Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Challenges of Loss to Follow-up in Tuberculosis Research.

In studies evaluating methods for diagnosing tuberculosis (TB), follow-up to verify the presence or absence of active TB is crucial and high dropout rates may significantly affect the validity of the results. In a study assessing the diagnostic performance of the QuantiFERON®-TB Gold In-Tube test in TB suspect children in Tanzania, factors influencing patient adherence to attend follow-up examinations and reasons for not attending were examined. In 160 children who attended and 102 children who did not attend scheduled 2-month follow-up baseline health characteristics, demographic data and risk factors for not attending follow-up were determined. Qualitative interviews were used to understand patient and caretakers reasons for not returning for scheduled follow-up. Being treated for active tb in the dots program (OR: 4.14; 95% CI:1.99-8.62;p-value<0.001) and receiving money for the bus fare (OR:129; 95% CI 16->100;P-value<0.001) were positive predictors for attending follow-up at 2 months, and 21/85(25%) of children not attending scheduled follow-up had died. Interviews revealed that limited financial resources, i.e. lack of money for transportation and poor communication, were related to non-adherence. Patients lost to follow-up is a potential problem for TB research. Receiving money for transportation to the hospital and communication is crucial for adherence to follow-up conducted at a study facility. Strategies to ensure follow-up should be part of any study protocol

Solving parabolic equations on the unit sphere via Laplace transforms and radial basis functions

We propose a method to construct numerical solutions of parabolic equations on the unit sphere. The time discretization uses Laplace transforms and quadrature. The spatial approximation of the solution employs radial basis functions restricted to the sphere. The method allows us to construct high accuracy numerical solutions in parallel. We establish $L_2$ error estimates for smooth and nonsmooth initial data, and describe some numerical experiments.Comment: 26 pages, 1 figur

Surface and Temporal Biosignatures

Recent discoveries of potentially habitable exoplanets have ignited the prospect of spectroscopic investigations of exoplanet surfaces and atmospheres for signs of life. This chapter provides an overview of potential surface and temporal exoplanet biosignatures, reviewing Earth analogues and proposed applications based on observations and models. The vegetation red-edge (VRE) remains the most well-studied surface biosignature. Extensions of the VRE, spectral "edges" produced in part by photosynthetic or nonphotosynthetic pigments, may likewise present potential evidence of life. Polarization signatures have the capacity to discriminate between biotic and abiotic "edge" features in the face of false positives from band-gap generating material. Temporal biosignatures -- modulations in measurable quantities such as gas abundances (e.g., CO2), surface features, or emission of light (e.g., fluorescence, bioluminescence) that can be directly linked to the actions of a biosphere -- are in general less well studied than surface or gaseous biosignatures. However, remote observations of Earth's biosphere nonetheless provide proofs of concept for these techniques and are reviewed here. Surface and temporal biosignatures provide complementary information to gaseous biosignatures, and while likely more challenging to observe, would contribute information inaccessible from study of the time-averaged atmospheric composition alone.Comment: 26 pages, 9 figures, review to appear in Handbook of Exoplanets. Fixed figure conversion error

Response to gefitinib and erlotinib in Non-small cell lung cancer: a retrospective study

<p>Abstract</p> <p>Background</p> <p>In Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype. Two tyrosine kinase inhibitors (TKIs) of EGFR, gefinitib and erlotinib, have been used with variable benefit.</p> <p>Methods</p> <p>We have analyzed outcome data of a population of NSCLC patients that received these TKIs to determine the benefit derived and to define the clinical and molecular parameters that correlate with response. Tumor tissue from a subgroup of these patients was analyzed by immunohistochemistry to measure the expression level of EGFR and four activated (phosphorylated) members of the pathway, pEGFR, pERK, pAKT, and pSTAT3.</p> <p>Results</p> <p>Erlotinib was slightly superior to gefitinib in all measures of response, although the differences were not statistically significant. The most robust clinical predictors of time to progression (TTP) were best response and rash (p < 0.0001). A higher level of pEGFR was associated with longer TTP, while the total EGFR level was not associated with response. Higher levels of pAKT and pSTAT3 were also associated with longer TTP. In contrast, a higher level of pERK1/2 was associated with shorter TTP.</p> <p>Conclusion</p> <p>These observations suggest the hypothesis that tumor cells that have activated EGFR pathways, presumably being utilized for survival, are clinically relevant targets for pathway inhibition. An accurate molecular predictive model of TKI response should include activated members of the EGFR pathway. TKIs may be best reserved for tumors expressing pEGFR and pAKT or pSTAT, and little pERK. In the absence of molecular predictors of response, the appearance of a rash and a positive first scan are good clinical indicators of response.</p

Vision in high-level football officials

YesOfficiating in football depends, at least to some extent, upon adequate visual function. However, there is no vision standard for football officiating and the nature of the relationship between officiating performance and level of vision is unknown. As a first step in characterising this relationship, we report on the clinically-measured vision and on the perceived level of vision in elite-level, Portuguese football officials. Seventy-one referees (R) and assistant referees (AR) participated in the study, representing 92% of the total population of elite level football officials in Portugal in the 2013/2014 season. Nine of the 22 Rs (40.9%) and ten of the 49 ARs (20.4%) were international-level. Information about visual history was also gathered. Perceived vision was assessed using the preference-values-assigned-to-global-visual-status (PVVS) and the Quality-of-Vision (QoV) questionnaire. Standard clinical vision measures (including visual acuity, contrast sensitivity and stereopsis) were gathered in a subset (n = 44, 62%) of the participants. Data were analysed according to the type (R/AR) and level (international/national) of official, and Bonferroni corrections were applied to reduce the risk of type I errors. Adopting criterion for statistical significance of p<0.01, PVVS scores did not differ between R and AR (p = 0.88), or between national- and international-level officials (p = 0.66). Similarly, QoV scores did not differ between R and AR in frequency (p = 0.50), severity (p = 0.71) or bothersomeness (p = 0.81) of symptoms, or between international-level vs national-level officials for frequency (p = 0.03) or bothersomeness (p = 0.07) of symptoms. However, international-level officials reported less severe symptoms than their national-level counterparts (p<0.01). Overall, 18.3% of officials had either never had an eye examination or if they had, it was more than 3 years previously. Regarding refractive correction, 4.2% had undergone refractive surgery and 23.9% wear contact lenses when officiating. Clinical vision measures in the football officials were similar to published normative values for young, adult populations and similar between R and AR. Clinically-measured vision did not differ according to officiating level. Visual acuity measured with and without a pinhole disc indicated that around one quarter of participants may be capable of better vision when officiating, as evidenced by better acuity (≥1 line of letters) using the pinhole. Amongst the clinical visual tests we used, we did not find evidence for above-average performance in elite-level football officials. Although the impact of uncorrected mild to moderate refractive error upon officiating performance is unknown, with a greater uptake of eye examinations, visual acuity may be improved in around a quarter of officials.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013

Agent-Based Model of Therapeutic Adipose-Derived Stromal Cell Trafficking during Ischemia Predicts Ability To Roll on P-Selectin

Intravenous delivery of human adipose-derived stromal cells (hASCs) is a promising option for the treatment of ischemia. After delivery, hASCs that reside and persist in the injured extravascular space have been shown to aid recovery of tissue perfusion and function, although low rates of incorporation currently limit the safety and efficacy of these therapies. We submit that a better understanding of the trafficking of therapeutic hASCs through the microcirculation is needed to address this and that selective control over their homing (organ- and injury-specific) may be possible by targeting bottlenecks in the homing process. This process, however, is incredibly complex, which merited the use of computational techniques to speed the rate of discovery. We developed a multicell agent-based model (ABM) of hASC trafficking during acute skeletal muscle ischemia, based on over 150 literature-based rules instituted in Netlogo and MatLab software programs. In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures. As verification, the model reasonably reproduced key aspects of ischemia and trafficking behavior including increases in wall shear stress, upregulation of key cellular adhesion molecules expressed on injured endothelium, increased secretion of inflammatory chemokines and cytokines, quantified levels of monocyte extravasation in selectin knockouts, and circulating monocyte rolling distances. Successful ABM verification prompted us to conduct a series of systematic knockouts in silico aimed at identifying the most critical parameters mediating hASC trafficking. Simulations predicted the necessity of an unknown selectin-binding molecule to achieve hASC extravasation, in addition to any rolling behavior mediated by hASC surface expression of CD15s, CD34, CD62e, CD62p, or CD65. In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 µm/s. Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications

Energy Sprawl or Energy Efficiency: Climate Policy Impacts on Natural Habitat for the United States of America

Concern over climate change has led the U.S. to consider a cap-and-trade system to regulate emissions. Here we illustrate the land-use impact to U.S. habitat types of new energy development resulting from different U.S. energy policies. We estimated the total new land area needed by 2030 to produce energy, under current law and under various cap-and-trade policies, and then partitioned the area impacted among habitat types with geospatial data on the feasibility of production. The land-use intensity of different energy production techniques varies over three orders of magnitude, from 1.9–2.8 km2/TW hr/yr for nuclear power to 788–1000 km2/TW hr/yr for biodiesel from soy. In all scenarios, temperate deciduous forests and temperate grasslands will be most impacted by future energy development, although the magnitude of impact by wind, biomass, and coal to different habitat types is policy-specific. Regardless of the existence or structure of a cap-and-trade bill, at least 206,000 km2 will be impacted without substantial increases in energy efficiency, which saves at least 7.6 km2 per TW hr of electricity conserved annually and 27.5 km2 per TW hr of liquid fuels conserved annually. Climate policy that reduces carbon dioxide emissions may increase the areal impact of energy, although the magnitude of this potential side effect may be substantially mitigated by increases in energy efficiency. The possibility of widespread energy sprawl increases the need for energy conservation, appropriate siting, sustainable production practices, and compensatory mitigation offsets

The Current Crisis in Emergency Care and the Impact on Disaster Preparedness

<p>Abstract</p> <p>Background</p> <p>The Homeland Security Act (HSA) of 2002 provided for the designation of a critical infrastructure protection program. This ultimately led to the designation of emergency services as a targeted critical infrastructure. In the context of an evolving crisis in hospital-based emergency care, the extent to which federal funding has addressed disaster preparedness will be examined.</p> <p>Discussion</p> <p>After 9/11, federal plans, procedures and benchmarks were mandated to assure a unified, comprehensive disaster response, ranging from local to federal activation of resources. Nevertheless, insufficient federal funding has contributed to a long-standing counter-trend which has eroded emergency medical care. The causes are complex and multifactorial, but they have converged to present a severely overburdened system that regularly exceeds emergency capacity and capabilities. This constant acute overcrowding, felt in communities all across the country, indicates a nation at risk. Federal funding has not sufficiently prioritized the improvements necessary for an emergency care infrastructure that is critical for an all hazards response to disaster and terrorist emergencies.</p> <p>Summary</p> <p>Currently, the nation is unable to meet presidential preparedness mandates for emergency and disaster care. Federal funding strategies must therefore be re-prioritized and targeted in a way that reasonably and consistently follows need.</p

Unique Structure and Dynamics of the EphA5 Ligand Binding Domain Mediate Its Binding Specificity as Revealed by X-ray Crystallography, NMR and MD Simulations

10.1371/journal.pone.0074040PLoS ONE89-POLN