Comparison of initial adenosine dose conversion rate for supraventricular tachycardia in the emergency department.

OBJECTIVE: To evaluate the rate of supraventricular tachycardia (SVT) termination between 6 mg and 12 mg initial adenosine doses. METHODS: This multi-center, retrospective cohort study evaluated patients presenting to the emergency department (ED) from January 1, 2020 to June 30, 2022 in SVT and received adenosine. The primary objective of the study is to compare the rate of SVT termination between adenosine 6 mg and 12 mg as documented on a formal electrocardiogram. Secondary endpoints include termination of SVT with subsequent adenosine dose, time to ED disposition, adverse effects, and subgroup analyses of patients with a body mass index greater than or equal to 40 kg/m2 and a history of SVT. RESULTS: Of 213 patients included, a 6 mg initial adenosine dose was administered to 117 patients (54.9 %) and a 12 mg initial adenosine dose was administered to 96 patients (45.1 %). SVT termination following the initial dose of 6 mg or 12 mg was 56.4 % and 79.1 %, respectively (p < 0.001). Among the 46 patients who failed to terminate SVT with an initial 6 mg dose, 33 converted to sinus rhythm with a subsequent adenosine dose in comparison to 1 of the 7 patients receiving an initial dose of 12 mg (71.7 % vs 14.3 %, p = 0.007). Median time to ED disposition, either inpatient admission or discharge, was 209 and 161 min, respectively (p = 0.104). There was no statistical difference in either subgroup analyses. CONCLUSION: A higher rate of SVT termination was observed with an initial adenosine dose of 12 mg in the ED in comparison to the guideline recommended dose of 6 mg. There were no significant differences in adverse effects observed.

Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Propylene glycol toxicity in an adolescent secondary to chronic cornstarch ingestion.

Propylene glycol (PG) is a diol (a double alcohol) that is commonly used as a food additive to preserve shelf life and enhance flavors, texture, and appearance. Although PG makes up only a small percentage of cornstarch, ingestion of large doses can cause lactic acidosis leading to hyperosmolarity, high anion gap metabolic acidosis (HAGMA), and a sepsis-like syndrome. A 17-year-old female presented to our emergency department (ED) with chronic chest pain, dyspnea, nausea, and vomiting. Laboratory testing showed an elevated anion gap of 18 mEq/L with no osmolar gap. Toxicology screening was negative. Twelve hours after ED arrival, she admitted to consuming one box of cornstarch daily for the past 6 months. She was admitted to the intensive care unit (ICU) with multisystem organ failure due to propylene glycol toxicity. After empiric treatment with fomepizole and continuous renal replacement therapy, her clinical status gradually improved. This case highlights the importance of obtaining a thorough dietary history in patients with suspected toxicities, especially when laboratory values demonstrate an unexplained HAGMA and/or lactic acidosis. Prompt recognition and therapeutic intervention with fomepizole, a potent inhibitor of alcohol dehydrogenase, is essential in reducing life-threatening sequelae following toxic alcohol ingestions.

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.

Mechanisms of cannabinoid tolerance.

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, ß-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.

Hepatic Activin E mediates liver-adipose inter-organ communication, suppressing adipose lipolysis in response to elevated serum fatty acids.

OBJECTIVE: The liver is a central regulator of energy metabolism exerting its influence both through intrinsic processing of substrates such as glucose and fatty acid as well as by secreting endocrine factors, known as hepatokines, which influence metabolism in peripheral tissues. Human genome wide association studies indicate that a predicted loss-of-function variant in the Inhibin ßE gene (INHBE), encoding the putative hepatokine Activin E, is associated with reduced abdominal fat mass and cardiometabolic disease risk. However, the regulation of hepatic Activin E and the influence of Activin E on adiposity and metabolic disease are not well understood. Here, we examine the relationship between hepatic Activin E and adipose metabolism, testing the hypothesis that Activin E functions as part of a liver-adipose, inter-organ feedback loop to suppress adipose tissue lipolysis in response to elevated serum fatty acids and hepatic fatty acid exposure. METHODS: The relationship between hepatic Activin E and non-esterified fatty acids (NEFA) released from adipose lipolysis was assessed in vivo using fasted CL 316,243 treated mice and in vitro using Huh7 hepatocytes treated with fatty acids. The influence of Activin E on adipose lipolysis was examined using a combination of Inhbe knockout mice, a mouse model of hepatocyte-specific overexpression of Activin E, and mouse brown adipocytes treated with Activin E enriched media. RESULTS: Increasing hepatocyte NEFA exposure in vivo by inducing adipose lipolysis through fasting or CL 316,243 treatment increased hepatic Inhbe expression. Similarly, incubation of Huh7 human hepatocytes with fatty acids increased expression of INHBE. Genetic ablation of Inhbe in mice increased fasting circulating NEFA and hepatic triglyceride accumulation. Treatment of mouse brown adipocytes with Activin E conditioned media and overexpression of Activin E in mice suppressed adipose lipolysis and reduced serum FFA levels, respectively. The suppressive effects of Activin E on lipolysis were lost in CRISPR-mediated ALK7 deficient cells and ALK7 kinase deficient mice. Disruption of the Activin E-ALK7 signaling axis in Inhbe KO mice reduced adiposity upon HFD feeding, but caused hepatic steatosis and insulin resistance. CONCLUSIONS: Taken together, our data suggest that Activin E functions as part of a liver-adipose feedback loop, such that in response to increased serum free fatty acids and elevated hepatic triglyceride, Activin E is released from hepatocytes and signals in adipose through ALK7 to suppress lipolysis, thereby reducing free fatty acid efflux to the liver and preventing excessive hepatic lipid accumulation. We find that disrupting this Activin E-ALK7 inter-organ communication network by ablation of Inhbe in mice increases lipolysis and reduces adiposity, but results in elevated hepatic triglyceride and impaired insulin sensitivity. These results highlight the liver-adipose, Activin E-ALK7 signaling axis as a critical regulator of metabolic homeostasis.

Formation of biologically influenced palladium microstructures by Desulfovibrio desulfuricans and Desulfovibrio ferrophilus IS5.

A range of Desulfovibrio spp. can reduce metal ions to form metallic nanoparticles that remain attached to their surfaces. The bioreduction of palladium (Pd) has been given considerable attention due to its extensive use in areas of catalysis and electronics and other technological domains. In this study we report, for the first time, evidence for Pd(II) reduction by the highly corrosive Desulfovibrio ferrophilus IS5 strain to form surface attached Pd nanoparticles, as well as rapid formation of Pd(0) coated microbial nanowires. These filaments reached up to 8 µm in length and led to the formation of a tightly bound group of interconnected cells with enhanced ability to attach to a low carbon steel surface. Moreover, when supplied with high concentrations of Pd (≥ 100 mmol Pd(II) g-1 dry cells), both Desulfovibrio desulfuricans and D. ferrophilus IS5 formed bacteria/Pd hybrid porous microstructures comprising millions of cells. These three-dimensional structures reached up to 3 mm in diameter with a dose of 1200 mmol Pd(II) g-1 dry cells. Under suitable hydrodynamic conditions during reduction, two-dimensional nanosheets of Pd metal were formed that were up to several cm in length. Lower dosing of Pd(II) for promoting rapid synthesis of metal coated nanowires and enhanced attachment of cells onto metal surfaces could improve the efficiency of various biotechnological applications such as microbial fuel cells. Formation of biologically stimulated Pd microstructures could lead to a novel way to produce metal scaffolds or nanosheets for a wide variety of applications.

Intermediate Crack Debonding of Externally Bonded FRP Reinforcement-Comparison of Methods.

Many researchers around the world have made extensive efforts to study the phenomenon of fiber-reinforced polymer (FRP) debonding. Based on these efforts, code provisions and various models have been proposed for predicting intermediate crack (IC) debonding failure. The paper presents a comparison of seven selected models: fib bulletin 14 approach, Teng et al. model, Lu model, Seracino et al. model, Said and Wu model, Elsanadedy et al. model and ACI 440. The accuracy of each model was evaluated based on the test results of 58 flexural specimens with IC debonding failures of externally bonded (EB), carbon FRP plates or sheets found in the existing literature. The experimental database was prepared to include a wide range of parameters affecting the issue under consideration. A comparison of the measured and predicted load capacity values was made to evaluate the prediction accuracy of the considered models. The analysis included the limitation of the load capacity estimated based on IC debonding models as well as concrete crushing and FRP rupture types of failure. The results indicate that the latest models proposed for direct implementation in design guidelines-the Said and Wu model and the Elsanadedy et al. model-offer the best accuracy in predicting the load capacity. In contrast, the fib bulletin 14 approach shows a wide dispersion of predictions and a large proportion of highly overestimated results.

Inhibition of Sulfate Reduction and Cell Division by Desulfovibrio desulfuricans Coated in Palladium Metal.

The growth of sulfate-reducing bacteria (SRB) and associated hydrogen sulfide production can be problematic in a range of industries such that inhibition strategies are needed. A range of SRB can reduce metal ions, a strategy that has been utilized for bioremediation, metal recovery, and synthesis of precious metal catalysts. In some instances, the metal remains bound to the cell surface, and the impact of this coating on bacterial cell division and metabolism has not previously been reported. In this study, Desulfovibrio desulfuricans cells (1g dry weight) enabled the reduction of up to 1500 mmol (157.5 g) palladium (Pd) ions, resulting in cells being coated in approximately 1 µm of metal. Thickly coated cells were no longer able to metabolize or divide, ultimately leading to the death of the population. Increasing Pd coating led to prolonged inhibition of sulfate reduction, which ceased completely after cells had been coated with 1200 mmol Pd g-1 dry cells. Less Pd nanoparticle coating permitted cells to carry out sulfate reduction and divide, allowing the population to recover over time as surface-associated Pd diminished. Overcoming inhibition in this way was more rapid using lactate as the electron donor, compared to formate. When using formate as an electron donor, preferential Pd(II) reduction took place in the presence of 100 mM sulfate. The inhibition of important metabolic pathways using a biologically enabled casing in metal highlights a new mechanism for the development of microbial control strategies. IMPORTANCE Microbial reduction of sulfate to hydrogen sulfide is highly undesirable in several industrial settings. Some sulfate-reducing bacteria are also able to transform metal ions in their environment into metal phases that remain attached to their outer cell surface. This study demonstrates the remarkable extent to which Desulfovibrio desulfuricans can be coated with locally generated metal nanoparticles, with individual cells carrying more than 100 times their mass of palladium metal. Moreover, it reveals the effect of metal coating on metabolism and replication for a wide range of metal loadings, with bacteria unable to reduce sulfate to sulfide beyond a specific threshold. These findings present a foundation for a novel means of modulating the activity of sulfate-reducing bacteria.

The Critical Role of Environmental Synergies in the Creation of Bionanohybrid Microbes.

A wide range of bacteria can synthesize surface-associated nanoparticles (SANs) through exogenous metal ions reacting with sulfide produced via cysteine metabolism, resulting in the emergence of a biological-nanoparticle hybrid (bionanohybrid). The attached nanoparticles may couple to extracellular electron transfer, facilitating de novo photoelectrochemical processes. While SAN-cell coupling in hybrid organisms is opening a range of biotechnological possibilities, observation of bionanohybrids in nature is not commonly reported and their lab-based behavior remains difficult to control. We describe the critical role environmental synergy (microbial growth stage, cell densities, cysteine, and exogenous metal concentrations) plays in controlling the form and occurrence of Escherichia coli and Moorella thermoacetica bionanohybrids. SAN development depends on an appropriate cell density to metal ratio, with too few cells resulting in nanoparticle suppression through cytotoxicity or inhibition of cysteine conversion, and with too many cells diluting the number and size of particles produced. This cell number is governed by the concentration of cysteine present, which acts to protect the cells from metal ion toxicity. Exposing cells to metal and cysteine during the lag phase leads to SAN development, whereas cells in the exponential growth phase predominantly produce dispersed nanoparticles. Applying these principles more broadly, E. coli is shown to biosynthesize composite Bi/Cu sulfide SANs, and Clostridioides difficile can be coaxed into a bionanohybrid lifestyle by fine-tuning the cysteine dosage. Bionanohybrids maintain a remarkable ability for binary fission and sustained growth, opening doors to the production of SANs tailored to specific technological functions. IMPORTANCE Some bacteria can produce nanoscale-sized particles, which remain attached to the surface of the organism. The surface association of these nanoparticles creates a new mode of interaction between the microbe's environment and its internal cellular function, giving rise to a new hybrid lifeform, a biological nanoparticle hybrid (bionanohybrid). These hybrid organisms gain new or enhanced biological functions, and thus their creation opens a wide range of biotechnological possibilities. Despite this potential, the fundamental controls on bionanohybrid formation and occurrence remain poorly constrained. In this study, Escherichia coli K-12, Moorella thermoacetica, and Clostridioides difficile were used to test the combined influences of the growth phase, cell density, cysteine dose, and metal concentration in determining single and composite metal sulfide surface-associated nanoparticle production. The significance of this study is that it defined the critical synergies controlling nanoparticle formation on bacterial cell surfaces, unlocking the potential for bionanohybrid applications in a range of organisms.

Contingency Management and SARS-CoV-2 Testing Among People Who Inject Drugs.

OBJECTIVES: People who inject drugs (PWID) are especially vulnerable to morbidity and mortality as a result of SARS-CoV-2 infection because of social and physical health vulnerabilities. Routine testing for SARS-CoV-2 is critical to reduce transmission. Contingency management-the provision of tangible rewards to reinforce positive behavior-can promote the use of health services among PWID. Evidence is scarce on the utility of contingency management to promote SARS-CoV-2 testing. The objective of this study was to evaluate the effectiveness of contingency management to increase testing among PWID. METHODS: SARS-CoV-2 testing was implemented at 9 syringe exchange program sites in partnership with an Oregon-based nonprofit organization for 5 weeks without contingency management and for 6 weeks with contingency management (a $10 financial incentive for testing) from February 1 through mid-April 2021. We measured rates of testing among syringe exchange program clients before and after implementation of contingency management. RESULTS: Before contingency management, SARS-CoV-2 testing occurred during approximately 131 of 1410 (9.3%) client encounters, and 123 of 997 (12.3%) unique clients were tested. During contingency management, testing occurred during approximately 571 of 1756 (32.5%) client encounters, and 407 of 1151 (35.4%) unique clients were tested. Rates of testing increased from 0.04 (SD, 0.04) before contingency management implementation to 0.25 (SD, 0.15) after implementation (t8 = -3.88; P = .005; Cohen d = 1.46). CONCLUSIONS: Contingency management facilitated uptake of SARS-CoV-2 testing among PWID. Contingency management may be an effective strategy for improving communicable disease testing beyond testing for SARS-CoV-2 and for improving vaccine uptake among PWID and warrants additional research.

Sex differences and the endocannabinoid system in pain.

Cannabis use has been increasing in recent years, particularly among women, and one of the most common uses of cannabis for medical purposes is pain relief. Pain conditions and response to analgesics have been demonstrated to be influenced by sex, and evidence is emerging that this is also true with cannabinoid-mediated analgesia. In this review we evaluate the preclinical evidence supporting sex differences in cannabinoid pharmacology, as well as emerging evidence from human studies, both clinical and observational. Numerous animal studies have reported sex differences in the antinociceptive response to natural and synthetic cannabinoids that may correlate to sex differences in expression, and function, of endocannabinoid system components. Female rodents have generally been found to be more sensitive to the effects of Δ9-THC. This finding is likely a function of both pharmacokinetic and pharmacodynamics factors including differences in metabolism, differences in cannabinoid receptor expression, and influence of ovarian hormones including estradiol and progesterone. Preclinical evidence supporting direct interactions between sex hormones and the endocannabinoid system may translate to sex differences in response to cannabis and cannabinoid use in men and women. Further research into the role of sex in endocannabinoid system function is critical as we gain a deeper understanding of the impact of the endocannabinoid system in various disease states, including chronic pain.

InCorr: Interactive Data-Driven Correlation Panels for Digital Outcrop Analysis.

Geological analysis of 3D Digital Outcrop Models (DOMs) for reconstruction of ancient habitable environments is a key aspect of the upcoming ESA ExoMars 2022 Rosalind Franklin Rover and the NASA 2020 Rover Perseverance missions in seeking signs of past life on Mars. Geologists measure and interpret 3D DOMs, create sedimentary logs and combine them in 'correlation panels' to map the extents of key geological horizons, and build a stratigraphic model to understand their position in the ancient landscape. Currently, the creation of correlation panels is completely manual and therefore time-consuming, and inflexible. With InCorr we present a visualization solution that encompasses a 3D logging tool and an interactive data-driven correlation panel that evolves with the stratigraphic analysis. For the creation of InCorr we closely cooperated with leading planetary geologists in the form of a design study. We verify our results by recreating an existing correlation analysis with InCorr and validate our correlation panel against a manually created illustration. Further, we conducted a user-study with a wider circle of geologists. Our evaluation shows that InCorr efficiently supports the domain experts in tackling their research questions and that it has the potential to significantly impact how geologists work with digital outcrop representations in general.

Ethics Committees: Team Perspectives and Organizational Responses.

Healthcare ethics committees can be valuable resources but are largely underutilized by nurses. The purpose of this project was to review ethics concerns and educational needs of nurses in a large, integrated healthcare delivery system. Seven themes were identified: organizational issues, nonbeneficial care, withdrawing life-sustaining therapies, discharge disposition, challenging patients and families, communication with physicians, and capacity versus competence. A process was then developed to better engage nurses in ethical discussions.

Vital sign based shock scores are poor at triaging South African trauma patients.

BACKGROUND: Traumatic shock cannot be diagnosed by a single physiological measurement and a number of vital sign based combined shock scores (CSS) have been proposed to identify and triage trauma patients with shock. This audit uses data from a prospectively entered electronic trauma registry to compare the ability of these CSS to predict in-hospital mortality, need for surgery, need for blood transfusion and ICU admission. MATERIALS AND METHODS: The data used in the study was obtained from the Hybrid Electronic Medical Record (HEMR) in Pietermaritzburg from January 2012-September 2015. The calculated scores (Systolic Blood Pressure [SBP], Mean Arterial Pressure [MAP], Shock Index [SI], Modified Shock Index [MSI] and Shock Index multiplied by Age [SIA]) were plotted against each outcome parameter and the inflection points at which they started to increase, for each parameter, was determined and compared. RESULTS: A total of 8793 patients met the inclusion criteria. After the datasets with missing data were removed, a total of 7623 patients were available for analyses. There was a slightly higher incidence of blunt trauma (46%) compared to penetrating trauma (43%). Area under the Receiver Operating Curves (AUROC) for prediction of mortality revealed the MSI and SIA performed best, with values of 0.69 and 0.70, respectively. In both the 'need for ICU' prediction as well as the 'need for blood transfusion' prediction, MSI performed best with scores of 0.73 and 0.79, respectively. None of the parameters performed well in the 'need for surgery' prediction. None of the CSS parameters reached a 'good predictor capability' score of 0.8. CONCLUSION: The currently available vital sign based scores (SBP, MAP, SI, MSI, SIA) used in the prediction of shock severity and triage are not good predictors of mortality, need for ICU, need for theatre or need for blood transfusion in our population where half the trauma is penetrating and there are long pre-hospital delays. Our data suggests that none of the proposed CSS's are capable of reliably and accurately identifying and categorizing shock states in South African trauma patients.

Assessment of Cardiac Troponin I Responses in Nonhuman Primates during Restraint, Blood Collection, and Dosing in Preclinical Safety Studies.

Limited information has been published on the use of cardiac troponin I (cTnI) as a biomarker of cardiac injury in monkeys. The purpose of these studies was to characterize the cTnI response seen in cynomolgus macaques during routine dosing and blood collection procedures typically used in preclinical safety studies and to better understand the pathogenesis of this response. We measured cTnI using two different methods, the Siemens Immulite cTnI assay and the more sensitive Siemens Troponin I-Ultra assay. We were able to demonstrate that after oral, subcutaneous, or intravenous dosing of common vehicles, as well as serial chair restraint for venipuncture blood collection, that minimal to mild transient increases in cTnI could be detected in monkeys with both assays. cTnI values typically peaked at 2, 3, 4, or 6 hr after sham dosing and returned to baseline at 22 or 24 hr. In addition, marked increases in heart rate (HR) and blood pressure (BP) occurred in monkeys during the restraint procedures, which likely initiated the cTnI release in these animals. Monkeys that were very well acclimated to the chairing procedures and had vascular access ports for blood sampling did not have marked increases in HRs and BP or increases in cTnI.

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein.

The P-glycoprotein (Pgp) transporter plays a central role in drug disposition by effluxing a chemically diverse range of drugs from cells through conformational changes and ATP hydrolysis. A number of drugs are known to activate ATP hydrolysis of Pgp, but coupling between ATP and drug binding is not well understood. The cardiovascular drug verapamil is one of the most widely studied Pgp substrates and therefore, represents an ideal drug to investigate the drug-induced ATPase activation of Pgp. As previously noted, verapamil-induced Pgp-mediated ATP hydrolysis kinetics was biphasic at saturating ATP concentrations. However, at subsaturating ATP concentrations, verapamil-induced ATPase activation kinetics became monophasic. To further understand this switch in kinetic behavior, the Pgp-coupled ATPase activity kinetics was checked with a panel of verapamil and ATP concentrations and fit with the substrate inhibition equation and the kinetic fitting software COPASI. The fits suggested that cooperativity between ATP and verapamil switched between low and high verapamil concentration. Fluorescence spectroscopy of Pgp revealed that cooperativity between verapamil and a non-hydrolyzable ATP analog leads to distinct global conformational changes of Pgp. NMR of Pgp reconstituted in liposomes showed that cooperativity between verapamil and the non-hydrolyzable ATP analog modulate each other's interactions. This information was used to produce a conformationally-gated model of drug-induced activation of Pgp-mediated ATP hydrolysis.

Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein.

Drug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.