact of Different Suspicion of Infection Criteria on the Accuracy of Quick Sepsis-Related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores.

Objective: Studies in sepsis are limited by heterogeneity regarding what constitutes suspicion of infection. We sought to compare potential suspicion criteria using antibiotic and culture order combinations in terms of patient characteristics and outcomes. We further sought to determine the impact of differing criteria on the accuracy of sepsis screening tools and early warning scores. Design: Observational cohort study. Setting: Academic center from November 2008 to January 2016. Patients: Hospitalized patients outside the ICU. Interventions: None. Measurements and Main Results: Six criteria were investigated: 1) any culture, 2) blood culture, 3) any culture plus IV antibiotics, 4) blood culture plus IV antibiotics, 5) any culture plus IV antibiotics for at least 4 of 7 days, and 6) blood culture plus IV antibiotics for at least 4 of 7 days. Accuracy of the quick Sepsis-related Organ Failure Assessment score, Sepsis-related Organ Failure Assessment score, systemic inflammatory response syndrome criteria, the National and Modified Early Warning Score, and the electronic Cardiac Arrest Risk Triage score were calculated for predicting ICU transfer or death within 48 hours of meeting suspicion criteria. A total of 53,849 patients met at least one infection criteria. Mortality increased from 3% for group 1 to 9% for group 6 and percentage meeting Angus sepsis criteria increased from 20% to 40%. Across all criteria, score discrimination was lowest for systemic inflammatory response syndrome (median area under the receiver operating characteristic curve, 0.60) and Sepsis-related Organ Failure Assessment score (median area under the receiver operating characteristic curve, 0.62), intermediate for quick Sepsis-related Organ Failure Assessment (median area under the receiver operating characteristic curve, 0.65) and Modified Early Warning Score (median area under the receiver operating characteristic curve 0.67), and highest for National Early Warning Score (median area under the receiver operating characteristic curve 0.71) and electronic Cardiac Arrest Risk Triage (median area under the receiver operating characteristic curve 0.73). Conclusions: The choice of criteria to define a potentially infected population significantly impacts prevalence of mortality but has little impact on accuracy. Systemic inflammatory response syndrome was the least predictive and electronic Cardiac Arrest Risk Triage the most predictive regardless of how infection was defined. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Hollow MXene Spheres and 3D Macroporous MXene Frameworks for Na-Ion Storage

2D transition metal carbides and nitrides, named MXenes, are attracting increasing attentions and showing competitive performance in energy storage devices including electrochemical capacitors, lithium- and sodium-ion batteries, and lithium–sulfur batteries. However, similar to other 2D materials, MXene nanosheets are inclined to stack together, limiting the device performance. In order to fully utilize MXenes' electrochemical energy storage capability, here, processing of 2D MXene flakes into hollow spheres and 3D architectures via a template method is reported. The MXene hollow spheres are stable and can be easily dispersed in solvents such as water and ethanol, demonstrating their potential applications in environmental and biomedical fields as well. The 3D macroporous MXene films are free-standing, flexible, and highly conductive due to good contacts between spheres and metallic conductivity of MXenes. When used as anodes for sodium-ion storage, these 3D MXene films exhibit much improved performances compared to multilayer MXenes and MXene/carbon nanotube hybrid architectures in terms of capacity, rate capability, and cycling stability. This work demonstrates the importance of MXene electrode architecture on the electrochemical performance and can guide future work on designing high-performance MXene-based materials for energy storage, catalysis, environmental, and biomedical applications.

Hollow Ti₃C₂T_x spheres and 3D macroporous MXene films are fabricated using a sacrificial template approach. The 3D MXene films are free-standing, flexible, and highly conductive. They can serve directly as electrodes for Na-ion storage and exhibit high capacities accompanied with excellent stabilities and rate performance.

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Transparent, Flexible, and Conductive 2D Titanium Carbide (MXene) Films with High Volumetric Capacitance

2D transition-metal carbides and nitrides, known as MXenes, have displayed promising properties in numerous applications, such as energy storage, electromagnetic interference shielding, and catalysis. Titanium carbide MXene (Ti₃C₂T_x), in particular, has shown significant energy-storage capability. However, previously, only micrometer-thick, nontransparent films were studied. Here, highly transparent and conductive Ti₃C₂T_x films and their application as transparent, solid-state supercapacitors are reported. Transparent films are fabricated via spin-casting of Ti₃C₂T_x nanosheet colloidal solutions, followed by vacuum annealing at 200 °C. Films with transmittance of 93% (≈4 nm) and 29% (≈88 nm) demonstrate DC conductivity of ≈5736 and ≈9880 S cm⁻¹, respectively. Such highly transparent, conductive Ti₃C₂T_x films display impressive volumetric capacitance (676 F cm⁻³) combined with fast response. Transparent solid-state, asymmetric supercapacitors (72% transmittance) based on Ti₃C₂T_x and single-walled carbon nanotube (SWCNT) films are also fabricated. These electrodes exhibit high capacitance (1.6 mF cm⁻²) and energy density (0.05 µW h cm⁻²), and long lifetime (no capacitance decay over 20 000 cycles), exceeding that of graphene or SWCNT-based transparent supercapacitor devices. Collectively, the Ti₃C₂T_x films are among the state-of-the-art for future transparent, conductive, capacitive electrodes, and translate into technologically viable devices for next-generation wearable, portable electronics.

Highly transparent and conductive Ti₃C₂T_x films and their application as transparent, solid-state supercapacitors are demonstrated. Films with transmittance of 93% (≈4 nm) and 29% (≈88 nm) demonstrate DC conductivity of ≈5736 and ≈9880 S cm⁻¹, respectively. The Ti₃C₂T_x films display impressive volumetric capacitance (676 F cm⁻³), high areal capacitance, and long lifetime in the transparent solid-state supercapacitor devices.

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Reversible, Fast, and Wide-Range Oxygen Sensor Based on Nanostructured Organometal Halide Perovskite

Nanostructured materials characterized by high surface–volume ratio hold the promise to constitute the active materials for next-generation sensors. Solution-processed hybrid organohalide perovskites, which have been extensively used in the last few years for optoelectronic applications, are characterized by a self-assembled nanostructured morphology, which makes them an ideal candidate for gas sensing. Hitherto, detailed studies of the dependence of their electrical characteristics on the environmental atmosphere have not been performed, and even the effect of a ubiquitous gas such as O₂ has been widely overlooked. Here, the electrical response of organohalide perovskites to oxygen is studied. Surprisingly, a colossal increase (3000-fold) in the resistance of perovskite-based lateral devices is found when measured in a full oxygen atmosphere, which is ascribed to a trap healing mechanism originating from an O₂-mediated iodine vacancies filling. A variation as small as 70 ppm in the oxygen concentration can be detected. The effect is fast (<400 ms) and fully reversible, making organohalide perovskites ideal active materials for oxygen sensing. The effect of oxygen on the electrical characteristics of organohalide perovskites must be taken into deep consideration for the design and optimization of any other perovskite-based (opto-) electronic device working in ambient conditions.

Oxygen gas is found to induce a colossal change in the electrical current flowing through organometallic hybrid perovskites, paving the way to the demonstration of fast, fully reversible, and wide-range oxygen sensors. The efficiency of the sensing element depends dramatically on the nanoscale morphology of the material, which can be controlled by optimization of the deposition process.

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Effect of Progressive Heart Failure on Cerebral Hemodynamics and Monoamine Metabolism in CNS

Compensated and decompensated heart failure are characterized by different associations of disorders in the brain and heart. In compensated heart failure, the blood flow in the common carotid and basilar arteries does not change. Exacerbation of heart failure leads to severe decompensation and is accompanied by a decrease in blood flow in the carotid and basilar arteries. Changes in monoamine content occurring in the brain at different stages of heart failure are determined by various factors. The functional exercise test showed unequal monoamine-synthesizing capacities of the brain in compensated and decompensated heart failure. Reduced capacity of the monoaminergic systems in decompensated heart failure probably leads to overstrain of the central regulatory mechanisms, their gradual exhaustion, and failure of the compensatory mechanisms, which contributes to progression of heart failure.

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Effects of Fullerene Derivatives on Activity of Ca 2+ -ATPase of the Sarcoplasmic Reticulum and cGMP Phosphodiesterase

We studied the effects of new water-soluble polysubstituted fullerene C60 (PFD) derivatives on activity of Ca²⁺-Mg²⁺ ATPase of the sarcoplasmic reticulum and cGMP phosphodiesterase. All examined fullerene derivatives inhibited activity of both enzymes. For instance, PFD-I, PFD-II, PFD-III, PFD-V, PFD-IX, PFD-X, and PFD-XI in a concentration of 5×10^—5 M completely inhibited hydrolytic and transport functions of Ca²⁺-ATPase. These compounds in a concentration of 5×10^—6 suppressed active transport of calcium ions by 51±5, 77±8, 52±5, 52±5, 100±10, 80±8, and 100±10%, respectively, and inhibited ATP hydrolysis by 31±3, 78±8, 18±2, 29±3, 78±8, 63±7, and 73±9%, respectively, uncoupling the hydrolytic and transport functions of the enzyme. PFD-I noncompetitive and reversibly reduced activity of Ca²⁺-ATPase (K_i=2.3×10^—6 M). All the studied fullerene derivatives (except for PFD-VII) inhibited cGMP phosphodiesterase by more than 80% in concentration of 10^—4 M and higher and by more than 50% in concentration of 10^—5 M. PFD-I is a non-competitive reversible inhibitor of cGMP phosphodiesterase (K_i=7×10^—6 M). These results allow us to expect antimetastatic, antiaggregatory, antihypertensive and vasodilative activity of the studied compounds.

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Effects of Chronic Tobacco Smoking on the Distribution of Tachykinin Receptors in Rat Pial Arteries

Pial arteries of different diameter were studied in intact rats and after 6-month modeling of chronic tobacco smoking in rats. Expression of tachykinin NK1 receptors in pial arteries was studied by biomicroscopy and immunohistochemical methods. Chronic tobacco smoking induced considerable reorganizations of the arterial bed. The intensity of changes depended on the diameter of vessels. In small pial vessels that directly participate in the blood supply to the brain, pronounced vasodilatation and enhanced expression of NK₁ receptors in the endothelium mediating the effects of substance P were observed; the number of these vessels also increased. The intensity of the response to tobacco smoke components decreased with increasing vessel diameter.

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Porous Organic Polymers for Post-Combustion Carbon Capture

One of the most pressing environmental concerns of our age is the escalating level of atmospheric CO₂. Intensive efforts have been made to investigate advanced porous materials, especially porous organic polymers (POPs), as one type of the most promising candidates for carbon capture due to their extremely high porosity, structural diversity, and physicochemical stability. This review provides a critical and in-depth analysis of recent POP research as it pertains to carbon capture. The definitions and terminologies commonly used to evaluate the performance of POPs for carbon capture, including CO₂ capacity, enthalpy, selectivity, and regeneration strategies, are summarized. A detailed correlation study between the structural and chemical features of POPs and their adsorption capacities is discussed, mainly focusing on the physical interactions and chemical reactions. Finally, a concise outlook for utilizing POPs for carbon capture is discussed, noting areas in which further work is needed to develop the next-generation POPs for practical applications.

Significant progress has been made in the exploration of porous organic polymers (POPs) as potential porous solid adsorbents for carbon capture. A detailed correlation study between the structural and chemical features of POPs and their adsorption capacities is discussed, mainly focusing on physical interactions and chemical reactions.

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Superparamagnetic Gold Nanoparticles Synthesized on Protein Particle Scaffolds for Cancer Theragnosis

Cancer theragnosis using a single multimodality agent is the next mainstay of modern cancer diagnosis, treatment, and management, but a clinically feasible agent with in vivo cancer targeting and theragnostic efficacy has not yet been developed. A new type of cancer theragnostic agent is reported, based on gold magnetism that is induced on a cancer-targeting protein particle carrier. Superparamagnetic gold-nanoparticle clusters (named SPAuNCs) are synthesized on a viral capsid particle that is engineered to present peptide ligands targeting a tumor cell receptor (TCR). The potent multimodality of the SPAuNCs is observed, which enables TCR-specific targeting, T₂-weighted magnetic resonance imaging, and magnetic hyperthermia therapy of both subcutaneous and deep-tissue tumors in live mice under an alternating magnetic field. Furthermore, it is analytically elucidated how the magnetism of the SPAuNCs is sufficiently induced between localized and delocalized spins of Au atoms. In particular, the SPAuNCs show excellent biocompatibility without the problem of in vivo accumulation and holds promising potential as a clinically effective agent for cancer theragnosis.

Superparamagnetic gold nanoparticle clusters (SPAuNCs) show a potent multimodality for targeted cancer theragnosis. They enable receptor-specific targeting, T₂-weighted magnetic resonance imaging, and magnetic hyperthermia therapy of subcutaneous and deep-tissue tumors in live mice under an alternating magnetic field. In particular, SPAuNCs show excellent biocompatibility without the problem of in vivo accumulation and hold promising potential as a clinically effective agent for cancer theragnosis.

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Castor oil for induction of labor in post-date pregnancies: A randomized controlled trial

Publication date: Available online 24 July 2017
Source:Women and Birth
Author(s): Ronit Gilad, Hagit Hochner, Bella Savitsky, Shay Porat, Drorith Hochner-Celnikier
BackgroundCastor oil is a substance used for labor induction in an inpatient setting. However, its efficacy as an agent for the induction of labor, for post-date pregnancies in an outpatient setup is unknown.ObjectiveEfficacy of castor oil as an agent for the induction of labor, for post-date pregnancies in outpatient settings.MethodsEighty-one women with a low-risk post-date singleton pregnancy with a Bishop score≤7, without effective uterine contractions were randomized to the intervention, 60ml of castor oil, or the control, 60ml of sun-flower oil. The primary outcome was proportion of women entering the active phase of labor 24, 36, 48h after ingestion. Secondary outcomes included meconium stained amniotic fluid, abnormal fetal heart rate tracing, cesarean section rate, instrumental deliveries, birth weight, 5min Apgar score, chorioamnionitis, hypertensive complications, retained placenta, and post-partum hemorrhage.FindingsIntervention and control groups included 38 and 43 women, respectively. No differences in baseline characteristics, except for age were noted. The observed interaction between castor oil and parity was significant (pinteraction=0.02). Multiparous women in the intervention group exhibited a significant beneficial effect on entering active labor within 24, 36 and 48h after castor oil consumption compared with the placebo (Hazard Ratio=2.93, p=0.048; Hazard Ratio=3.29, p=0.026; Hazard Ratio=2.78, p=0.042 respectively). This effect was not noted among primiparous women. No differences in rate of obstetric complications or adverse neonatal outcomes were noted.ConclusionCastor oil is effective for labor induction, in post-date multiparous women in outpatient settings.



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Course-Based Undergraduate Research Experiences in Molecular Biosciences – patterns, trends, and faculty support

Abstract

Inquiry-driven learning, research internships, and course-based undergraduate research experiences all represent mechanisms through which educators can engage undergraduate students in scientific research. In life sciences education, the benefits of undergraduate research have been thoroughly evaluated, but limitations in infrastructure and training can prevent widespread uptake of these practices. It is not clear how faculty members can integrate complex laboratory techniques and equipment into their unique context, while finding the time and resources to implement undergraduate research according to best practice guidelines. This review will go through the trends and patterns in inquiry-based undergraduate life science projects with particular emphasis on molecular biosciences—the research-aligned disciplines of biochemistry, molecular cell biology, microbiology, and genomics and bioinformatics. This will provide instructors with an overview of the model organisms, laboratory techniques, and research questions that are adaptable for semester-long projects, and serve as starting guidelines for course-based undergraduate research.

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Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues

Human Gene Therapy , Vol. 0, No. 0.


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Psoriasis: a mixed autoimmune and autoinflammatory disease

Yun Liang | Mrinal K Sarkar | Lam C Tsoi | Johann E Gudjonsson

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The immunopathology of dengue and Zika virus infections

Abigail Culshaw | Juthathip Mongkolsapaya | Gavin R Screaton

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Germinal center enhancement by extended antigen availability

Kimberly M Cirelli | Shane Crotty

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Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-Abdominal Abscess Model [PublishAheadOfPrint]

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents. Yet, their clinical effectiveness is highly variable with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption/ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic dose. However, CD101 but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs may be limited by penetration at the site of infection, which have implications for clinical outcomes and emergence of resistance in patients with IAC.

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Multicenter Evaluation of Ceftazidime-avibactam and Ceftolozane-tazobactam Inhibitory Activity against Meropenem Non-Susceptible P. aeruginosa from Blood, Respiratory Tract and Wounds [PublishAheadOfPrint]

The recent escalation of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of this class of compounds for this prevalent healthcare associate pathogen. Herein, we compared the in-vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem non-susceptible Pseudomonas aeruginosa non-duplicate clinical isolates from 34 US hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood or wound) and non-susceptibility to other β-lactam antimicrobials was considered. An extensive genotypic search for enzymatically-driven β-lactam resistance mechanisms revealed the exclusive presence of VIM among only 4% of the subset of isolates non-susceptible to ceftazidime-avibactam, ceftolozane-tazobactam or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem non-susceptible Pseudomonas aeruginosa. Further in-vitro and in-vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multi-drug resistant Pseudomonas aeruginosa.

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Contribution of TetB Efflux Pump on Minocycline Susceptibility among Carbapenem-Resistant Acinetobacter baumannii [PublishAheadOfPrint]

Minocycline, a semi-synthetic tetracycline developed in the 1970s, has become an important treatment option against MDR A. baumannii infections, particularly those caused by carbapenem-resistant strains (1)....

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Benzoxazoles, phthalazinones, and arylurea-based compounds with IMPDH-independent antibacterial activity against Francisella tularensis [PublishAheadOfPrint]

Francisella tularensis is the causative agent of tularemia and a potential biowarfare agent. The virulence of F. tularensis is decreased by deletion of guaB, the gene encoding inosine monophosphate dehydrogenase (IMPDH), suggesting that this enzyme is a target for antibacterial design. Here we report that F. tularensis growth is blocked by inhibitors of bacterial IMPDHs. Seventeen compounds from two different frameworks, designated D and Q, display antibacterial activity with minimum inhibitory concentrations less than 1 μM. These compounds are also active against intracellular infections. Surprisingly, antibacterial activity does not correlate with IMPDH inhibition. In addition, the presence of guanine does not affect the antibacterial activity of most compounds, nor does the deletion of guaB. These observations suggest that antibacterial activity derives from inhibition of another target(s). Moreover, D compounds only display antibacterial activity against F. tularensis, suggesting the presence of a unique target or uptake mechanism. A guaB mutant resistant to compound D73 contained a missense mutation (Gly45Cys) in nuoB, which encodes a subunit of bacterial complex I. Over-expression of the mutant nuoB conferred resistance to D73 in both wild-type and guaB strains. This strain was not resistant to Q compounds, suggesting that a different off-target mechanism operates for these compounds. Several Q compounds are also effective against Mycobacterium tuberculosis, where a second target has also been implicated in addition to IMPDH. The fortuitous presence of multiple targets with overlapping structure-activity relationships presents an intriguing opportunity for the development of robust antibiotics that may avoid the emergence of resistance.

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Emergence of mcr-1 in Raoultella ornithinolytica and Escherichia coli from retail vegetables, China [PublishAheadOfPrint]

The presence of mcr-1 among Enterobacteriaceae isolates collected from retail vegetables in China between 2015 and 2016 were investigated. Two Raoultella ornithinolytica and seven Escherichia coli strains recovered from lettuce and tomato samples were identified as MCR-1-producers. Similar to isolates from animals and humans, the mcr-1 gene was located on the IncHI2/ST3, IncI2 or IncX4 plasmids. The presence of MCR-1-producing organisms in ready-to-eat food samples represents a serious risk for human health.

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Clinical Characteristics and Treatment Outcomes of Patients with Acquired Macrolide-resistant Mycobacterium abscessus Lung Disease [PublishAheadOfPrint]

Macrolide antibiotics are mainstays in the treatment of lung disease due to the Mycobacterium abscessus complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant M. abscessus subspecies abscessus (hereafter M. abscessus). This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of M. abscessus. We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant M. abscessus lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form, and two (15%) patients had the fibrocavitary form of the disease. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for M. abscessus, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range: 16.0--43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at positions 2058 (n = 10) or 2059 (n = 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with M. abscessus lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant M. abscessus lung disease.

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Systematic Therapeutic Drug Monitoring for Linezolid: Variability and Clinical Impact [PublishAheadOfPrint]

Linezolid serum trough (Cmin) and peak levels were determined prospectively in 90 patients. Adequate exposure was defined as a Cmin of 2-8 mg/L. Therapy was empirical (73.3%) or targeted (26.7%). Wide interindividual variability in linezolid trough levels was recorded (0.1-25.2 μg/mL). Overall 65.5% of the patients had out of range trough levels, 41.1% subtherapeutic and 24.4% supratherapeutic.

We did not find a correlation between abnormal levels and adverse events, in-hospital mortality, or overall poor outcome.

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Resistance to ceftazidime-avibactam is due to transposition of KPC in a porin-deficient strain of Klebsiella pneumoniae with increased efflux activity. [PublishAheadOfPrint]

Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including KPC. Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258 Klebsiella pneumoniae that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a non-functional OmpK35, whereas we demonstrate a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced activity of this porin and impacted ceftazidime-avibactam susceptibility. Additionally, we demonstrate that the increased expression of bla_KPC-3 and bla_SHV-12 observed in the ceftazidime-avibactam resistant isolate was due to transposition of the Tn4401 transposon harboring bla_KPC-3 into a second plasmid, pIncX3, which also harbored bla_SHV-12, ultimately resulting in a higher copy number of bla_KPC-3 in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35/36 deficient K. pneumoniae background that harbored mutation to the ramR regulator of the acrAB efflux operon re-created the ceftazidime-avibactam resistant MIC of 32 μg/mL, confirming this constellation of mutations is responsible for the resistance phenotype.

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Population Pharmacokinetics of AZD-5847 in Adults with Pulmonary Tuberculosis [PublishAheadOfPrint]

AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis. In this study we describe the population pharmacokinetics of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug susceptible TB. Patients were randomized to four doses (500 mg once daily, 1200 mg once daily, 500 mg twice daily and 800 mg twice daily). Patients were intensively sampled on day 1 and 14. AZD-5847 pharmacokinetics were best described with a two compartment system with tlag for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PKPD of AZD-5847, linezolid and sutezolid. AZD 5847 PKPD in terms of both fAUC/MIC and fT>MIC was less favorable compared to linezolid and sutezolid. This could help explain the poor bactericidal activity for AZD-5847 in the recent phase II study.

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In vitro drug susceptibility of bedaquiline, delamanid, linezolid, clofazimine, moxifloxacin, and gatifloxacin against extensively drug -resistant tuberculosis from Beijing, China [PublishAheadOfPrint]

Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore in vitro drug susceptibility of bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MXF), and gatifloxacin (GAT) against 90 XDR-TB strains isolated from patients in China. We also described the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD and BDQ was found in 82 (91.1%), 76 (84.4%), 5 (5.6%), 5 (5.6%), 4 (4.4%) and 3 (3.3%) isolates among the XDR-TB strains, respectively. The most frequent mutations conferring fluoroquinolone resistance occurred in codon 94 of gyrA gene (57.8%), and the strains with these mutations (69.2%) were associated with high-level MFX-resistance compared to strains with mutations in codon 90 (25.0%, P<0.01). All the 5 CLO-resistant isolates exhibited >=4-fold upward shifts in BDQ minimal inhibitory concentration, which were attributed to mutations of codons 53 (60.0%) and 157 (20.0%) in Rv0678 gene. Additionally, mutation in codon 318 of fbiC gene was identified as the sole mutation related to DMD resistance. In conclusion, our data demonstrate that the XDR-TB strains exhibit strikingly high proportion of resistance to the current anti-TB drugs, whereas BDQ, DMD, LZD and CLO exhibit excellent in vitro activity against XDR-TB in a National TB Center of China. The extensive cross-resistance between OFX and later-generation fluoroquinolones indicates that MFX and GAT may have difficulty in producing the desired effect for XDR-TB patients under current settings.

http://ift.tt/2tV2fYk

Multicenter and international study of MIC/MEC distributions for definition of epidemiological cutoff values (ECVs) for species of Sporothrix identified by molecular methods [PublishAheadOfPrint]

Clinical and Laboratory Standards Institute (CLSI) conditions for testing the susceptibilities of pathogenic Sporothrix species to antifungal agents are based on a collaborative study that evaluated five clinically relevant isolates of Sporothrix schenckii sensu lato and some antifungal agents. With the advent of molecular identification, there are two basic needs: to confirm the suitability of these testing conditions for all agents and Sporothrix species and to establish species-specific epidemiologic cutoff values (ECVs) or breakpoints (BPs) for these species. We collected available CLSI MICs/MECs of amphotericin B, five triazoles, terbinafine, flucytosine and caspofungin for 301 Sporothrix schenckii sensu stricto, 486 S. brasiliensis, 75 S. globosa and 13 S. mexicana molecularly identified isolates. Data were obtained in 17 independent laboratories (Australia, Europe, India, South Africa, South and North America) using conidial inoculum suspensions and 48-72 h of incubation at 35°C. Sufficient and suitable data (modal MICs within 2-fold concentrations) allowed the proposal of the following ECVs for S. schenckii and S. brasiliensis, respectively: amphotericin B 4 and 4 μg/ml, itraconazole 2 and 2 μg/ml; posaconazole 2 and 2 μg/ml; and voriconazole 64 and 32 μg/ml; ketoconazole and terbinafine ECVs for S. brasiliensis were 2 and 0.12 μg/ml, respectively. Insufficient or unsuitable data precluded the calculation of ketoconazole and terbinafine ECVs for S. schenckii as well as ECVs for S. globosa and S. mexicana or any other antifungal agent. These ECVs could aid the clinician in identifying potentially resistant isolates (non-wild type) less likely to respond to therapy.

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Assessment of bactericidal drug activity and treatment outcome in a mouse tuberculosis model using a clinical Beijing strain [PublishAheadOfPrint]

Objectives: Mycobacterium tuberculosis Beijing strains are associated with lower treatment success rates in tuberculosis patients. In contrast, laboratory strains such as H37Rv are often used in preclinical tuberculosis models. Therefore, we explored the impact of using a clinical Beijing strain on treatment outcome in our mouse tuberculosis model. Additionally, the predictive value of bactericidal activity on treatment outcome was assessed.

Methods: BALB/c mice were infected with a Beijing strain and treated with one of ten different combinations of conventional anti-TB drugs. Bactericidal activity was assessed by determining reductions in mycobacterial load after 7, 14 and 28 days and after 2, 3 and 6 months of treatment. Treatment outcome was evaluated after a 6-months treatment-course and was based on lung culture-status 3 months post-treatment.

Results: None of the anti-TB drug regimens tested could achieve 100% treatment success. Treatment outcome depended critically on rifampicin. Four non-rifampicin-containing regimens showed 0% treatment success compared to success rates ranging between 81-95% for six rifampicin-containing regimens. Bactericidal activity was only predictive for treatment outcome after 3 months of treatment.

Conclusion: Our data advocate the use of multiple mycobacterial strains, including a Beijing strain, to increase the translational value of mouse TB models evaluating treatment outcome. Additionally, our findings support the notion that bactericidal activity in the first two months of treatment, as measured in clinical phase IIa/b trials, has limited predictive value for tuberculosis treatment outcome, thus emphasizing the need for better parameters to guide future phase-IIII trials.

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Oxidative stress response tips the balance in Aspergillus terreus AmB resistance [PublishAheadOfPrint]

In this study we characterize the impact of antioxidative enzymes in AmB resistant (ATR) and rare susceptible (ATS) clinical A. terreus isolates. We elucidate the expression profiles of superoxide dismutases (SODs) and catalases (CATs) encoding genes, enzymatic activity of SODs, superoxide anion production and signaling pathways involved in oxidative stress response (OSR) under AmB treatment in ATS and ATR strains. We show that ATR possess almost doubled basal SOD activity compared to ATS and that ATR exhibits an enhanced OSR, with significantly higher sod2 mRNA levels and significantly increased cat transcripts in ATR upon AmB treatment. In particular, inhibition of SOD- and CAT proteins rendered resistant isolates considerably susceptible to the drug in vitro. In conclusion, this study shows that Sods and Cats are crucial for AmB resistance in A. terreus and targeting the OSR might offer new treatment perspectives for resistant species.

http://ift.tt/2tF0X8P

Transfersomal phage cocktail: an effective treatment against methicillin resistant S.aureus (MRSA) mediated Skin and Soft tissue infections (SSTIs) [PublishAheadOfPrint]

Emergence of drug resistance has rekindled the interest in phage therapy as an alternative treatment option. Its potency, safety and proven efficacy is worth noting. However, phage therapy still suffers from issues of poor stability, narrow spectrum and poor pharmacokinetic profile. It therefore becomes essential to look into the use of Drug Delivery Systems (DDS) for efficient delivery of lytic phages in vivo. For the first time, the present study has evaluated the use of nano-structured lipid based carriers i.e. Transfersomes as transdermal delivery systems for encapsulating MRSA phage cocktail. Further, therapeutic potential of the encapsulated phage cocktail has been studied in resolving experimental soft tissue infection in rats. Results from in vitro stability as well as in vivo phage titer experiments indicate that transfersome entrapped phage cocktail showed better persistence and stability than free phages. Besides this, rats administered with transfersome entrapped phage cocktail resolved the experimental thigh infection within a period of seven days, unlike the twenty-day time period required for untreated animals. The findings of the present study advocate the use of transferosme as delivery agents for enhancing the stability and in vivo persistence of the encapsulated phages. In addition, this study also highlights the advantage offered by transfersome encapsulated phages in providing better therapeutic option than free phage in treating skin and soft tissue infection. Transfersome entrapped phage cocktail was able to protect all test animals (with no mortality) even when administered at a delay of twelve-hour post infection unlike free phages, thus making this treatment option more suitable in clinical settings.

http://ift.tt/2tUYimp

Co-administration of allopurinol to increase anti-mycobacterial efficacy of pyrazinamide: evaluation in a whole-blood bactericidal activity model [PublishAheadOfPrint]

Co-administering pyrazinamide (PZA) with the xanthine oxidase inhibitor, allopurinol, increases systemic levels of the active metabolite, pyrazinoic acid (POA), but effects on bactericidal activity against tuberculosis are unknown. We randomized healthy volunteers to take a single dose of PZA (either 10mg/kg or 25mg/kg) and the same dose 7 days later co-administered with allopurinol (100mg daily, 2 days before to 1 day after PZA dose). Blood was drawn at intervals to 48 hours after each PZA dose and drug levels were measured using liquid chromatography-tandem mass spectrometry. Whole-blood bactericidal activity (WBA) was measured by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units (CFU) after 72 hours incubation. Allopurinol increased POA AUC (AUC_(0-8) 18.32h*μg/mL versus 24.63h*μg/mL for PZA alone versus PZA+allopurinol respectively; p<0.001) and C_max (2.81μg/mL versus 4.00μg/mL; p<0.001). There was no effect of allopurinol on mean cumulative WBA (0.01±0.02logCFU versus 0.00±0.02logCFU for PZA alone versus PZA+allopurinol respectively; p=0.49). Higher systemic POA levels were associated with greater WBA (p <0.001) but the relationship was evident only at low POA concentrations. The lack of an effect of allopurinol on WBA in spite of a significant increase in blood POA levels suggests that host-generated POA may be less effective than POA generated inside bacteria. Co-administration of allopurinol does not appear to be a useful strategy for increasing efficacy of PZA in clinical practice.

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Protection of hamsters from mortality by reducing fecal moxifloxacin concentration with DAV131A in a model of moxifloxacin-induced Clostridium difficile colitis [PublishAheadOfPrint]

Background

Lowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effect of an activated charcoal-based adsorbent, DAV131A, on fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced C. difficile infection.

Methods

215 hamsters receiving moxifloxacin subcutaneously (D₁-D₅) were orally infected at D₃ with C. difficile spores. They received various doses (0-1800mg/kg/day) and schedules (BID, TID) of DAV131A (D₁-D₈). Moxifloxacin concentration and C. difficile counts were determined at D₃, and mortality at D₁₂. We compared mortality, moxifloxacin concentration and C. difficile counts according to DAV131A regimens, and modelled the link between DAV131A regimen, moxifloxacin concentration and mortality.

Results

All hamsters that received no DAV131A died, but none of those that received 1800mg/kg/day. A significant dose-dependent relationship between DAV131A dose and (i) mortality rates, (ii) moxifloxacin concentration and (iii) C. difficile counts was evidenced. Mathematical modeling suggested that (i) lowering moxifloxacin concentration at D₃, which was 58μg/g (95%CI=50-66) without DAV131A, to 17μg/g (14-21) would reduce mortality by 90% and (ii) this would be achieved with a daily DAV131A dose of 703mg/kg (596-809).

Conclusions

In this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing fecal free moxifloxacin concentration.

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Effect of Rifampin on the Single-Dose Pharmacokinetics of Oral Cabotegravir in Healthy Subjects [PublishAheadOfPrint]

Introduction: Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection.

Methods: This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir. Subjects received a single oral dose of cabotegravir 30 mg on Day 1 followed by plasma sampling on Days 1 to 8. Treatment with once-daily oral rifampin 600 mg occurred on Days 8 to 28. Subjects received a second dose of cabotegravir 30 mg on Day 21 followed by pharmacokinetic sampling on Days 21 to 28.

Results: Fifteen subjects were enrolled and completed the study. Rifampin decreased cabotegravir area under the concentration-time curve over infinite time and half-life by 59% and 57%, respectively, whereas oral clearance was increased by 2.4-fold. The maximum plasma concentration of cabotegravir was unaffected by coadministration with rifampin. All adverse events were mild in severity, with chromaturia attributed to rifampin observed in all subjects.

DISCUSSION: Rifampin induction of cabotegravir metabolism resulted in increased cabotegravir oral clearance and significantly decreased cabotegravir exposures. Rifampin is expected to increase cabotegravir clearance following long-acting injectable administration. Concomitant administration of rifampin with oral and long-acting formulations of cabotegravir is not recommended currently without further study.

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Structural insights into the TLA-3 extended-spectrum {beta}-lactamase and its inhibition by avibactam and OP0595 [PublishAheadOfPrint]

Development of effective inhibitors that block extended-spectrum β-lactamases (ESBLs) and restore the action of β-lactams represents an effective strategy against ESBL-producing Enterobacteriaceae. We evaluated the inhibitory effect of the diazabicyclooctanes avibactam and OP0595 against TLA-3, an ESBL we identified previously. Avibactam and OP0595 inhibited TLA-3 with apparent K_{i app} of 1.71 ± 0.10 and 1.49 ± 0.05 μM, respectively, and could restore susceptibility to cephalosporins in TLA-3-producing Escherichia coli. The acylation rate constant [k₂/K, (3.25 ± 0.03) x 10³ M^-1s^-1] of avibactam was closer to those of class C and D β-lactamases (k₂/K, <10⁴ M^-1s^-1) than those of class A β-lactamases (k₂/K, >10⁴ M^-1s^-1). In addition, we determined the structure of TLA-3, and those of TLA-3 complexed with avibactam or OP0595, at resolutions of 1.6-, 1.6-, and 2.0-Å, respectively. TLA-3 contains an inverted -loop and an extended loop between the β5 and β6 strands (insertion after Ser237), which appear only in PER-type class A β-lactamases. These structures might favor the accommodation of cephalosporins harboring bulky R1 side chains. TLA-3 presented high catalytic efficiency (k_cat/K_m) against cephalosporins, including cephalothin, cefuroxime, and cefotaxime. Avibactam and OP0595 bound covalently to TLA-3 via the Ser70 residue, and made contacts with residues Ser130, Thr235, and Ser237, which are conserved in ESBLs. Additionally, the sulfate group of the inhibitors formed polar contacts with amino acid residues in a positively charged pocket of TLA-3. Our findings provide a structural template for designing improved diazabicyclooctane-based inhibitors that are effective against ESBL-producing Enterobacteriaceae.

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A cationic polymer that shows high antifungal activity against diverse human pathogens [PublishAheadOfPrint]

Invasive fungal diseases are generally difficult to treat and often fatal. The therapeutic agents available to treat fungi are limited, and there is a critical need for new agents to combat these deadly infections. Antifungal compound development has been hindered by the challenge of creating agents that are highly active against fungal pathogens but not toxic to the host. Host-defense peptides (HDPs) are produced by eukaryotes as a component of the innate immune response to pathogens and have served as inspiration for the development of many new antibacterial compounds. HDP mimics, however, have largely failed to exhibit potent and selective antifungal activity. Here, we present an HDP-like nylon-3 copolymer that is effective against diverse fungi while displaying only mild to moderate toxicity toward mammalian cells. This polymer is active on its own and in synergy with existing antifungal drugs against multiple species of Candida and Cryptococcus, reaching levels of efficacy comparable to those of the clinical agents amphotericin B and fluconazole in some cases. In addition, the polymer acts synergistically with azoles against different species of Aspergillus, including some azole-resistant strains. These findings indicate that nylon-3 polymers are a promising lead for development of new antifungal therapeutic strategies.

http://ift.tt/2tF45RT

Spreading Colon Cancer Can Bypass Lymph Nodes [News in Brief]

Many metastases arise from distinct subclones in the primary tumor.

http://ift.tt/2uUagRu

New Biomarker Identified for PDAC [News in Brief]

THBS2 concentration can point to pancreatic ductal adenocarcinoma—and may lead to testing for early-stage disease.

http://ift.tt/2txdqHk

Taking the Guesswork Out of Stopping TKIs [News in Brief]

Oncologists aim to boost success in ending therapy for patients with CML.

http://ift.tt/2uTRJon

EMCrit Wee – An Amazing (Wearable) Cric Trainer from Laura Duggan and the AirwayCollaboration Folks

The new amazing cric trainer

EMCrit by Scott Weingart.

http://ift.tt/2gYbs0Z

Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease

Abstract

Cerebral and systemic organ microvascular pathologies coexist with human Alzheimer's disease (AD) neuropathology. In this study, we hypothesised that both cerebral and systemic microvascular pathologies exist in 4- to 5-month-old male APPswe/PS1dE9 (APP/PS1) transgenic mice prior to the onset of cognitive impairment. To assess this we examined recognition memory in both wild-type and APP/PS1 mice using the object recognition task (ORT; n = 11 per group) and counted thioflavin-S-positive plaques in brain (n = 6 per group). Vascular casts of brain, liver, spleen and kidneys were examined using scanning electron microscopy (n = 6 per group), and the urinary albumin-to-creatinine ratio (uACR; n = 5 per group) was measured as an index of glomerular permeability. Murine recognition memory was intact, as demonstrated by a significant preference for the novel object in the ORT paradigm. Brain sections of wild-type mice were devoid of thioflavin-S positivity, whereas age-matched APP/PS1 mice had an average of 0.88 ± 0.22 thioflavin-S-positive plaques in the cortex, 0.42 ± 0.17 plaques in the dentate gyrus and 0.30 ± 0.07 plaques in the cornus ammonis 1 region. The profiles of casted cerebral capillaries of wild-type mice were smooth and regular in contrast to those of APP/PS1 mice which demonstrate characteristic (0.5–4.6 μm) 'tags'. APP/PS1 mice also had a significantly reduced hepatic vessel number (p = 0.0002) and an increase in the number of splenic microvascular pillars (p = 0.0231), in the absence of changes in either splenic microvascular density (p = 0.3746) or glomerular ultrastructure. The highly significant reduction in uACR in APP/PS1 mice compared to wild-type (p = 0.0079) is consistent with glomerular microvascular dysfunction. These findings highlight early microvascular pathologies in 4- to 5-month-old APP/PS1 transgenic mice and may indicate an amenable target for pharmacological intervention in AD.

http://ift.tt/2uTl2r9

Whole-Genome Sequencing and Concordance Between Antimicrobial Susceptibility Genotypes and Phenotypes of Bacterial Isolates Associated with Bovine Respiratory Disease

Extended laboratory culture and antimicrobial susceptibility testing timelines hinder rapid species identification and susceptibility profiling of bacterial pathogens associated with bovine respiratory disease, the most prevalent cause of cattle mortality in the United States. Whole genome sequencing offers a culture-independent alternative to current bacterial identification methods but requires a library of bacterial reference genomes for comparison. To contribute new bacterial genome assemblies and evaluate genetic diversity and variation in antimicrobial resistance genotypes, whole-genome sequencing was performed on bovine respiratory disease associated bacterial isolates (Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida) from dairy and beef cattle. One hundred genomically distinct assemblies were added to NCBI, doubling the available genomic sequences for these four species. Computer-based methods identified 11 predicted antimicrobial resistance genes in three species, with none being detected in M. bovis. While computer-based analysis can identify antibiotic resistance genes within whole genome sequences (genotype), it may not predict the actual antimicrobial resistance observed in a living organism (phenotype). Antimicrobial susceptibility testing on 64 H. somni, M. haemolytica, and P. multocida isolates had an overall concordance rate between genotype and phenotypic resistance to the associated class of antimicrobials of 72.7% (P < 0.001), showing substantial discordance. Concordance rates varied greatly among different antimicrobial, antibiotic resistance gene, and bacterial species combinations. This suggests that antimicrobial susceptibility phenotypes are needed to complement genomically predicted antibiotic resistance gene genotypes to better understand how the presence of antibiotic resistance genes within a given bacterial species could potentially impact optimal bovine respiratory disease treatment and morbidity/mortality outcomes.

http://ift.tt/2v1UftJ

Evolutionary Dynamics of Male Reproductive Genes inthe Drosophila virilis Subgroup

Postcopulatory sexual selection (PCSS) is a potent evolutionary force that can drive rapid changes of reproductive genes within species, and thus has the potential to generate reproductive incompatibilities between species. Male seminal fluid proteins (SFPs) are major players in postmating interactions, and are important targets of PCSS in males. The virilis subgroup of Drosophila exhibits strong interspecific gametic incompatibilities, and can serve as a model to study the genetic basis of PCSS and gametic isolation. However, reproductive genes in this group have not been characterized. Here we utilize short-read RNA sequencing of male reproductive organs to examine the evolutionary dynamics of reproductive genes in members of the virilis subgroup: D. americana, D. lummei, D. novamexicana, and D. virilis. We find that the majority of male reproductive transcripts are testes-biased, accounting for ~15% of all annotated genes. Ejaculatory bulb-biased transcripts largely code for lipid metabolic enzymes, and contain orthologs of the D. melnaogaster ejaculatory bulb protein, Peb-me, which is involved in mating-plug formation. In addition, we identify 71 candidate SFPs, and show that this gene set has the highest rate of nonsynonymous codon substitution relative to testes- and ejaculatory bulb-biased genes. Furthermore, we identify orthologs of 35 D. melanogaster SFPs that have conserved accessory gland expression in the virilis group. Finally, we show that several of the SFPs that have the highest rate of nonsynonymous codon substitution reside on chromosomal regions which contributes to paternal gametic incompatibility between species. Our results show that SFPs rapidly diversify in the virilis group, and suggest that they likely play a role in PCSS and/or gametic isolation.

http://ift.tt/2vUvKet

Sequence-Based Mapping and Genome Editing Reveal Mutations in Stickleback Hps5 Cause Oculocutaneous Albinism and the casper Phenotype

Here we present and characterize the spontaneous X-linked recessive mutation casper, which causes oculocutaneous albinism in threespine sticklebacks (Gasterosteus aculeatus). In humans, Hermansky-Pudlak syndrome results in pigmentation defects due to disrupted formation of the melanin-containing lysosomal-related organelle (LRO), the melanosome. casper mutants display not only reduced pigmentation of melanosomes in melanophores, but also reductions in the iridescent silver color from iridophores, while the yellow pigmentation from xanthophores appears unaffected. We mapped casper using high-throughput sequencing of genomic DNA from bulked casper mutants to a region of the stickleback X chromosome (chromosome 19) near the stickleback ortholog of Hermansky-Pudlak syndrome 5 (Hps5). casper mutants have an insertion of a single nucleotide in the 6th exon of Hsp5, predicted to generate an early frameshift. Genome editing using CRISPR/Cas9 induced lesions in Hsp5 and phenocopied the casper mutation. Injecting single or paired Hps5 guide RNAs revealed higher incidences of genomic deletions from paired guide RNAs compared to single gRNAs. Stickleback Hps5 provides a genetic system where a hemizygous locus in XY males and a diploid locus in XX females can be used to generate an easily scored visible phenotype, facilitating quantitative studies of different genome editing approaches. Lastly, we show the ability to better visualize patterns of fluorescent transgenic reporters in Hps5 mutant fish. Thus, Hps5 mutations present an opportunity to study pigmented LROs in the emerging stickleback model system, as well as a tool to aid in assaying genome editing and visualizing enhancer activity in transgenic fish.

http://ift.tt/2v1RqZK

A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder

In heterozygous females affected by an X-linked skin disorder, lesions often appear in a characteristic pattern, the so-called Blaschko's lines. We investigated a female Labrador Retriever and her crossbred daughter, which both showed similar clinical lesions that followed Blaschko's lines. The two male littermates of the affected daughter had died at birth suggesting a monogenic X-chromosomal semi-dominant mode of inheritance. Whole genome sequencing of the affected daughter and subsequent automated variant filtering with respect to 188 non-affected control dogs of different breeds revealed 332 heterozygous variants on the X-chromosome private to the affected dog. None of these variants was protein-changing. By visual inspection of candidate genes located on the X-chromosome, we identified a large deletion in the NSDHL gene, encoding NAD(P) dependent steroid dehydrogenase-like, a 3β-hydroxysteroid dehydrogenase involved in cholesterol biosynthesis. The deletion spanned more than 14 kb and included the last three exons of the NSDHL gene. By PCR and fragment length analysis, we confirmed the presence of the variant in both affected dogs, and its absence in 50 control Labrador Retrievers. Variants in the NSDHL gene cause CHILD syndrome in humans and the bare patches (Bpa) and striated (Str) phenotypes in mice. Taken together, our genetic data and the known role of NSDHL in X-linked skin disorders strongly suggest that the identified structural variant in the NSDHL gene is causative for the phenotype in the two affected dogs.

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Charting the Future of Cancer Health Disparities Research: A Position Statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute

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Influence of commercial inactivated yeast derivatives on the survival of probiotic bacterium Lactobacillus rhamnosus HN001 in an acidic environment

This study evaluated the influence of three inactivated yeast derivatives (IYDs) used in wine production, namely OptiRed®, OptiWhite® and Noblesse®, on the viability of the probiotic strain Lactobacillus rhamnosu...

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Ethanol Extract of Mylabris phalerata Inhibits M2 Polarization Induced by Recombinant IL-4 and IL-13 in Murine Macrophages

Mylabris phalerata (MP) is an insect used in oriental herbal treatments for tumor, tinea infections, and stroke. Recent studies have shown that tumor-associated macrophages (TAM) have detrimental roles such as tumor progression, angiogenesis, and metastasis. Although TAM has phenotypes and characteristics in common with M2-polarized macrophages, M1 macrophages have tumor suppression and immune stimulation effects. Medicines polarizing macrophages to M1 have been suggested to have anticancer effects via the modulation of the tumor microenvironment. In this line, we screened oriental medicines to find M1 polarizing medicines in M2-polarized macrophages. Among approximately 400 types of oriental medicine, the ethanol extract of M. phalerata (EMP) was the most proficient in increasing TNF-α secretion in M2-polarized macrophages and TAM. Although EMP enhanced the levels of an M1 cytokine (TNF-α) and a marker (CD86), it significantly reduced the levels of an M2 marker (arginase-1) in M2-polarized macrophages. In addition, EMP-treated macrophages increased the levels of M1 markers (Inos and Tnf-α) and reduced those of the enhanced M2 markers (Fizz-1, Ym-1, and arginase-1). EMP-treated macrophages significantly reduced Lewis lung carcinoma cell migration in a transwell migration assay and inhibited EL4-luc2 lymphoma proliferation. In our mechanism study, EMP was found to inhibit STAT3 phosphorylation in M2-polarized macrophages. These results suggest that EMP is effective in treating TAM-mediated tumor progression and metastasis.

http://ift.tt/2v1jBYw

Spinal Cord Injury due to Tumour or Metastasis in Aragón, Northeastern Spain (1991–2008): Incidence, Time Trends, and Neurological Function

Purpose. Understanding the presentation of spinal cord injury (SCI) due to tumours considering population distribution and temporal trends is key to managing SCI health services. This study quantified incidence rates, function scores, and trends of SCI due to tumour or metastasis over an 18-year time period in a defined region in Spain. Methods. A retrospective cohort study included in-and outpatients with nontraumatic SCI due to tumour or metastasis admitted to a metropolitan hospital in Spain between 1991 and 2008. Main outcome measures were crude and age- and sex-adjusted incidence rates, tumour location and type, distribution by spinal level, neurological level of injury, and impairment ASIA scores. Results. Primary tumour or metastasis accounted for 32.5% of nontraumatic SCI with an incidence rate of 4.1 per million population. Increasing rates with age and over time were observed. Major pathology groups were intradural-extramedullary masses from which meningiomas and neurinomas accounted for 40%. Lesions were mostly incomplete with predominant ASIA Grade D. Conclusions. Increasing incidence rates of tumour-related SCI over time in the middle-aged and the elderly suggest a growing need for neurooncology health resources in the future.

http://ift.tt/2gXWHLy

Use of a Polyethylene Bag to Reduce Perioperative Regional and Whole-Body Heat Losses in Low-Birth-Weight Neonates

In the delivery room, wrapping a low-birth-weight neonate (defined as ≤2.499 g) in a polyethylene bag reduces the risk of hypothermia. However, extended use of the bag (e.g., during neonatal surgery) might conceivably increase the risk of thermal stress and thus body overheating. Here, we assessed the efficacy of a polyethylene bag in infants assigned to wrap (W) or nonwrap (NW, control) groups during placement of a percutaneous vena cava catheter by applying a new mathematical model that calculates heat exchanges for covered and uncovered body segments. At the end of the placement procedure, the W and NW groups did not differ significantly in terms of whole-body heat loss (15.80 versus 14.97 kJ·h−1·kg−1, resp.), whereas the abdominal skin temperature was slightly but significantly higher (by 0.32°C) in the W group. Greater evaporation in the W group (2.49 kJ·h−1·kg−1) was primarily balanced by greater whole-body radiant heat loss (3.44 kJ·h−1·kg−1). Wrapping the neonate in a polyethylene bag provides a small thermal benefit when catheter placement takes a long time. Given that polyethylene is transparent to radiant energy, it might be of value to incorporate polymers that are less transparent at infrared wavelengths.

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Evidence of Immunosuppressive and Th2 Immune Polarizing Effects of Antidiabetic Momordica charantia Fruit Juice

The mechanism of action of the antidiabetic capacity of Momordica charantia is still under investigation. Here, we assessed phytochemical compositions, antioxidant activity, and effects of total and filtered fruit and leafy stem juices of Momordica charantia on human T cell proliferation and differentiation through quantification of Th1/Th2 cytokines. In the absence of stimulation, total fruit and leafy stem juices induced significant T cell proliferation. Under PHA stimulation, both juices potentiated plant-induced T cell proliferation. However, the filtered fruit and leafy stem juices significantly inhibited PHA-stimulated T cell proliferation, while neither juice influenced T cell proliferation. Moreover, total and filtered fruit juice increased IL-4 secretion, while total and filtered leafy stem juice enhanced IFN-γ production. Phytochemical screening revealed the presence of tannins, flavonoids, anthocyans, steroids, and triterpenoids in both juices. Alkaloids, quinone derivatives, cardenolides, and cyanogenic derivatives were undetectable. The saponins present in total juices were undetectable after filtration. Moreover, both juices had appreciable antioxidant capacity. Our study supports the type 1 antidiabetic effect of filtered fruit juice of M. charantia which may be related to its immunosuppressive and T-helper 2 cell inducing capacities. Due to their immune-stimulatory activities and their ability to increase T-helper 1 cell cytokines, total fruit and leafy stem juices may serve in the treatment of immunodeficiency and certain infections.

http://ift.tt/2vUozTi

Can procalcitonin be used to diagnose Gram-negative bloodstream infection? Evidence based on a meta-analysis

OBJECTIVE: Procalcitonin (PCT) is a useful biomarker for systemic bacterial infection, and many studies have described the correlation between high serum PCT level and Gram-negative bloodstream infection (BSI), whereas the diagnostic accuracy of PCT for this kind of episode has not been summarized. This study aimed to estimate the overall accuracy of serum PCT for diagnosing Gram-negative BSI through a meta-analysis.

MATERIALS AND METHODS: We searched PubMed, EMBASE, Web of Science, and Scopus database for studies that met the inclusion criteria. The pooled sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were calculated using bivariate random-effects models. Summary receiver operating characteristic (SROC) curve and area under the curve (AUC) were used to summarize overall diagnostic accuracy.

RESULTS: Our meta-analysis included 13 studies involving 4,513 subjects. Summary estimates for PCT in diagnosing Gram-negative BSI were as follows: sensitivity, 0.73 (95% CI 0.68 to 0.78); specificity, 0.74 (95% CI 0.64 to 0.81); PLR, 2.77 (95% CI 2.07 to 3.70); NLR, 0.37 (95% CI 0.31 to 0.42); DOR, 7.59 (95% CI 5.31 to 10.85); AUC, 0.79 (95% CI 0.75 to 0.82). The corresponding summary performance estimates for using PCT in differentiating Gram-negative BSI from gram-positive BSI were as follows: sensitivity, 0.73 (95% CI 0.66 to 0.78); specificity, 0.70 (95% CI 0.59 to 0.78); PLR, 2.40 (95% CI, 1.83 to 3.15); NLR, 0.39 (95% CI 0.33 to 0.46); DOR, 6.15 (95% CI 4.40 to 8.60); AUC, 0.77 (95% CI 0.73 to 0.81).

CONCLUSIONS: PCT may have a limited diagnostic value for Gram-negative BSI.

L'articolo Can procalcitonin be used to diagnose Gram-negative bloodstream infection? Evidence based on a meta-analysis sembra essere il primo su European Review.

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The role of mitochondrial DNA mutations in a Han Chinese population on sepsis pathogenesis

OBJECTIVE: Individual susceptibility to sepsis has received increasing attention in recent years, and the study of genetic variations has become a hotspot regarding sepsis pathogenesis. We, therefore, investigated the association between mitochondrial genotype and sepsis susceptibility.

PATIENTS AND METHODS: One hundred patients admitted with sepsis and registered by five intensive care units (ICUs) in the People's Liberation Army Hospital and the Beijing Aerospace Center Hospital between January 2015 and January 2016 were enrolled as a case group, and 100 healthy persons were recruited as a control group. Patients' general information was obtained, and clinical evaluations and mitochondrial sequence screening were performed.

RESULTS: A total of 718 single nucleotide polymorphisms (SNPs) were detected in 708 loci in 100 patients. There were 1754 mutations in 456 loci in the coding region and 567 mutations were found in the RNA region. A total of 34 loci (from 40 cases) were novel mutations. A10398G (52.52%), C5178A (24.24%), C150T (17.17%), G3010A (17.17%), and T16189C (16.16%) were the most frequently observed conserved non-synonymous mutations that were differently expressed between the case and control groups (p<0.05). A5863T and C3270 deletion mutations were located on the genes encoding tRNATyr and tRNALeu, respectively. Small changes in the tRNA gene were likely to result in protein level changes.

CONCLUSIONS: We suggest that mitochondrial SNPs may be associated with the pathogenesis of sepsis.

L'articolo The role of mitochondrial DNA mutations in a Han Chinese population on sepsis pathogenesis sembra essere il primo su European Review.

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Leisure Time Physical Activity in Young Adults Born Preterm

To evaluate the amount of self-reported physical activity in young adults born prematurely compared with those born at term.

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Down Syndrome and Pediatric Nonalcoholic Fatty Liver Disease: A Causal or Casual Relationship?

The incidence of overweight/obesity in patients with Down syndrome is high. In a recent systemic review, Down syndrome was associated with varying prevalence rates of obesity (23%-70%).1 Likely determinants of obesity, in addition to short stature, were an increase in circulating leptin (a marker of leptin resistance), reduced adiponectin expression, adherence to an unfavorable diet, presence of comorbidities, gait disorder, and decreased resting energy expenditure with low levels of fitness and physical activity.

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Caregiver-Reported Quality of Life in Youth with Down Syndrome

To describe caregiver-reported quality of life (QOL) in youth with Down syndrome (DS) and to examine the role of obesity on QOL.

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Awards, Scholarships, and Grants Awarded at the SICB Meeting in January 2017

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Erratum

Integrative and Comparative Biology 56(6); doi:10.1093/icb/icw023.

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Broadening Participation in the Society for Integrative and Comparative Biology

Synopsis

The goal of the Society for Integrative and Comparative Biology's Broadening Participation Committee (SICB BPC) is to increase the number of underrepresented group (URG) members within the society and to expand their capabilities as future researchers and leaders within SICB. Our short-term 10-year goal was to increase the recruitment and retention of URG members in the society by 10%. Our long-term 25-year goal is to increase the membership of URG in the society through recruitment and retention until the membership demographic mirrors that of the US Census. Our plans to accomplish this included establishment of a formal standing committee, establishment of a moderate budget to support BPC activities, hosting professional development workshops, hosting diversity and mentor socials, and obtaining grant funds to supplement our budget. This paper documents broadening participation activities in the society, discusses the effectiveness of these activities, and evaluates BPC goals after 5 years of targeted funded activities. Over the past 5 years, the number of URG members rose by 5.2% to a total of 16.2%, members who report ethnicity and gender increased by 25.2% and 18%, respectively, and the number of members attending BPC activities has increased to 33% by 2016. SICB has made significant advances in broadening participation, not only through increased expenditures, but also with a commitment by its members and leadership to increase diversity. Most members realize that increasing diversity will both improve the Society's ability to develop different approaches to tackling problems within integrative biology, and help solve larger global issues that are evident throughout science and technology fields. In addition, having URG members as part of the executive committee would provide other URG members role models within the society, as well as have a voice in the leadership that represents diversity and inclusion for all scientists.

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Erratum

Integrative and Comparative Biology 56(6); doi:10.1093/icb/icw083.

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Erratum

Integrative and Comparative Biology, 54(6):1084–98; doi:10.1093/icb/icu033

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Announcement of New Members 2017

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Erratum

Integrative and Comparative Biology; doi:10.1093/icb/icw127

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Predation in High CO 2 Waters: Prey Fish from High-Risk Environments are Less Susceptible to Ocean Acidification

Synopsis

Most studies investigating the effects of anthropogenic environmental stressors do so in conditions that are often optimal for their test subjects, ignoring natural stressors such as competition or predation. As such, the quantitative results from such studies may often underestimate the lethality of certain toxic compounds. A well-known example of this concept is illustrated by the marked increase in the lethality of pesticides when larval amphibians are concurrently exposed to the odor of potential predators. Here, we investigated the interaction between background levels of environmental predation risk (high vs. low) and ocean acidification (ambient vs. elevated CO₂) in 2 × 2 design. Wild-caught juvenile damselfish, Pomacentrus amboinensis, were exposed in the laboratory to the different risk and CO₂ conditions for 4 days and released onto coral reef patches. Using a well-established field assay, we monitored the in situ behavior and mortality of the damselfish for 2 days. We predicted that juvenile fish exposed to elevated CO₂ and high-risk conditions would display more severe behavioral impairments and increased mortality compared to fish exposed to elevated CO₂ maintained under low-risk conditions. As expected, elevated CO₂ exposure led to impaired antipredator responses and increased mortality in low-risk fish compared to ambient CO₂ controls. However, we failed to find an effect of elevated CO₂ on the behavior and survival of the high-risk fish. We hypothesized that the results may stem from either a behavioral compensation or a physiological response to high risk. Our results provide insights into the interactive nature of environmental and natural stressors and advance our understanding of the predicted effect of ocean acidification on aquatic ecosystems.

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Data Management Rubric for Video Data in Organismal Biology

Synopsis

Standards-based data management facilitates data preservation, discoverability, and access for effective data reuse within research groups and across communities of researchers. Data sharing requires community consensus on standards for data management, such as storage and formats for digital data preservation, metadata (i.e., contextual data about the data) that should be recorded and stored, and data access. Video imaging is a valuable tool for measuring time-varying phenotypes in organismal biology, with particular application for research in functional morphology, comparative biomechanics, and animal behavior. The raw data are the videos, but videos alone are not sufficient for scientific analysis. Nearly endless videos of animals can be found on YouTube and elsewhere on the web, but these videos have little value for scientific analysis because essential metadata such as true frame rate, spatial calibration, genus and species, weight, age, etc. of organisms, are generally unknown. We have embarked on a project to build community consensus on video data management and metadata standards for organismal biology research. We collected input from colleagues at early stages, organized an open workshop, "Establishing Standards for Video Data Management," at the Society for Integrative and Comparative Biology meeting in January 2017, and then collected two more rounds of input on revised versions of the standards. The result we present here is a rubric consisting of nine standards for video data management, with three levels within each standard: good, better, and best practices. The nine standards are: (1) data storage; (2) video file formats; (3) metadata linkage; (4) video data and metadata access; (5) contact information and acceptable use; (6) camera settings; (7) organism(s); (8) recording conditions; and (9) subject matter/topic. The first four standards address data preservation and interoperability for sharing, whereas standards 5–9 establish minimum metadata standards for organismal biology video, and suggest additional metadata that may be useful for some studies. This rubric was developed with substantial input from researchers and students, but still should be viewed as a living document that should be further refined and updated as technology and research practices change. The audience for these standards includes researchers, journals, and granting agencies, and also the developers and curators of databases that may contribute to video data sharing efforts. We offer this project as an example of building community consensus for data management, preservation, and sharing standards, which may be useful for future efforts by the organismal biology research community.

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Species as Stressors: Heterospecific Interactions and the Cellular Stress Response under Global Change

Synopsis

Anthropogenic global change is predicted to increase the physiological stress of organisms through changes in abiotic conditions such as temperature, pH, and pollution. However, organisms can also experience physiological stress through interactions with other species, especially parasites, predators, and competitors. The stress of species interactions could be an important driver of species' responses to global change as the composition of biological communities change through factors such as distributional and phenological shifts. Interactions between biotic and abiotic stressors could also induce non-linear physiological stress responses under global change. One of the primary means by which organisms deal with physiological stress is through the cellular stress response (CSR), which is broadly the upregulation of a conserved set of genes that facilitate the removal and repair of damaged macromolecules. Here, we present data on behavioral interactions and CSR gene expression for two competing species of intertidal zone porcelain crab (Petrolisthes cinctipes and Petrolisthes manimaculis). We found that P. cinctipes and P. manimaculis engage in more agonistic behaviors when interacting with heterospecifics than conspecifics; however, we found no evidence that heterospecific interactions induced a CSR in these species. In addition to our new data, we review the literature with respect to CSR induction via species interactions, focusing on predator–prey systems and heterospecific competition. We find extensive evidence for predators to induce cellular stress and aspects of the CSR in prey, even in the absence of direct physical contact between species. Effects of heterospecific competition on the CSR have been studied far less, but we do find evidence that agonistic interactions with heterospecifics can induce components of the CSR. Across all published studies, there is clear evidence that species interactions can lead to cellular stress and induction of the CSR. Nonetheless, our understanding of species-induced cellular stress lags far behind our understanding of abiotic cellular stress.

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Indirect Effects of Global Change: From Physiological and Behavioral Mechanisms to Ecological Consequences

Synopsis

A major focus of current ecological research is to understand how global change makes species vulnerable to extirpation. To date, mechanistic ecophysiological analyses of global change vulnerability have focused primarily on the direct effects of changing abiotic conditions on whole-organism physiological traits, such as metabolic rate, locomotor performance, cardiac function, and critical thermal limits. However, species do not live in isolation within their physical environments, and direct effects of climate change are likely to be compounded by indirect effects that result from altered interactions with other species, such as competitors and predators. The Society for Integrative and Comparative Biology 2017 Symposium "Indirect Effects of Global Change: From Physiological and Behavioral Mechanisms to Ecological Consequences" was designed to synthesize multiple approaches to investigating the indirect effects of global change by bringing together researchers that study the indirect effects of global change from multiple perspectives across habitat, type of anthropogenic change, and level of biological organization. Our goal in bringing together researchers from different backgrounds was to foster cross-disciplinary insights into the mechanistic bases and higher-order ecological consequences of indirect effects of global change, and to promote collaboration among fields.

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Searching for Biotic Multipliers of Climate Change

Synopsis

As climates change, biologists need to prioritize which species to understand, predict, and protect. One way is to identify key species that are both sensitive to climate change and that disproportionately affect communities and ecosystems. These "biotic multipliers" provide efficient targets for research and conservation. Here, we propose eight mechanistic hypotheses related to impact and sensitivity that suggest that top consumers might often act as biotic multipliers of climate change. For impact, top consumers often affect communities and ecosystems through strong top-down effects. For sensitivity, metabolic theory and data suggest that photosynthesis and respiration differ in temperature responses, potentially increasing the sensitivity of consumers relative to plants. Larger-bodied organisms are typically more thermally sensitive than smaller ones, suggesting how large top consumers might be more sensitive than their smaller prey. In addition, traits related to predation are more sensitive than defensive traits to temperature. Top consumers might also be more sensitive because they often lag behind prey in phenological responses. The combination of low population sizes and demographic traits of top consumers could make them more sensitive to disturbances like climate change, which could slow their recovery. As top consumers are positioned at the top of the food chain, many small effects can accumulate from other trophic levels to affect top consumers. Finally, top consumers also often disperse more frequently and farther than prey, potentially leading to greater sensitivity to climate-induced changes in ranges and subsequent impacts on invaded communities. Overall, we expect that large, ectothermic top consumers and mobile predators might frequently be biotic multipliers of climate change. However, this prediction depends on the particular features of species, habitats, and ecosystems. In specific cases, herbivores, plants, or pathogens might be more sensitive than top consumers or have greater community impacts. To predict biotic multipliers, we need to compare sensitivities and impacts across trophic groups in a broader range of ecosystems as well as perform experiments that uncouple proposed mechanisms. Overall, the biotic multiplier concept offers an alternative prioritization scheme for research and conservation that includes impacts on communities and ecosystems.

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Incorporating Context Dependency of Species Interactions in Species Distribution Models

Synopsis

Species distribution models typically use correlative approaches that characterize the species–environment relationship using occurrence or abundance data for a single species. However, species distributions are determined by both abiotic conditions and biotic interactions with other species in the community. Therefore, climate change is expected to impact species through direct effects on their physiology and indirect effects propagated through their resources, predators, competitors, or mutualists. Furthermore, the sign and strength of species interactions can change according to abiotic conditions, resulting in context-dependent species interactions that may change across space or with climate change. Here, we incorporated the context dependency of species interactions into a dynamic species distribution model. We developed a multi-species model that uses a time-series of observational survey data to evaluate how abiotic conditions and species interactions affect the dynamics of three rocky intertidal species. The model further distinguishes between the direct effects of abiotic conditions on abundance and the indirect effects propagated through interactions with other species. We apply the model to keystone predation by the sea star Pisaster ochraceus on the mussel Mytilus californianus and the barnacle Balanus glandula in the rocky intertidal zone of the Pacific coast, USA. Our method indicated that biotic interactions between P. ochraceus and B. glandula affected B. glandula dynamics across >1000 km of coastline. Consistent with patterns from keystone predation, the growth rate of B. glandula varied according to the abundance of P. ochraceus in the previous year. The data and the model did not indicate that the strength of keystone predation by P. ochraceus varied with a mean annual upwelling index. Balanus glandula cover increased following years with high phytoplankton abundance measured as mean annual chlorophyll-a. M. californianus exhibited the same pattern to a lesser degree, although this pattern was not significant. This work bridges the disciplines of biogeography and community ecology to develop tools to better understand the direct and indirect effects of abiotic conditions on ecological communities.

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Scaling from Metabolism to Population Growth Rate to Understand How Acclimation Temperature Alters Thermal Performance

Synopsis

The mean and variance of environmental temperature are changing as a consequence of human activities. Ectotherms are sensitive to these temperature changes in the short term, typically displaying a unimodal response of most biological rates to temperature (thermal performance curves; TPCs). Many organisms, however, may acclimate or evolve in response to new temperature regimes. In particular, population growth rate TPCs (r TPCs) reflect the ability to maintain positive growth under a range of temperatures, and therefore shifts in r TPCs due to acclimation are fundamental to our understanding of how ectotherms will respond to changes in climate. Here, we derive a model for r TPCs rooted in temperature dependent metabolic rate (through enzyme kinetics and activity). We then use this model to interpret the effects of acclimation to different temperatures on r TPCs of the protist Paramecium bursaria. Intermediate acclimation temperatures generally resulted in higher upper critical thermal limits, thermal optima, maximum population growth rate, and the area under the TPC. Lower critical thermal limits increased linearly with acclimation temperature, causing a decrease in thermal breadth with increased acclimation temperature. Thus, rather than showing improved performance at the acclimation temperature, P. bursaria appeared to pay a price at all temperatures for acclimating to higher temperatures. The fits of our data to our model also suggest that changes in the structure and function of metabolic enzymes may underlie the changes in the TPCs. Specifically, our results suggest that both the delta heat capacity and delta enthalpy of formation of metabolic enzymes may have increased with acclimation. Since these two factors are correlated across acclimation temperatures, our data also suggest potential trade-offs that may constrain changes in TPCs.

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Predicting Indirect Effects of Predator–Prey Interactions

Synopsis

Predicting the effects of climate change on species and communities remains a pre-eminent challenge for biologists. Critical among this is understanding the indirect effects of climate change, which arise when the direct, physiological effects of climate on one species change the outcome of its interaction with a second species, altering the success of the second species. A diverse array of approaches to predicting indirect effects exists from mechanistic models, which attempt to build-up from physiological changes to ecological consequences, to ecological models that focus solely on the ecological scale. Here I review studies of the indirect effects of temperature on two predator–prey systems in rocky intertidal habitats. Laboratory and field studies have shown that temperature can indirectly affect interactions through both physiological and behavioral changes in predator and prey, but no model yet captures the full range of these effects. The three main categories of changes are metabolic rate effects, stress effects, and behavioral avoidance. Mechanistic models best capture the first two of these three dynamics, while ecological models have focused mainly on the last two. The challenge remains to correctly identify a species' vulnerability to climate change, which differs from its physiological sensitivity. The best approach may be to use detailed physiological-scale studies of indirect effect in a few systems to ground truth simpler models that can be applied more broadly. Model development and testing is also hampered by the small number of field studies of indirect effects in natural systems, particularly studies that examine natural temporal or spatial variation in climate.

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Glowing Worms: Biological, Chemical, and Functional Diversity of Bioluminescent Annelids

Abstract

Bioluminescence, the ability to produce light by living organisms, has evolved independently in numerous lineages across the tree of life. Luminous forms are found in a wide range of taxonomic groups from bacteria to vertebrates, although the great majority of bioluminescent organisms are marine taxa. Within the phylum Annelida, bioluminescence is widespread, present in at least 98 terrestrial and marine species that represent 45 genera distributed in thirteen lineages of clitellates and polychaetes. The ecological diversity of luminous annelids is unparalleled, with species occupying a great variety of habitats including both terrestrial and marine ecosystems, from coastal waters to the deep-sea, in benthic and pelagic habitats from polar to tropical regions. This great taxonomic and ecological diversity is matched by the wide array of bioluminescent colors—including yellow light, which is very rare among marine taxa—different emission wavelengths even between species of the same genus, and varying patterns, chemical reactions and kinetics. This diversity of bioluminescence colors and patterns suggests that light production in annelids might be involved in a variety of different functions, including defensive mechanisms like sacrificial lures or aposematic signals, and intraspecific communication systems. In this review, we explore the world of luminous annelids, particularly focusing on the current knowledge regarding their taxonomic and ecological diversity and discussing the putative functions and chemistries of their bioluminescent systems.

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Impacts of Ocean Acidification on Sensory Function in Marine Organisms

Synopsis

Ocean acidification has been identified as a major contributor to ocean ecosystem decline, impacting the calcification, survival, and behavior of marine organisms. Numerous studies have observed altered sensory perception of chemical, auditory, and visual cues after exposure to elevated CO₂. Sensory systems enable the observation of the external environment and therefore play a critical role in survival, communication, and behavior of marine organisms. This review seeks to (1) summarize the current knowledge of sensory impairment caused by ocean acidification, (2) discuss potential mechanisms behind this disruption, and (3) analyze the expected taxa differences in sensitivities to elevated CO₂ conditions. Although a lack of standardized methodology makes cross-study comparisons challenging, trends and biases arise from this synthesis including a substantial focus on vertebrates, larvae or juveniles, the reef ecosystem, and chemosensory perception. Future studies must broaden the scope of the field by diversifying the taxa and ecosystems studied, incorporating ontogenetic comparisons, and focusing on cryptic sensory systems such as electroreception, magnetic sense, and the lateral line system. A discussion of possible mechanisms reveals GABA_A receptor reversal as the conspicuous physiological mechanism. However, the potential remains for alternative disruption through structure or cue changes. Finally, a taxonomic comparison of physiological complexity reveals few trends in sensory sensitivities to lowered pH, but we hypothesize potential correlations relating to habitat, life history or relative use of sensory systems. Elevated CO₂, in concordance with other global and local stressors, has the potential to drastically shift community composition and structure. Therefore research addressing the extent of sensory impairment, the underlying mechanisms, and the differences between taxa is vital for improved predictions of organismal response to ocean acidification.

http://ift.tt/2urpahE

Role of CD4 T cell helper subsets in immune response and deviation of CD8 T cells in mice

The ability of different CD4⁺ T cell subsets to help CD8⁺ T-cell response is not fully understood. Here, we found using the murine system that Th17 cells induced by IL-1β, unlike Th1, were not effective helpers for antiviral CD8 responses as measured by IFNγ-producing cells or protection against virus infection. However, they skewed CD8 responses to a Tc17 phenotype. Thus, the apparent lack of help was actually immune deviation. This skewing depended on both IL-21 and IL-23. To overcome this effect, we inhibited Th17 induction by blocking TGF-β. Anti-TGF-β allowed the IL-1β adjuvant to enhance CD8⁺ T-cell responses without skewing the phenotype to Tc17, thereby providing an approach to harness the benefit of common IL-1-inducing adjuvants like alum without immune deviation.

This article is protected by copyright. All rights reserved

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High Risk, Low Frequency: Optimizing Performance of Emergency Intubation for Children

SEE RELATED ARTICLE, P. ■■■.

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The Effect of Medicaid Expansion on Utilization in Maryland Emergency Departments

A proposed benefit of expanding Medicaid eligibility under the Patient Protection and Affordable Care Act (ACA) was a reduction in emergency department (ED) utilization for primary care needs. Pre-ACA studies found that new Medicaid enrollees increased their ED utilization rates, but the effect on system-level ED visits was less clear. Our objective was to estimate the effect of Medicaid expansion on aggregate and individual-based ED utilization patterns within Maryland.

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EUS-guided gastroenterostomy: a multicenter study comparing the direct and balloon-assisted techniques

Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a developing modality in the management of gastric outlet obstruction (GOO) with several technical approaches including the direct and balloon-assisted techniques. The aim of this study is to compare the direct with the balloon-assisted modality while further defining the role of EUS-GE in GOO.

http://ift.tt/2vUdZvD

Impact of Mucosal Inflammation on Risk of Colorectal Neoplasia in Patients with Ulcerative Colitis: A Systematic Review and Meta-Analysis

Long-standing ulcerative colitis is an established risk factor for colorectal neoplasia. A number of observational studies have suggested that evidence of mucosal inflammation (endoscopic or histologic) is associated with a greater risk for colorectal neoplasia than is mucosal healing. Our goal was to systematically analyze the risk of colorectal neoplasia in ulcerative colitis patients with ongoing mucosal inflammation to better inform surveillance strategies.

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Electroacupuncture-reduced sedative and analgesic requirements for diagnostic EUS: a prospective, randomized, double-blinded, sham-controlled study

The role of electroacupuncture (EA) in reducing sedative and analgesic requirements during EUS is uncertain. The aim of the current study is to investigate the efficacy of EA in reducing procedure-related pain and discomfort during EUS.

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Endoscopic treatment of fistulas after sleeve gastrectomy: a comparison of internal drainage versus closure

Post-sleeve gastrectomy fistulas (PSGF) are major adverse events of bariatric surgery. The endoscopic management strategy evolved from closure to internal drainage (ID) after 2013. The main objective was to evaluate and compare these different approaches.

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Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia

Abstract

Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive effects; however, there is limited understanding of its mechanism. This was a double-blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n-back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The 'real' and 'sham' groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post-transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post-stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task-related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro-cognitive effects in schizophrenia.

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