Disease Surveillance of Cougars (Puma concolor) in Utah, USA.

Adult, free-ranging cougars (Puma concolor) were sampled in three regions of Utah, US, from 2018 to 2021. A total of 68% (23/34) of the sampled cougars had antibodies to feline parvovirus, 15% (5/33) to canine distemper virus, 18% (6/34) to calicivirus, and 22% (8/37) to Yersinia pestis. Forty-one percent (13/32) had IgG antibodies to Toxoplasma gondii and 6% (2/33) to feline immunodeficiency virus, and 3% (1/32) were positive for Dirofilaria immitis (heartworm) antigen. All were seronegative for Toxoplasma gondii IgM, feline enteric coronavirus, SARS-CoV-2, feline leukemia virus, feline herpesvirus, and Francisella tularensis. Tapeworms and Toxascaris leonina eggs were detected in the feces. The disease exposures detected were similar to what has been reported from cougar populations in other western US states, and the current level of exposures is unlikely to have a negative impact on the state's population.

Recolonizing carnivores: Is cougar predation behaviorally mediated by bears?

Conservation and management efforts have resulted in population increases and range expansions for some apex predators, potentially changing trophic cascades and foraging behavior. Changes in sympatric carnivore and dominant scavenger populations provide opportunities to assess how carnivores affect one another. Cougars (Puma concolor) were the apex predator in the Great Basin of Nevada, USA, for over 80 years. Black bears (Ursus americanus) have recently recolonized the area and are known to heavily scavenge on cougar kills. To evaluate the impacts of sympatric, recolonizing bears on cougar foraging behavior in the Great Basin, we investigated kill sites of 31 cougars between 2009 and 2017 across a range of bear densities. We modeled the variation in feeding bout duration (number of nights spent feeding on a prey item) and the proportion of primary prey, mule deer (Odocoileus hemionus), in cougar diets using mixed-effects models. We found that feeding bout duration was driven primarily by the size of the prey item being consumed, local bear density, and the presence of dependent kittens. The proportion of mule deer in cougar diet across all study areas declined over time, was lower for male cougars, increased with the presence of dependent kittens, and increased with higher bear densities. In sites with feral horses (Equus ferus), a novel large prey, cougar consumption of feral horses increased over time. Our results suggest that higher bear densities over time may reduce cougar feeding bout durations and influence the prey selection trade-off for cougars when alternative, but more dangerous, large prey are available. Shifts in foraging behavior in multicarnivore systems can have cascading effects on prey selection. This study highlights the importance of measuring the impacts of sympatric apex predators and dominant scavengers on a shared resource base, providing a foundation for monitoring dynamic multipredator/scavenger systems.

Intravenous Fat Emulsion Does Not Significantly Alter Clotting Markers in Dabigatran-Treated Blood.

Dabigatran etexilate is an oral direct thrombin (Factor IIa) inhibitor approved for patients with atrial fibrillation and for management of risk of deep vein thrombosis and pulmonary embolism. Dabigatran offers advantages over treatment with warfarin, including limited laboratory monitoring. It is equivalent in prevention of stroke and deep vein thrombosis with essentially equivalent complication rates. In contrast to warfarin, reversal of the anticoagulation is less well established. Idarucizumab is available for reversal, however supporting research is mixed; the agent also happens to be quite expensive making availability difficult. Hemodialysis has been proposed as a method of reversal, but this is difficult in patients with life threatening hemorrhage, and is not available at many hospitals. Intravenous fat emulsion (IFE) has been used for treatment of overdose of lipophilic drugs. Most toxicologists only recommend IFE for patients in extremis after ingestion of a lipid soluble substance. Dabigatran is lipid soluble, although the pro-drug more so than the active metabolite. The authors sought to see if dabigatran-induced coagulopathy of human in vitro blood samples could be reversed with IFE. Blood samples were spiked with dabigatran or dabigatran plus IFE. Values for Ecarin clot time (ECT-primary outcome), PT/INR, and aPTT, were compared across both study arms. A total of 18 healthy volunteers were included in our study. There were no significant differences in the ECT, PT/INR, and aPTT between the dabigatran arm and the dabigatran plus IFE arm. Based on these methods, IFE does not reverse dabigatran-induced coagulopathy.

Effect of Methylene Blue on a Porcine Model of Amlodipine Toxicity.

INTRODUCTION: Calcium channel blocker (CCB) overdoses cause significant morbidity and mortality. Dihydropyridine CCBs cause peripheral vascular dilation and at high doses cardiac dysfunction. Amlodipine, a dihydropyridine, causes peripheral vasodilation from release of nitric oxide (NO) in addition to calcium channel blockade; NO scavenging is a potential treatment. Methylene blue (MB) inhibits NO directly and inhibits NO production. We compared the effects of MB versus norepinephrine (NE), with time to death as the primary outcome, in a porcine amlodipine toxicity model. METHODS: Animals were anesthetized and instrumented, and an amlodipine infusion was administered to mimic oral overdose. After 70 minutes, each group was resuscitated with normal saline. Animals in each group were then randomized to receive either MB or NE. Hemodynamic parameters, including mean arterial pressure and cardiac output, were recorded every 10 minutes. The primary outcome was survival time (Kaplan-Meier analysis and log-rank test). RESULTS: Interim analysis after 15 animals (7 MB, 8 NE) revealed that MB was clearly not superior to NE. Overall, 1 of 7 animals in the MB group survived to 300 minutes compared with 2 of 8 animals in the NE group. The median survival time was 100 minutes for the MB group and 177 minutes for the NE group. Survival time did not differ by group (log-rank test p = 0.29). CONCLUSION: In this porcine model of amlodipine toxicity, methylene blue did not improve survival time compared with norepinephrine. Whether methylene blue is beneficial in combatting distributive shock in amlodipine toxicity remains unclear and requires further study.

Use of a Porcine Model to Evaluate the Risks and Benefits of Vasopressors in Propranolol Poisoning.

INTRODUCTION: Vasopressors are a commonly used treatment in beta-blocker poisoning despite evidence they may be ineffective or harmful. The primary objective of the present study is to use previously collected data from two prior studies (high-dose insulin (HDI) versus vasopressin + epinephrine and a placebo-controlled HDI study) to compare survival between vasopressin + epinephrine and placebo. Secondary outcomes included a comparison with HDI as well as comparisons with hemodynamic parameters, including mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), and systemic vascular resistance (SVR). METHODS: Cardiogenic shock was induced in healthy pigs with a bolus of 0.5 mg/kg of intravenous propranolol followed by an infusion of 0.25 mg/kg/minute until the point of toxicity, defined as (0.75 × initial HR × initial MAP), at which point the infusion was reduced to 0.125 mg/kg/minute for 240 (vasopressin + epinephrine or HDI) or 360 minutes (placebo) or until death. RESULTS: Survival was significantly lower in pigs receiving vasopressin + epinephrine (0%, 0/5) than in pigs receiving placebo (50%, 2/4) (p < 0.01). Survival was significantly higher with HDI compared with both groups (100%, 5/5) (p < 0.01). All vasopressin + epinephrine pigs died within 100 minutes after reaching toxicity. Over the course of the resuscitation, we observed a statistically significant steady decrease in CO and HR in the vasopressin + epinephrine group compared with placebo (p < 0.01). In contrast, we observed a statistically significant change in MAP and SVR that followed a parabolic arc, with MAP and SVR rising significantly initially in the vasopressin + epinephrine group then rapidly falling until death (p < 0.01). CONCLUSIONS: Mortality was higher with vasopressors compared with placebo in this porcine model of propranolol poisoning. Further studies are warranted to define the optimal timing and role of vasopressors in beta-blocker poisoning.

Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload.

INTRODUCTION: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so-lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). METHODS AND RESULTS: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/-) hearts compared to wild-type (WT) controls. LUM+/- mice were subjected to AB. There was no difference in survival between LUM+/- and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/- and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/- mice. LUM+/- hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/- compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/- and WT mice post-AB, as assessed by histology and qPCR. CONCLUSIONS: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

Development and Feasibility of a Porcine Model of Amlodipine Toxicity.

INTRODUCTION: Toxicity related to calcium-channel blockers remains a significant cause of morbidity and mortality. Amlodipine-induced shock is unique in that its mechanism of action is thought to occur in part via the release of nitric oxide (NO) in the peripheral vasculature. Specific therapeutic interventions, including methylene blue (an NO scavenger), have been suggested, but efficacy studies are severely limited. To facilitate a larger porcine study into the effect of various interventions on amlodipine toxicity, we undertook this model development and feasibility study. METHODS: Intravenous amlodipine was prepared by dissolving commercially obtained amlodipine tablets in dimethylsulfoxide. The concentration of the drug was verified using ultraviolet spectroscopy. We administered this solution to three animals in order to determine a toxic dose, capable of facilitating a two-arm study of amlodipine toxicity. RESULTS: The first pig died rapidly after the bolus infusion. The second pig developed mild toxicity, but the dissolution of the plastic tubing by the solvent and subsequent leakage limited the interpretability of the result. The third animal developed expected toxicity with an infusion rate between 2.0  and 5.5 mg/kg/h. CONCLUSION: This study demonstrates a potentially repeatable model of amlodipine-induced toxic shock using intravenous administration of amlodipine and several methodological considerations for researchers undertaking similar work.

The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload.

Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF. Lumican (LUM) is a collagen binding proteoglycan with increased expression in hearts of patients and mice with HF, however, its role in cardiac function remains poorly understood. To examine the role of LUM in pressure overload induced cardiac remodeling, we subjected LUM knock-out (LUMKO) mice to aortic banding (AB) and treated cultured cardiac fibroblasts (CFB) with LUM. LUMKO mice exhibited increased mortality 1-14 days post-AB. Echocardiography revealed increased LV dilatation, altered hypertrophic remodeling and exacerbated contractile dysfunction in surviving LUMKO 1-10w post-AB. LUMKO hearts showed reduced collagen expression and cross-linking post-AB. Transcriptional profiling of LUMKO hearts by RNA sequencing revealed 714 differentially expressed transcripts, with enrichment of cardiotoxicity, ECM and inflammatory pathways. CFB treated with LUM showed increased mRNAs for markers of myofibroblast differentiation, proliferation and expression of ECM molecules important for fibrosis, including collagens and collagen cross-linking enzyme lysyl oxidase. In conclusion, we report the novel finding that lack of LUM attenuates collagen cross-linking in the pressure-overloaded heart, leading to increased mortality, dilatation and contractile dysfunction in mice.

A Swine Model of Severe Propranolol Toxicity Permitting Direct Measurement of Brain Tissue Oxygenation.

INTRODUCTION: High-dose insulin (HDI) therapy has been used successfully for beta-blocker toxicity, but needs further study when hypotension persists despite HDI. The objective was to develop a model of propranolol toxicity with persistent hypotension despite HDI and to develop means to measure cerebral oxygen tension (PbrO2). METHODS: Eight anesthetized Yorkshire pigs were instrumented with a tracheostomy, Swan-Ganz catheter, arterial catheter, and intra-cerebral pressure and oxygen monitor. Intravenous propranolol was given until the initial point of toxicity (POT); 25% reduction from baseline mean arterial pressure (MAP) × heart rate (HR). At the initial POT, normal saline (NS) bolus and infusion along with HDI infusion were started. The propranolol infusion was titrated up slowly to induce hypotension. Group 2 pigs received a norepinephrine (NE) infusion after a secondary POT defined as a MAP < 50 mmHg. NE was titrated to maintain subsequent MAPs > 50 mmHg. Cardiac output, HR, MAP, PbrO2, and intracranial pressure were then recorded every 5 min until death or 4 h. Systemic vascular resistance, potassium, and glucose were also measured. Surviving pigs were euthanized. RESULTS: Two pigs received unique doses for protocol development. One pig developed a tachyarrhythmia prior to protocol, one failed to reach secondary POT, leaving 2 pigs in each group reaching secondary POT. The range of PbrO2 recordings for group 1 was 12.7-48.5 mmHg and 9.2-26.2 mmHg for group 2. CONCLUSION: We report a pilot study swine model of propranolol toxicity with hypotension despite HDI, in which physiologic measures including PbrO2 are achieved. Our toxicity model can be used in the future, and the hemodynamic and brain monitoring model may prove important for subsequent research in various contexts.

A randomized controlled study comparing high-dose insulin to vasopressors or combination therapy in a porcine model of refractory propranolol-induced cardiogenic shock.

Context: Although cerebral perfusion (CP) is preserved across a wide range of mean arterial pressures (MAP) through cerebral-vascular autoregulation, the relationship between MAP and CP in refractory poison-induced cardiogenic shock (PICS) has never been studied. We compared the effects of therapies used in PICS: high-dose insulin (HDI), HDI plus norepinephrine (NE), and vasopressors alone (NE plus epinephrine (Epi)) on cerebral tissue oxygenation (PtO2). Methods: Fifteen swine were randomized to either HDI, HDI + NE, or NE + Epi. All animals received a propranolol infusion using an established model of toxicity. At primary toxicity (P1), defined as a 25% reduction in heart rate (HR) multiplied by MAP, the HDI and HDI + NE groups received HDI and the NE + Epi group received NE. Once a sustained MAP < 55 mmHg was reached (P2), the HDI group received saline (NS), the HDI + NE group received NE and the NE + Epi group received Epi until death or censoring. PtO2 and hemodynamic parameters including MAP, cardiac output (CO) and central venous pressure (CVP) were measured every 10 minutes. Glucose and potassium were measured at predetermined intervals. Results: Animals treated with HDI + NE maintained PtO2 over time more than the HDI-alone group. Due to rapid hemodynamic collapse, we were unable to analyze PtO2 data in the vasopressor only animals. Mean survival time was 1.9, 2.9 and 0.1 hours for the HDI, HDI + NE and NE + Epi groups, respectively. Survival time from P2 (sustained MAP <55 mmHg) to death or censoring was not different between HDI and HDI + NE groups. Conclusions: HDI + NE treatment was superior to HDI-alone at preserving PtO2 when MAP < 55 mmHg. We were unable to compare the PtO2 between the NE + Epi to the HDI or HDI + NE due to rapid decline in CO and death. If MAP is sustained at < 55 mmHg after maximizing HDI, adjunctive treatment with NE should be considered to preserve PtO2.

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling.

Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.

Are vasopressors useful in toxin-induced cardiogenic shock?

OBJECTIVE: Overdoses with cardio-depressive medications can result in toxin-induced cardiogenic shock (TICS), a life-threatening condition characterized by severe hypotension and ineffective tissue perfusion. Vasopressors are often employed in the treatment of shock to increase heart rate and blood pressure. We sought to conduct a systematic review of the literature to evaluate the effectiveness of vasopressors in improving hemodynamic function and survival in the treatment of TICS. DATA SOURCES: We searched PubMed, EMBASE, TOXLINE, and International Pharmaceutical Abstracts. STUDY SELECTION: We included studies evaluating the use of vasopressors in humans or animals with TICS. We limited human study types to randomized controlled trials, clinical trials, observational studies, and case reports. DATA EXTRACTION: Our search yielded 913 citations and 144 of these met our inclusion criteria. 130 were human case reports and 14 were animal studies. DATA SYNTHESIS: Human case report data showed vasopressors were ineffective more often than they were partially or fully effective. In the majority of animal studies, vasopressor treatment failed to improve hemodynamic parameters and resulted in decreased survival. CONCLUSIONS: Human case reports and controlled animal experiments lead to different conclusions about vasopressors in TICS. Most animal studies indicate that vasopressors impair hemodynamic function and increase mortality. In contrast, human case reports suggest that vasopressors are often ineffective but not necessarily harmful.

Quantifying the spatiotemporal dynamics in a chorus frog (Pseudacris) hybrid zone over 30 years.

Although theory suggests that hybrid zones can move or change structure over time, studies supported by direct empirical evidence for these changes are relatively limited. We present a spatiotemporal genetic study of a hybrid zone between Pseudacris nigrita and P. fouquettei across the Pearl River between Louisiana and Mississippi. This hybrid zone was initially characterized in 1980 as a narrow and steep "tension zone," in which hybrid populations were inferior to parentals and were maintained through a balance between selection and dispersal. We reanalyzed historical tissue samples and compared them to samples of recently collected individuals using microsatellites. Clinal analyses indicate that the cline has not shifted in roughly 30 years but has widened significantly. Anthropogenic and natural changes may have affected selective pressure or dispersal, and our results suggest that the zone may no longer best be described as a tension zone. To the best of our knowledge, this study provides the first evidence of significant widening of a hybrid cline but stasis of its center. Continued empirical study of dynamic hybrid zones will provide insight into the forces shaping their structure and the evolutionary potential they possess for the elimination or generation of species.

A prospective study of ketamine versus haloperidol for severe prehospital agitation.

CONTEXT: Ketamine is an emerging drug for the treatment of acute undifferentiated agitation in the prehospital environment, however no prospective comparative studies have evaluated its effectiveness or safety in this clinical setting. OBJECTIVE: We hypothesized 5 mg/kg of intramuscular ketamine would be superior to 10 mg of intramuscular haloperidol for severe prehospital agitation, with time to adequate sedation as the primary outcome measure. METHODS: This was a prospective open label study of all patients in an urban EMS system requiring chemical sedation for severe acute undifferentiated agitation that were subsequently transported to the EMS system's primary Emergency Department. All paramedics were trained in the Altered Mental Status Scale and prospectively recorded agitation scores on all patients. Two 6-month periods where either ketamine or haloperidol was the first-line therapy for severe agitation were prospectively compared primarily for time to adequate sedation. Secondary outcomes included laboratory data and adverse medication events. RESULTS: 146 subjects were enrolled; 64 received ketamine, 82 received haloperidol. Median time to adequate sedation for the ketamine group was 5 minutes (range 0.4-23) vs. 17 minutes (range 2-84) in the haloperidol group (difference 12 minutes, 95% CI 9-15). Complications occurred in 49% (27/55) of patients receiving ketamine vs. 5% (4/82) in the haloperidol group. Complications specific to the ketamine group included hypersalivation (21/56, 38%), emergence reaction (5/52, 10%), vomiting (5/57, 9%), and laryngospasm (3/55, 5%). Intubation was also significantly higher in the ketamine group; 39% of patients receiving ketamine were intubated vs. 4% of patients receiving haloperidol. CONCLUSIONS: Ketamine is superior to haloperidol in terms of time to adequate sedation for severe prehospital acute undifferentiated agitation, but is associated with more complications and a higher intubation rate.

What Can a Urine Drug Screening Immunoassay Really Tell Us?

Urine drug screening has become standard of care in many medical practice settings to assess compliance, detect misuse, and/or to provide basis for medical or legal action. The antibody-based enzymatic immunoassays used for qualitative analysis of urine have significant drawbacks that clinicians are often not aware of. Recent literature suggests that there is a lack of understanding of the shortcomings of these assays by clinicians who are ordering and/or interpreting them. This article addresses the state of each of the individual immunoassays that are most commonly used today in order to help the reader become proficient in the interpretation and application of the results. Some literature already exists regarding sources of "false positives" and "false negatives," but none seem to present the material with the practicing clinician in mind. This review aims to avoid overwhelming the reader with structures and analytical chemistry. The reader will be presented relevant clinical knowledge that will facilitate appropriate interpretation of immunoassays regardless of practice settings. Using this review as a learning tool and a reference, clinicians will be able to interpret the results of commonly used immunoassays in an evidence-based, informed manner and minimize the negative impact that misinterpretation has on patient care.

Lack of collagen VIII reduces fibrosis and promotes early mortality and cardiac dilatation in pressure overload in mice.

AIMS: In pressure overload, left ventricular (LV) dilatation is a key step in transition to heart failure (HF). We recently found that collagen VIII (colVIII), a non-fibrillar collagen and extracellular matrix constituent, was reduced in hearts of mice with HF and correlated to degree of dilatation. A reduction in colVIII might be involved in LV dilatation, and we here examined the role of reduced colVIII in pressure overload-induced remodelling using colVIII knock-out (col8KO) mice. METHODS AND RESULTS: Col8KO mice exhibited increased mortality 3-9 days after aortic banding (AB) and increased LV dilatation from day one after AB, compared with wild type (WT). LV dilatation remained increased over 56 days. Forty-eight hours after AB, LV expression of main structural collagens (I and III) was three-fold increased in WT mice, but these collagens were unaltered in the LV of col8KO mice together with reduced expression of the pro-fibrotic cytokine TGF-ß, SMAD2 signalling, and the myofibroblast markers Pxn, α-SMA, and SM22. Six weeks after AB, LV collagen mRNA expression and protein were increased in col8KO mice, although less pronounced than in WT. In vitro, neonatal cardiac fibroblasts from col8KO mice showed lower expression of TGF-ß, Pxn, α-SMA, and SM22 and reduced migratory ability possibly due to increased RhoA activity and reduced MMP2 expression. Stimulation with recombinant colVIIIα1 increased TGF-ß expression and fibroblast migration. CONCLUSION: Lack of colVIII reduces myofibroblast differentiation and fibrosis and promotes early mortality and LV dilatation in response to pressure overload in mice.

Acute Methylenedioxypyrovalerone Toxicity.

The objective of this study was to characterize the acute clinical effects, laboratory findings, complications, and disposition of patients presenting to the hospital after abusing synthetic cathinone. We conducted a retrospective multicenter case series of patients with synthetic cathinone abuse by searching for the terms bath salts, MDPV, methylenedioxypyrovalerone, mephedrone, methcathinone, methylone, methedrone, and cathinone within the "agent" field of a national clinical toxicology database (ToxIC). The medical records of these patients were obtained and abstracted by investigators at each study site. Patients with confirmatory testing that identified a synthetic cathinone in either blood or urine were included in the series. Patients who had either an undetectable synthetic cathinone test or no confirmatory testing were excluded. A data abstraction sheet was used to obtain information on each patient. We entered data into an Excel spreadsheet and calculated descriptive statistics. We identified 23 patients with confirmed synthetic cathinone exposure--all were positive for methylenedioxyprovalerone (MDPV). Eighty-three percent were male and 74 % had recreational intent. The most common reported clinical effects were tachycardia (74 %), agitation (65 %), and sympathomimetic syndrome (65 %). Acidosis was the most common laboratory abnormality (43 %). Seventy-eight percent of patients were treated with benzodiazepines and 30 % were intubated. Ninety-six percent of patients were hospitalized and 87 % were admitted to the ICU. The majority (61 %) of patients was discharged home but 30 % required inpatient psychiatric care. There was one death in our series. The majority of patients presenting to the hospital after abusing MDPV have severe sympathomimetic findings requiring hospitalization. A number of these patients require inpatient psychiatric care after their acute presentation.

The association between ketamine given for prehospital chemical restraint with intubation and hospital admission.

INTRODUCTION: Intramuscular ketamine has become increasingly popular for prehospital chemical restraint of severely agitated or violent patients because of its favorable adverse effect profile, rapid onset, and wide therapeutic window. However, there is currently no literature quantifying the need for intubation or hospital admission for these patients once they reach the emergency department. METHODS: Medical records for patients receiving prehospital ketamine who were transported to a single level 1 trauma center were abstracted. Ketamine dose, patient weight, final disposition, and presence of intubation were recorded. Exclusion criteria were missing dose or weight and ketamine given for an indication other than chemical restraint. Statistical analysis was preformed with unadjusted Student t test. Statistical significance was defined as P < .05. RESULTS: A convenience sample of 51 consecutive patients was identified with 2 excluded because of missing data, leaving 49 for analysis. Ketamine dosing ranged from 2.25 to 9.42 mg/kg (mean, 5.26 ± 1.65 mg/kg). Significant differences were noted between those who required intubation (n = 14) and those who did not (n = 35) (6.16 ± 1.62 mg/kg vs 4.90 ± 1.54 mg/kg, P = .02). No patients were intubated prehospital. There was an increased dose in patients admitted to a medical ward (57%, 28/49) that approached statistical significance (5.62 ± 1.80 vs 4.78 ± 1.31, P = .06). CONCLUSION: Intubation was observed in our emergency department in 29% of patients administered intramuscular ketamine for prehospital chemical restraint. There was a positive association between higher ketamine doses and both endotracheal intubation and hospital admission. Future research should aim to define the minimum effective ketamine dose for successful chemical restraint.

Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5.

Pressure overload-induced TGF-ß signaling activates cardiac fibroblasts (CFB) and leads to increased extracellular matrix (ECM) protein synthesis including fibrosis. Excessive ECM accumulation may in turn affect cardiac function contributing to development of heart failure. The aim of this study was to examine the effects of SM16, an orally active small molecular inhibitor of ALK5, on pressure overload-induced cardiac fibrosis. One week after aortic banding (AB), C57Bl/6J mice were randomized to standard chow or chow with SM16. Sham operated animals served as controls. Following 4 weeks AB, mice were characterized by echocardiography and cardiovascular magnetic resonance before sacrifice. SM16 abolished phosphorylation of SMAD2 induced by AB in vivo and by TGF-ß in CFB in vitro. Interestingly, Masson Trichrome and Picrosirius Red stained myocardial left ventricular tissue revealed reduced development of fibrosis and collagen cross-linking following AB in the SM16 treated group, which was confirmed by reduced hydroxyproline incorporation. Furthermore, treatment with SM16 attenuated mRNA expression following induction of AB in vivo and stimulation with TGF-ß in CFB in vitro of Col1a2, the cross-linking enzyme LOX, and the pro-fibrotic glycoproteins SPARC and osteopontin. Reduced ECM synthesis by CFB and a reduction in myocardial stiffness due to attenuated development of fibrosis and collagen cross-linking might have contributed to the improved diastolic function and cardiac output seen in vivo, in combination with reduced lung weight and ANP expression by treatment with SM16. Despite these beneficial effects on cardiac function and development of heart failure, mice treated with SM16 exhibited increased mortality, increased LV dilatation and inflammatory heart valve lesions that may limit the use of SM16 and possibly also other small molecular inhibitors of ALK5, as future therapeutic drugs.

Asystole immediately following intravenous fat emulsion for overdose.

Use of intravenous fat emulsion (IFE) for the treatment of poisoned patients in extremis is increasing. Little literature exists describing failures and complications of IFE. We describe two cardiac arrests temporally associated with IFE. A 50-year-old woman presented after ingesting 80 total tablets of metoprolol 25 mg and bupropion 150 mg. Bradycardia and hypotension were refractory to calcium salts, catecholamines, and high dose insulin (HDI). With a pulse of 40/min and mean arterial pressure (MAP) of 30 mmHg, 100 mL of 20 % IFE was given; within 30 s, brady-asystolic arrest occurred. Pulses returned after 3 min of CPR. The patient died on hospital day 4 of multisystem organ failure (MSOF). A 53-year-old man presented after ingesting of 3,600 mg of diltiazem and 1,200 mg of propranolol. Bradycardia and hypotension were refractory to calcium salts, catecholamines, HDI, bicarbonate, and atropine. With a pulse of 30/min and a MAP of 40 mmHg, 150 mL of 20 % IFE was given; within 1 min, a brady-asystolic arrest occurred. Pulses returned after 6 min of CPR. The patient died on hospital day 7 of MSOF. Reported cases of IFE failures or potential complications are sparse. This report adds only case experience, not clarity. We report two cardiac arrests that were temporally associated with IFE.