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Find video protocols related to scientific articles indexed in Pubmed.
An emergency department registration kiosk can increase HIV screening in high risk patients.
J Telemed Telecare
PUBLISHED: 10-16-2014
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We evaluated the feasibility and the patient acceptability of integrating a kiosk into routine emergency department (ED) practice for offering HIV testing. The work was conducted in four phases: phase 1 was a baseline, in which external testing staff offered testing at the bedside; phase 2 was a pilot assessment of a prototype kiosk; phase 3 was a pilot implementation and phase 4 was the full implementation with automated login. Feasibility was assessed by the proportion of offering HIV tests, acceptance, completion and result reporting. During the study period, the number of ED patients and eligible patients for screening were similar in the three main phases. However, the number and proportion of patients offered testing of those eligible for screening increased significantly from phase 1 (32%) to phase 3 (37%) and phase 4 (40%). There were slightly higher prevalences of newly diagnosed HIV with kiosk versus bedside testing (phase 1, 0%; phase 3, 0.2%; phase 4, 0.5%). Compared to patients tested at the bedside, patients tested via the kiosk were significantly younger, more likely to be female, to be black, and to report high risk behaviours. ED-based HIV screening via a registration-based kiosk was feasible, yielded similar proportions of testing, and increased the proportion of engagement of higher-risk patients in testing.
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Evaluation of the xpert flu rapid PCR assay in high-risk emergency department patients.
J. Clin. Microbiol.
PUBLISHED: 09-24-2014
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We prospectively evaluated the performance of Cepheid's GeneXpert Xpert Flu assay in a target population of 281 adults presenting to the emergency department with an acute respiratory illness who met Centers for Disease Control and Prevention (CDC) criteria for recommended antiviral treatment. Compared with the Prodesse ProFlu+ assay, Xpert Flu had an overall sensitivity of 95.3% and specificity of 99.2%.
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Alpha-ethyltryptamines as dual dopamine-serotonin releasers.
Bioorg. Med. Chem. Lett.
PUBLISHED: 07-29-2014
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The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT2A receptor. The unique combination of dual DA/5-HT releasing activity and 5-HT2A receptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential.
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Multisite exploration of clinical decision making for antibiotic use by emergency medicine providers using quantitative and qualitative methods.
Infect Control Hosp Epidemiol
PUBLISHED: 07-23-2014
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To explore current practices and decision making regarding antimicrobial prescribing among emergency department (ED) clinical providers.
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Improved sensitivity for molecular detection of bacterial and Candida infections in blood.
J. Clin. Microbiol.
PUBLISHED: 06-20-2014
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The rapid identification of bacteria and fungi directly from the blood of patients with suspected bloodstream infections aids in diagnosis and guides treatment decisions. The development of an automated, rapid, and sensitive molecular technology capable of detecting the diverse agents of such infections at low titers has been challenging, due in part to the high background of genomic DNA in blood. PCR followed by electrospray ionization mass spectrometry (PCR/ESI-MS) allows for the rapid and accurate identification of microorganisms but with a sensitivity of about 50% compared to that of culture when using 1-ml whole-blood specimens. Here, we describe a new integrated specimen preparation technology that substantially improves the sensitivity of PCR/ESI-MS analysis. An efficient lysis method and automated DNA purification system were designed for processing 5 ml of whole blood. In addition, PCR amplification formulations were optimized to tolerate high levels of human DNA. An analysis of 331 specimens collected from patients with suspected bloodstream infections resulted in 35 PCR/ESI-MS-positive specimens (10.6%) compared to 18 positive by culture (5.4%). PCR/ESI-MS was 83% sensitive and 94% specific compared to culture. Replicate PCR/ESI-MS testing from a second aliquot of the PCR/ESI-MS-positive/culture-negative specimens corroborated the initial findings in most cases, resulting in increased sensitivity (91%) and specificity (99%) when confirmed detections were considered true positives. The integrated solution described here has the potential to provide rapid detection and identification of organisms responsible for bloodstream infections.
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Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics.
ACS Med Chem Lett
PUBLISHED: 06-12-2014
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As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes. Substitution on the aromatic ring yielded compounds that maintained hybrid activity, with the two disubstituted analogues (PAL-787 and PAL-820) having the most potent hybrid activity.
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Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys.
Exp Clin Psychopharmacol
PUBLISHED: 05-05-2014
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d-Amphetamine selectively promotes release of both dopamine (DA) and norepinephrine (NE) versus serotonin (5HT), and chronic d-amphetamine treatment decreases cocaine-taking behavior in rats, nonhuman primates, and humans. However, abuse liability limits the clinical utility of amphetamine maintenance for treating cocaine abuse. One strategy to improve safety and efficacy of monoamine releasers as candidate anticocaine medications has been to develop dual DA/5HT releasers like 1-napthyl-2-aminopropane (PAL-287), but the pharmacology of this class of compounds has not been extensively examined. In particular, PAL-287 has similar potencies to release DA, 5HT, and NE, and the role of manipulating NE release potency on abuse-related or anticocaine effects of dual DA/5HT releasers is not known. To address this issue, the present study compared effects of four novel DA/5HT releasers that varied >800-fold in their selectivities to release DA/5HT versus NE: [1-(5-chloro-1H-indol-3-yl)propan-2-amine (PAL-542), 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (PAL-544), 1-(1H-indol-5-yl)propan-2-amine (PAL-571), and (R)-1-(1H-indol-1-yl)propain-2-amine (PAL-569). Abuse-related effects of all four compounds were evaluated in assays of intracranial self-stimulation (ICSS) in rats and cocaine discrimination in rats and monkeys, and none of the compounds reliably facilitated ICSS or substituted for cocaine. Anticocaine effects of the compound with highest selectivity to release DA/5HT versus NE (PAL-542) were tested in an assay of cocaine versus food choice in rhesus monkeys, and PAL-542 failed to reduce cocaine choice. These results suggests that potency to release NE has minimal influence on abuse liability of dual DA/5HT releasers, and reducing relative potency to release NE versus DA/5HT does not improve anticocaine efficacy.
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A rabbit model of non-typhoidal Salmonella bacteremia.
Comp. Immunol. Microbiol. Infect. Dis.
PUBLISHED: 04-30-2014
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Bacteremia is an important cause of morbidity and mortality in humans. In this study, we focused on the development of an animal model of bacteremia induced by non-typhoidal Salmonella. New Zealand White rabbits were inoculated with a human isolate of non-typhoidal Salmonella strain CVD J73 via the intra-peritoneal route. Blood samples were collected at specific time points and at euthanasia from infected rabbits. Additionally, tissue samples from the heart, lungs, spleen, gastrointestinal tract, liver and kidneys were obtained at euthanasia. All experimentally infected rabbits displayed clinical signs of disease (fever, dehydration, weight loss and lethargy). Tissues collected at necropsy from the animals exhibited histopathological changes indicative of bacteremia. Non-typhoidal Salmonella bacteria were detected in the blood and tissue samples of infected rabbits by microbiological culture and real-time PCR assays. The development of this animal model of bacteremia could prove to be a useful tool for studying how non-typhoidal Salmonella infections disseminate and spread in humans.
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Proximal deep venous thrombosis and pulmonary embolus following total joint arthroplasty.
J Arthroplasty
PUBLISHED: 04-11-2014
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It has been proposed that prevention of deep venous thrombosis (DVT) will lead to a reduction in pulmonary embolism (PE). This retrospective comparative study examines the association between symptomatic proximal DVT (occurring at or proximal to the popliteal fossa) and PE in total joint arthroplasty (TJA) patients. We evaluated 1031 patients with DVT symptoms and 428 with PE symptoms. A total of 227 patients were evaluated for both. No statistically significant association found between developing PE and DVT within 90 days after TJA (P=0.94). Our findings raise into question the mechanical propagation theory. Formation of DVT and PE may be independent events in patients undergoing TJA. Evaluating the efficacy of thromboprophylaxis using DVT as end point may not reflect its efficacy for prevention of PE.
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Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes.
Psychopharmacology (Berl.)
PUBLISHED: 03-19-2014
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Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT2A) receptors.
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A Novel Approach to Realizing Routine HIV Screening and Enhancing Linkage to Care in the United States: Protocol of the FOCUS Program and Early Results.
JMIR Res Protoc
PUBLISHED: 03-05-2014
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The United States health care system remains far from implementing the Centers for Disease Control and Prevention's recommendation of routine human immunodeficiency virus (HIV) screening as part of health care for adults. Although consensus for the importance of screening has grown, innovations in implementing routine screening are still lacking. HIV on the Frontlines of Communities in the United States (FOCUS) was launched in 2010 to provide an environment for testing innovative approaches to routine HIV screening and linkage to care.
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A case-control study evaluating RT-PCR/ESI-MS technology compared to direct fluorescent antibody and xTAG RVP PCR.
Diagn. Microbiol. Infect. Dis.
PUBLISHED: 02-03-2014
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Waste nasopharyngeal swabs (N = 244) were evaluated by the reverse-transcriptase polymerase chain reaction/electrospray ionization mass spectrometry PLEX-ID Broad Respiratory Virus Surveillance Kit version 2.5 compared to direct fluorescent antibody and xTAG Respiratory Virus Panel for percent agreement, sensitivity, and specificity. Sensitivity and specificity were 91% (111/122) and 95.1% (116/122), respectively. Sensitivity by virus, except parainfluenza, was 92.9-100%, and specificity was 99-100%.
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Validation of an abbreviated version of the Denver HIV risk score for prediction of HIV infection in an urban ED.
Am J Emerg Med
PUBLISHED: 01-20-2014
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We sought to evaluate the performance of an abbreviated version of the Denver HIV Risk Score in 2 urban emergency departments (ED) with known high undiagnosed HIV prevalence.
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Rapid PCR/ESI-MS-based molecular genotyping of Staphylococcus aureus from nasal swabs of emergency department patients.
BMC Infect. Dis.
PUBLISHED: 01-06-2014
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A limitation of both culture-based and molecular methods of screening for staphylococcal infection is that current tests determine only the presence or absence of colonization with no information on the colonizing strain type. A technique that couples polymerase chain reaction to mass spectrometry (PCR/ESI-MS) has recently been developed and an assay validated to identify and genotype S. aureus and coagulase-negative staphylococci (CoNS).
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Prevalence and factors associated with herpes simplex virus type 2 infection in patients attending a Baltimore City emergency department.
PLoS ONE
PUBLISHED: 01-01-2014
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Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted disease, but there is limited data on its epidemiology among urban populations. The urban Emergency Department (ED) is a potential venue for surveillance as it predominantly serves an inner city minority population. We evaluate the seroprevalence and factors associated with HSV-2 infection among patients attending the Johns Hopkins Hospital Adult Emergency Department (JHH ED).
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Trends in Antibiotic Resistance in Coagulase Negative Staphylococci, United States, 1999--2012.
Antimicrob. Agents Chemother.
PUBLISHED: 12-16-2013
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Coagulase-negative staphylococci (CoNS) are important bloodstream pathogens typically resistant to multiple antibiotics. Despite concern about increasing resistance, there have been no recent studies describing the national prevalence in CoNS pathogens. We used national resistance data over a period of 13 years (1999-2012) from The Surveillance Network (TSN) to determine prevalence and assess trends in resistance for S. epidermidis, the most common CoNS pathogen, as well as all CoNS pathogens. Over the course of the study period, S. epidermidis resistance to ciprofloxacin and clindamycin increased steadily from 58.3% to 68.4% and from 43.4% to 48.5%, respectively. Resistance to levofloxacin increased rapidly from 57.1% in 1999 to a high of 78.6% in 2005, followed by a decrease to 68.1% in 2012. Multidrug resistance for CoNS followed a similar pattern, and this rise and small decline in resistance was found to be strongly correlated with levofloxacin prescribing patterns. Resistance patterns were similar for the aggregate of CoNS pathogens. The results from our study demonstrate that antibiotic resistance in CoNS pathogens has increased significantly over the past 13 years. These results are important as CoNS can serve as sentinels for monitoring resistance, and they play a role as a reservoir of resistance genes that can be transmitted to other pathogens. The link between the levofloxacin prescription rate and resistance levels suggest a critical role for reducing inappropriate use of fluoroquinolones and other broad-spectrum antibiotics in both healthcare settings and the community to help curb the reservoir of resistance in these colonizing pathogens.
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Streamlining HIV Testing in the Emergency Department-Leveraging Kiosks to Provide True Universal Screening: A Usability Study.
Telemed J E Health
PUBLISHED: 11-08-2013
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Abstract Background: Emergency department (ED) human immunodeficiency virus (HIV) screening programs are challenged by the unsustainable cost of exogenous staff and the relatively low penetration rates. Kiosk systems have increased registration efficiency in various clinical settings and have shown promising results for advancing various public health initiatives. This study evaluated the usability of kiosks within the existing HIV testing program and assessed patients perceived acceptability of kiosk-based screening in the ED. Subjects and Methods: ED patients (n=88) were asked to complete both a Registration Module (intended to integrate into the EDs pending kiosk registration system) and a Risk Assessment Module using a pen-based touchscreen tablet platform. Participants provided feedback upon program completion. All comments, questions, and errors were documented. Kiosk programs tracked time spent on each screen. Quantitative (chi-squared test or t test) and qualitative data analyses were performed. Results: Consented subjects (n=62) were 60% female, 69% were black, the mean±standard deviation age was 37.8±11.4 years, 52% had a high school degree or less, and 50% reported no prior kiosk experience. Mean time spent on the Registration and Risk Assessment Modules was 2:35±1:24?min and 5:09±1:58?min, respectively. The leading technical challenge identified was login: 84% of patients required assistance. Removal of the login screen reduced times to 1:05±0:36?min and 4:10±1:38?min. Ninety-five percent of subjects reported length of use as "just right," and over 75% of patients found the software easy to use, answered questions without help, and preferred screening on the kiosk to in-person interviews. Favorite aspects of the program included ease of use (52%), privacy (48%), and speed (30%). Sixty-six percent of patients reported there was nothing they disliked or would change. Conclusions: ED patient response to the kiosk system was favorable. Subjects easily and quickly navigated the program, with the exception of a login screen, which could be eliminated via automated login using ID bracelet scanners.
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Nonlinear Pharmacokinetics of ({+/-})3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat.
Drug Metab. Dispos.
PUBLISHED: 10-18-2013
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3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMAs safety are needed. We evaluated MDMAs pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (±)-3,4-dihydroxymethamphetamine (HHMA), (±)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (±)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA Cmax was 164 ± 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5- and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3- and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMAs behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses.
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Universal digital high-resolution melt: a novel approach to broad-based profiling of heterogeneous biological samples.
Nucleic Acids Res.
PUBLISHED: 08-09-2013
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Comprehensive profiling of nucleic acids in genetically heterogeneous samples is important for clinical and basic research applications. Universal digital high-resolution melt (U-dHRM) is a new approach to broad-based PCR diagnostics and profiling technologies that can overcome issues of poor sensitivity due to contaminating nucleic acids and poor specificity due to primer or probe hybridization inaccuracies for single nucleotide variations. The U-dHRM approach uses broad-based primers or ligated adapter sequences to universally amplify all nucleic acid molecules in a heterogeneous sample, which have been partitioned, as in digital PCR. Extensive assay optimization enables direct sequence identification by algorithm-based matching of melt curve shape and Tm to a database of known sequence-specific melt curves. We show that single-molecule detection and single nucleotide sensitivity is possible. The feasibility and utility of U-dHRM is demonstrated through detection of bacteria associated with polymicrobial blood infection and microRNAs (miRNAs) associated with host response to infection. U-dHRM using broad-based 16S rRNA gene primers demonstrates universal single cell detection of bacterial pathogens, even in the presence of larger amounts of contaminating bacteria; U-dHRM using universally adapted Lethal-7 miRNAs in a heterogeneous mixture showcases the single copy sensitivity and single nucleotide specificity of this approach.
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Reverse transcription-PCR-electrospray ionization mass spectrometry for rapid detection of biothreat and common respiratory pathogens.
J. Clin. Microbiol.
PUBLISHED: 07-31-2013
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Electrospray ionization mass spectrometry (ESI-MS) analysis of reverse transcription (RT)-PCR amplicons from human respiratory samples allows for broad pathogen identification approximately 8 h after collection. We investigated the performance characteristics of a high-throughput RT-PCR-coupled ESI-MS assay for distinguishing biothreat (BT) agents from common bacterial, fungal, and viral respiratory pathogens in bronchoalveolar lavage (BAL) fluid specimens from subjects with suspected respiratory infections. In a retrospective case series, 202 BAL fluid specimens were collected at the Johns Hopkins Hospital between August 2010 and February 2011 from patients with suspected acute respiratory infections. Samples were processed using standard bacterial, viral, and fungal testing in the clinical microbiology laboratory as part of routine care and then were blindly spiked with either water or nucleic acids from BT organisms (Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella spp., Burkholderia spp., and Rickettsia prowazekii) and tested by RT-PCR-ESI-MS. The sensitivities and specificities of RT-PCR-ESI-MS versus standard clinical methods were as follows: for mock BT DNA, 98.5% sensitivity (95% confidence interval [CI], 94.2 to 99.7%) and 100% specificity (95% CI, 93.1 to 100.0%); for bacterial pathogens, 81.8% sensitivity (95% CI, 74.3 to 87.6%) and 73.6% specificity (95% CI, 64.2 to 81.4%); for viral pathogens, 93.3% sensitivity (95% CI, 66.0 to 99.7%) and 97.3% specificity (95% CI, 89.7 to 99.5%); for fungal pathogens, 42.6% sensitivity (95% CI, 29.5 to 56.7%) and 97.8% specificity (95% CI, 91.8 to 99.6%). Our data suggest that RT-PCR-ESI-MS is a useful adjunct to standard culture protocols for rapid detection of both BT and common respiratory pathogens; further study is required for assay validation, especially for fungal detection, and potential implementation.
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Use of tablet-based kiosks in the emergency department to guide patient HIV self-testing with a point-of-care oral fluid test.
Int J STD AIDS
PUBLISHED: 07-19-2013
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Despite successes in efforts to integrate HIV testing into routine care in emergency departments, challenges remain. Kiosk-facilitated, directed HIV self-testing offers one novel approach to address logistical challenges. Emergency department patients, 18-64 years, were recruited to evaluate use of tablet-based-kiosks to guide patients to conduct their own point-of-care HIV tests followed by standard-of-care HIV tests by healthcare workers. Both tests were OraQuick Advance tests. Of 955 patients approached, 473 (49.5%) consented; 467 completed the test, and 100% had concordant results with healthcare workers. Median age was 41 years, 59.6% were female, 74.8% were African-American, and 19.6% were White. In all, 99.8% of patients believed the self-test was "definitely" or "probably" correct; 91.7% of patients "trusted their results very much"; 99.8% reported "overall" self-testing was "easy or somewhat easy" to perform. Further, 96.9% indicated they would "probably" or "definitely" test themselves at home were the HIV test available for purchase; 25.9% preferred self-testing versus 34.4% who preferred healthcare professional testing (p>0.05). Tablet-based kiosk testing proved to be highly feasible, acceptable, and an accurate method of conducting rapid HIV self-testing in this study; however, rates of engagement were moderate. More research will be required to ascertain barriers to increased engagement for self-testing.
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Sensitive Detection and Serovar Differentiation of Typhoidal and Nontyphoidal Salmonella enterica Species Using 16S rRNA Gene PCR Coupled with High-Resolution Melt Analysis.
J Mol Diagn
PUBLISHED: 07-17-2013
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Salmonella enterica species infections are a significant public health problem causing high morbidity rates worldwide and high mortality rates in the developing world. These infections are not always rapidly diagnosed as a cause of bloodstream infections because of the limitations of blood culture, which greatly affects clinical care as a result of treatment delays. A molecular diagnostic assay that could rapidly detect and identify S. enterica species infections as a cause of sepsis is needed. Nine typhoidal and nontyphoidal S. enterica serovars were used to establish the limit of detection (LOD) of a previously published 16S rRNA gene PCR (16S PCR) in mock whole blood specimens. In addition, 16 typhoidal and nontyphoidal S. enterica serovars were used to evaluate the serovar differentiation capability of 16S PCR coupled with high-resolution melt analysis. The overall LOD of 16S PCR for the nine typhoidal and nontyphoidal S. enterica serovars analyzed was <10 colony-forming units per milliliter (CFU/mL) in mock whole blood specimens, with the lowest and highest LOD at <1 CFU/mL and 9 CFU/mL, respectively. By high-resolution melt analysis, the typhoidal and nontyphoidal S. enterica serovar groups analyzed each generated a unique grouping code, allowing for serovar-level identification. 16S PCR coupled with high-resolution melt analysis could be a useful molecular diagnostic that could enhance the current diagnostic, treatment, and surveillance methods of S. enterica bloodstream infections.
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Interventions to mitigate emergency department and hospital crowding during an infectious respiratory disease outbreak: results from an expert panel.
PLoS Curr
PUBLISHED: 07-17-2013
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To identify and prioritize potential Emergency Department (ED) and hospital-based interventions which could mitigate the impact of crowding during patient surge from a widespread infectious respiratory disease outbreak and determine potential data sources that may be useful for triggering decisions to implement these high priority interventions.
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Symptomatic Pulmonary Embolus After Joint Arthroplasty: Stratification of Risk Factors.
Clin. Orthop. Relat. Res.
PUBLISHED: 06-18-2013
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Prophylaxis for pulmonary embolism (PE) after total joint arthroplasty (TJA) presents the clinical dilemma of balancing the risk of postoperative thrombotic risk and anticoagulation-related complications such as bleeding, hematoma formation, and infection. Risk stratification of patients undergoing TJA is needed to tailor prophylaxis based on thrombotic and bleeding risk.
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Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys.
Int. J. Neuropsychopharmacol.
PUBLISHED: 06-17-2013
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Monoamine releasers with varying selectivity for dopamine (DA)/norepinephrine and serotonin (5-HT) release are potential treatment medications for cocaine abuse. Although DA-selective monoamine releasers effectively reduce cocaine abuse, their clinical usefulness is limited by abuse liability. It is hypothesized that increasing 5-HT neurotransmission may reduce the abuse-related effects of DA releasers, but the optimal DA:5-HT release ratio remains to be determined. This study in rhesus monkeys compared the effects of two compounds with differing potency for 5-HT release. Methcathinone and 3-Cl-methcathinone (PAL-434) have equal potency for DA release, but PAL-434 has 10-fold higher potency for 5-HT release. In drug discrimination studies, monkeys were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline in a two-key, food-reinforced procedure. In drug self-administration studies, a separate group of monkeys was trained to respond for cocaine [0.01 mg/kg/injection (inj)] and food (1 g pellets) under a second order schedule of reinforcement [FR2(VR16:S)]. When responding was stable, methcathinone (0.1–0.56 mg/kg.h i.v.) or PAL-434 (0.32–1.8 mg/kg.h i.v.) was administered chronically (one injection every 20 min for 23 h/d) for 7–10 d. In discrimination studies, both compounds dose-dependently increased cocaine-like responding but with different potencies (cocaine=methcathinone >PAL-434). Chronic treatment with methcathinone or PAL-434 dose-dependently and selectively reduced cocaine self-administration. PAL-434 was about 4-fold and methcathinone about 1.6-fold more potent at decreasing cocaine- over food-maintained responding. These data suggest that compounds with moderate selectivity for DA vs. 5-HT release (8–15-fold) may be effective for the treatment of cocaine dependence.
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Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates.
Neuropsychopharmacology
PUBLISHED: 05-31-2013
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Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., 4 doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, two weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.Neuropsychopharmacology accepted article preview online, 28 November 2013. doi:10.1038/npp.2013.331.
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Agreement between routine emergency department care and clinical decision support recommended care in patients evaluated for mild traumatic brain injury.
Acad Emerg Med
PUBLISHED: 05-16-2013
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Emergency department (ED) computed tomography (CT) use has increased significantly during the past decade. It has been suggested that adherence to clinical decision support (CDS) may result in a safe decrease in CT ordering. In this study, the authors quantified the percentage agreement between routine and CDS-recommended care and the anticipated consequence of strict adherence to CDS on CT use in mild traumatic brain injury (mTBI).
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Emergency Physicians Adherence to Center for Disease Control and Prevention Guidance During the 2009 Influenza A H1N1 Pandemic.
West J Emerg Med
PUBLISHED: 04-20-2013
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Little is known regarding compliance with management guidelines for epidemic influenza in adult emergency department (ED) settings during the 2009 novel influenza A (H1N1) epidemic, especially in relation to the Centers for Disease Control and Prevention (CDC) guidance.
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Probes for narcotic receptor mediated phenomena. 48. C7- and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation.
Eur J Med Chem
PUBLISHED: 04-17-2013
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The exploration of the effect of substituents at C7 and C8 of the 5-phenylmorphans on their affinity for opioid receptors was enabled by our recently introduced "one pot" diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, C8-alkyl substituted 5-phenylmorphans, and compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. The affinity of the 5-phenylmorphans for opioid receptors is increased by a C8-methyl substituent, compared with its C7 analog. The affinity of the newly synthesized compounds is generally for the ?-opioid receptor, rather than the ?- or ?-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances ?-receptor affinity, bringing the Ki to the subnanomolar level. Unexpectedly, the N-methyl substituted compounds generally had higher affinity than comparable N-phenethyl-substituted relatives. The configurations of two compounds were determined by single-crystal X-ray crystallographic analyses.
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Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates.
J. Pharmacol. Exp. Ther.
PUBLISHED: 04-08-2013
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The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic, and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. Because both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands possess an addictive liability equivalent to that of cocaine. However, certain recently developed ligands, such as atypical benztropine-like DAT inhibitors with reduced or even a complete lack of cocaine-like rewarding effects, suggest that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classic preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific pleiotropic functional qualities inherent to G-protein-coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein that can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychological effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders.
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Quantitative video-oculography to help diagnose stroke in acute vertigo and dizziness: toward an ECG for the eyes.
Stroke
PUBLISHED: 03-05-2013
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Strokes can be distinguished from benign peripheral causes of acute vestibular syndrome using bedside oculomotor tests (head impulse test, nystagmus, test-of-skew). Using head impulse test, nystagmus, test-of-skew is more sensitive and less costly than early magnetic resonance imaging for stroke diagnosis in acute vestibular syndrome but requires expertise not routinely available in emergency departments. We sought to begin standardizing the head impulse test, nystagmus, test-of-skew diagnostic approach for eventual emergency department use through the novel application of a portable video-oculography device measuring vestibular physiology in real time. This approach is conceptually similar to ECG to diagnose acute cardiac ischemia.
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Probes for narcotic receptor mediated phenomena. 47. Novel C4a- and N-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols.
Bioorg. Med. Chem.
PUBLISHED: 02-20-2013
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A series of N-methyl rac-cis-4a-aralkyl- and alkyl-substituted-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols have been prepared (2a-l) using a simple previously designed synthetic route, in order to find a ligand that would interact with both ?- and ?-opioid receptors. A C4a-phenethyl derivative 2a, was found to have modest receptor affinity both at ?- (K(i)=60 nM) and ?-opioid receptors (K(i)=64 nM). The N-methyl substituent of 2a and that of other ligands in the series was then modified to obtain compounds with different N-substituents that might provide higher affinity at both receptors. A number of compounds differently substituted at C4a and N were synthesized and evaluated. Binding studies and functional assays revealed a moderately selective ?-antagonist (2l), selective ?-? antagonists (3d, 3g), and a ?-? antagonist (3f).
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Surgical care improvement project (SCIP): has its mission succeeded?
J Arthroplasty
PUBLISHED: 02-06-2013
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The purpose of this study was to determine if adherence to the surgical care improvement project (SCIP) measures could further reduce rate of surgical site infection (SSI) and venous thromboembolism (VTE) in total joint arthroplasty (TJA) patients. We retrospectively identified all patients who underwent primary or revision TJA at our institution between July 2000 and June 2009. After implementation of SCIP measures, rate of superficial SSI increased (0.42% versus 0.60%, P=0.05) while rate of deep SSI decreased from 0.92% to 0.82% (P=0.46). The rate of DVT was 0.92% before and 0.83% after implementation of SCIP (P=0.51); however, rate of PE increased from 0.87% to 1.30% (P=0.002). Our findings indicated that SCIP has not been successful in reducing complications in TJA patients.
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Emergency management of community-acquired bacterial pneumonia: what is new since the 2007 Infectious Diseases Society of America/American Thoracic Society guidelines.
Am J Emerg Med
PUBLISHED: 02-04-2013
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Community-acquired pneumonia (CAP) is a major health problem in the United States and is associated with substantial morbidity, mortality, and health care costs. Patients with CAP commonly present to emergency departments where physicians must make critical decisions regarding diagnosis and management of pneumonia in a timely fashion, with emphasis on efficient and cost-effective diagnostic choices, consideration of emerging antimicrobial resistance, timely initiation of antibiotics, and appropriate site-of-care decisions. In light of the burden that pneumonia places on health care systems and the emergency department in particular, this article reviews significant developments in the management of CAP in the United States 5 years since the publication of the 2007 Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of CAP in adults, focusing on recent studies and recommendations for managing CAP, the primary bacterial pathogens responsible for CAP, and trends in resistance, new diagnostic technologies, and newer antimicrobials approved for the treatment of CAP. These new data and additional guidelines pertaining to the treatment of CAP further our knowledge and understanding of this challenging infection. Furthermore, appreciation of the availability of new diagnostic testing and therapeutic options will help meet the demand for improved management of CAP.
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Derivation of a clinical prediction rule to predict hospitalization for influenza in EDs.
Am J Emerg Med
PUBLISHED: 02-04-2013
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Early, rapid, and accurate identification of those patients who have severe influenza is important for emergency physicians. Influenza viral load, which has been proposed as a predictor of severe influenza, could be useful in facilitating decision making of resource use. We aimed to derive a clinical prediction rule to indicate probability for inpatient hospitalization for patients with influenza, which includes influenza viral load in addition to other clinical information commonly collected in the emergency department (ED).
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Influenza forecasting with Google Flu Trends.
PLoS ONE
PUBLISHED: 01-07-2013
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We developed a practical influenza forecast model based on real-time, geographically focused, and easy to access data, designed to provide individual medical centers with advanced warning of the expected number of influenza cases, thus allowing for sufficient time to implement interventions. Secondly, we evaluated the effects of incorporating a real-time influenza surveillance system, Google Flu Trends, and meteorological and temporal information on forecast accuracy.
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Cost-utility of rapid polymerase chain reaction-based influenza testing for high-risk emergency department patients.
Ann Emerg Med
PUBLISHED: 01-02-2013
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We evaluate the cost-effectiveness of polymerase chain reaction (PCR)-based rapid influenza testing and treatment for influenza in adult emergency department (ED) patients who are at high risk for or have evidence of influenza-related complications.
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Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation.
PLoS ONE
PUBLISHED: 01-01-2013
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The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of ?-opioid receptor (MOR)-related G proteins by iboga alkaloids.
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The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.
Neuropsychopharmacology
PUBLISHED: 12-14-2011
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The nonmedical use of designer cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.
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Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A.
Medchemcomm
PUBLISHED: 08-20-2011
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Previous structure-activity relationship studies of salvinorin A have shown that modification of the acetate functionality off the C-2 position to a methoxy methyl or methoxy ethyl ether moiety leads to increased potency at KOP receptors. However, the reason for this increase remains unclear. Here we report our efforts towards the synthesis and evaluation of C-2 constrained analogs of salvinorin A. These analogs were evaluated at opioid receptors in radioligand binding experiments as well as in the GTP-?-S functional assay. One compound, 5, was found to have affinity and potency at ? opioid (KOP) receptors comparable to salvinorin A. In further studies, 5 was found to attenuate cocaine-induced drug seeking behavior in rats comparably to salvinorin A. This finding represents the first example of a salvinorin A analog that has demonstrated anti-addictive capabilities.
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Effects of MDMA and related analogs on plasma 5-HT: relevance to 5-HT transporters in blood and brain.
Eur. J. Pharmacol.
PUBLISHED: 07-01-2011
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(±)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g., blood), and evidence suggests that MDMA targets platelet SERT to increase plasma 5-HT. Here we tested two hypotheses related to the effects of MDMA on circulating 5-HT. First, to determine if MDMA metabolites might contribute to actions of the drug in vivo, we used in vitro microdialysis in rat blood specimens to examine the effects of MDMA and its metabolites on plasma 5-HT. Second, to determine whether effects of MDMA on plasma 5-HT might be used as an index of central SERT activity, we carried out in vivo microdialysis in blood and brain after intravenous MDMA administration. The in vitro results show that test drugs evoke dose-related increases in plasma 5-HT ranging from two- to sevenfold above baseline, with MDMA and its metabolite, (±)-3,4-methylenedioxyamphetamine (MDA), producing the largest effects. The ability of MDMA and related analogs to elevate plasma 5-HT is correlated with their potency as SERT substrates in rat brain synaptosomes. The in vivo results reveal that MDMA causes concurrent increases in extracellular 5-HT in blood and brain, but there are substantial individual differences in responsiveness to the drug. Collectively, our findings indicate that MDMA and its metabolites increase plasma 5-HT by a SERT-dependent mechanism, and suggest the possibility that measures of evoked 5-HT release in blood may reflect central SERT activity.
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Computer-facilitated rapid HIV testing in emergency care settings: provider and patient usability and acceptability.
AIDS Educ Prev
PUBLISHED: 06-24-2011
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Providers in emergency care settings (ECSs) often face barriers to expanded HIV testing. We undertook formative research to understand the potential utility of a computer tool, "CARE," to facilitate rapid HIV testing in ECSs. Computer tool usability and acceptability were assessed among 35 adult patients, and provider focus groups were held, in two ECSs in Washington State and Maryland. The computer tool was usable by patients of varying computer literacy. Patients appreciated the tools privacy and lack of judgment and their ability to reflect on HIV risks and create risk reduction plans. Staff voiced concerns regarding ECS-based HIV testing generally, including resources for follow-up of newly diagnosed people. Computer-delivered HIV testing support was acceptable and usable among low-literacy populations in two ECSs. Such tools may help circumvent some practical barriers associated with routine HIV testing in busy settings though linkages to care will still be needed.
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Operational methods of HIV testing in emergency departments: a systematic review.
Ann Emerg Med
PUBLISHED: 06-21-2011
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Casual review of existing literature reveals a multitude of individualized approaches to emergency department (ED) HIV testing. Cataloging the operational options of each approach could assist translation by disseminating existing knowledge, endorsing variability as a means to address testing barriers, and laying a foundation for future work in the area of operational models and outcomes investigation. The objective of this study is to provide a detailed account of the various models and operational constructs that have been described for performing HIV testing in EDs.
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Will patients "opt in" to perform their own rapid HIV test in the emergency department?
Ann Emerg Med
PUBLISHED: 06-21-2011
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We evaluate the feasibility and accuracy of existing point-of-care HIV tests performed by an untrained patient compared with the routinely used HIV point-of-care test offered to patients in 2 urban emergency departments (EDs).
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Ethical, financial, and legal considerations to implementing emergency department HIV screening: a report from the 2007 conference of the National Emergency Department HIV Testing Consortium.
Ann Emerg Med
PUBLISHED: 06-21-2011
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We seek to identify and analyze, from a group of participants experienced with HIV screening, the perceived challenges and solutions to the ethical, financial, and legal considerations of emergency department (ED)-based HIV screening.
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2009 US emergency department HIV testing practices.
Ann Emerg Med
PUBLISHED: 06-21-2011
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We characterize HIV testing practices and programs in US emergency departments (EDs) in 2009.
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Public health and clinical impact of increasing emergency department-based HIV testing: perspectives from the 2007 conference of the National Emergency Department HIV Testing Consortium.
Ann Emerg Med
PUBLISHED: 06-21-2011
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Understanding perceived benefits and disadvantages of HIV testing in emergency departments (EDs) is imperative to overcoming barriers to implementation. We codify those domains of public health and clinical care most affected by implementing HIV testing in EDs, as determined by expert opinion.
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Outcomes and cost analysis of 3 operational models for rapid HIV testing services in an academic inner-city emergency department.
Ann Emerg Med
PUBLISHED: 06-21-2011
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We compare the outcomes and costs of alternative staffing models for an emergency department (ED) rapid HIV testing program.
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HIV screening programs in US emergency departments: a cross-site comparison of structure, process, and outcomes.
Ann Emerg Med
PUBLISHED: 06-21-2011
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We present findings from a multisite evaluation that systematically compares HIV screening programs in 6 emergency departments (EDs).
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HIV testing in emergency departments in the United States: a national survey.
Ann Emerg Med
PUBLISHED: 06-21-2011
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In 2006, the Centers for Disease Control and Prevention (CDC) published recommendations for HIV testing in health care settings, calling for nontargeted opt-out rapid HIV screening in most settings, including emergency departments (EDs). Although a number of ED-based testing strategies exist, it is unclear to what extent they are used. The objective of this study is to survey academic and community EDs throughout the United States to determine ED-based HIV testing practices.
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Who needs autologous blood donation in joint replacement?
J Knee Surg
PUBLISHED: 05-31-2011
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Conflicting results are available about the efficacy of routine preoperative autologous donation (PAD) in reducing allogenic blood transfusion during total joint arthroplasty (TJA). This study aimed to determine if PAD is effective in reducing the need for allogenic transfusion after TJA. For this retrospective study, data on 409 patients who received total knee arthroplasty (TKA) and 513 who underwent total hip arthroplasty (THA) from January to June 2005 were evaluated. It is our institutional policy to offer preoperative donation to all patients. Based on patient decision, preoperative hemoglobin, and other factors, PAD may or may not take place. Five hundred forty-six (61%) patients donated on average 1.3 units (range, 1 to 2) of blood. Autologous and allogenic transfusions were respectively performed in 91% (514 patients) and 24% of our cohort. The rate of allogenic transfusion after TKA was lower in the PAD group at 21% versus 27% among the nondonors, although it was not statistically significant (p = 0.10). The allogenic transfusion rate after THA was significantly lower among autologous donors (16% versus 34%, p = 0.003). Advanced age, lower body mass index, simultaneous bilateral arthroplasty, and lower preoperative hemoglobin were independently associated with increased allogenic blood transfusion. PAD seems to be effective in reducing allogenic transfusions after THA but not TKA.
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Insights into the Sigma-1 receptor chaperones cellular functions: a microarray report.
Synapse
PUBLISHED: 04-20-2011
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We previously demonstrated that Sig-1Rs are critical regulators in neuronal morphogenesis and development via the regulation of oxidative stress and mitochondrial functions. In the present study, we sought to identify pathways and genes that are affected by Sig-1R. Gene expression profiles were examined in rat hippocampal neurons that had been cultured for 18 days in vitro (DIV). The cells were transduced with AAV siRNA targeting Sig-1R on DIV 10 for 7 days, followed by gene expression analysis using a rat genome cDNA array. The gene array results indicated that Sig-1R knockdown hampered cellular functions including steroid biogenesis, protein ubiquitination, actin cytoskeleton network, and Nrf-2 mediated oxidative stress. Many of the cellular components important for actin polymerization and synapse plasticity, including F-actin capping protein and neurofilaments, were significantly changed in AAV-siSig-1R neurons. Further, cytochrome c was reduced in AAV-Sig-1R neurons whereas free-radical generating enzymes including cytochrome p450 and cytochrome b-245 were increased. The microarray results also suggest that Sig-1Rs may regulate genes that are involved in the pathogenesis of many CNS diseases including Alzheimers disease and Parkinsons disease. These data further confirmed that Sig-1Rs play critical roles in the CNS and thus these findings may aid in future development of therapeutic treatments targeting neurodegenerative disorders.
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Secondary resurfacing of the patella after primary total knee arthroplasty does the anterior knee pain resolve?
J Arthroplasty
PUBLISHED: 04-16-2011
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Although it has been shown that the risk of anterior knee pain is greater in patients with nonresurfaced patellae, it is not exactly clear whether the pain would resolve with secondary resurfacing of the patella. Thirty-nine patients (41 knees) underwent secondary patellar resurfacing between January 2001 and January 2007. The mean age was 66 years. The mean body mass index was 29.2 kg/m(2). The average time from primary total knee arthroplasty to resurfacing procedure was 29 months. The mean follow-up was 54 months. Anterior knee pain was the indication for secondary resurfacing in all patients. Although the clinical and functional knee scores improved significantly for whole cohort, 8 patients (8 knees) were dissatisfied with the outcome of surgery. This study highlights that secondary resurfacing is not an always rewarding procedure and patients need to be consulted appropriately with regard to the outcome.
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Probes for narcotic receptor mediated phenomena. 43. Synthesis of the ortho-a and para-a, and improved synthesis and optical resolution of the ortho-b and para-b oxide-bridged phenylmorphans: compounds with moderate to low opioid-receptor affinity.
Bioorg. Med. Chem.
PUBLISHED: 04-07-2011
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N-Phenethyl-substituted ortho-a and para-a oxide-bridged phenylmorphans have been obtained through an improved synthesis and their binding affinity examined at the various opioid receptors. Although the N-phenethyl substituent showed much greater affinity for ?- and ?-opioid receptors than their N-methyl relatives (e.g., K(i)=167 nM and 171 nM at ?- and ?-receptors vs >2800 and 7500 nM for the N-methyl ortho-a oxide-bridged phenylmorphan), the a-isomers were not examined further because of their relatively low affinity. The N-phenethyl substituted ortho-b and para-b oxide-bridged phenylmorphans were also synthesized and their enantiomers were obtained using supercritical fluid chromatography. Of the four enantiomers, only the (+)-ortho-b isomer had moderate affinity for ?- and ?-receptors (K(i)=49 and 42 nM, respectively, and it was found to also have moderate ?- and ?-opioid antagonist activity in the [(35)S]GTP-?-S assay (K(e)=31 and 26 nM).
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Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A.
Pharmacol. Rev.
PUBLISHED: 03-28-2011
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Salvia divinorum is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease panzón de borrego. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolized smoke, S. divinorum has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT(2A) receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biological processes responsible for its observed psychological effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.
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A meta-analysis of point-of-care laboratory tests in the diagnosis of novel 2009 swine-lineage pandemic influenza A (H1N1).
Diagn. Microbiol. Infect. Dis.
PUBLISHED: 03-15-2011
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This paper reviews 14 published studies describing performance characteristics, including sensitivity and specificity, of commercially available rapid, point-of-care (POC) influenza tests in patients affected by an outbreak of a novel swine-related influenza A (H1N1) that was declared a pandemic in 2009. Although these POC tests were not intended to be specific for this pandemic influenza strain, the nonspecialized skills required and the timeliness of results make these POC tests potentially valuable for clinical and public health use. Pooled sensitivity and specificity for the POC tests studied were 68% and 81%, respectively, but published values were not homogeneous with sensitivities and specificities ranging from 10% to 88% and 51% to 100%, respectively. Pooled positive and negative likelihood ratios were 5.94 and 0.42, respectively. These results support current recommendations for use of rapid POC tests when H1N1 is suspected, recognizing that positive results are more reliable than negative results in determining infection, especially when disease prevalence is high.
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Hip dislocation: are hip precautions necessary in anterior approaches?
Clin. Orthop. Relat. Res.
PUBLISHED: 02-25-2011
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In 2005, we reported removal of functional restriction after primary THA performed through the anterolateral approach did not increase the incidence of dislocation.
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Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.
J. Nat. Prod.
PUBLISHED: 02-21-2011
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As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.
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Poor provider adherence to the Centers for Disease Control and Prevention treatment guidelines in US emergency department visits with a diagnosis of pelvic inflammatory disease.
Sex Transm Dis
PUBLISHED: 02-15-2011
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Pelvic inflammatory disease (PID) is commonly diagnosed in US emergency departments (EDs). We aimed to estimate national rates of provider adherence to the Centers for Disease Control and Prevention (CDC) treatment guidelines for PID among patient visits, with a diagnosis of acute PID in US ED settings.
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Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension.
PLoS ONE
PUBLISHED: 02-10-2011
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The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (Tph1(-/-) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in Tph1(-/-) mice. We postulated that: 1) Tph1(-/-) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) Tph1(-/-) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female Tph1(-/-) mice. The expression of 51 distinct genes was significantly altered in the lungs of female Tph1(-/-) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female Tph1(-/-) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized.
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Primary total hip arthroplasty with an uncemented femoral component five- to nine-year results.
J Arthroplasty
PUBLISHED: 02-07-2011
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This study reports the outcome of total hip arthroplasty with use of an uncemented, tapered stem with a 5- to 9-year follow-up. The first 200 consecutive patients (214 hips) undergoing total hip arthroplasty with the Accolade TMZF stem (Stryker Orthopaedics, Mahwah, NJ) were enrolled prospectively. Follow-up for these patients averaged 7.6 years and encompassed review of clinical records as well as review of serial anteroposterior and lateral radiographs. There were 5 revision surgeries for aseptic loosening, 2 cases of infection, instability, and polyethylene wear. Our failure rate, defined as hips needing revision, was 2.6%, and the failure rate due to aseptic loosening of the femoral component was 0.6%. These results demonstrate the high success rate of this implant providing support for its continued use.
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A squeaky reputation: the problem may be design-dependent.
Clin. Orthop. Relat. Res.
PUBLISHED: 01-29-2011
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Squeaking is reportedly a complication in patients having ceramic-on-ceramic total hip implants. The etiology remains unknown and multifactorial with recent studies suggesting a relationship between the audible squeak and implant design. When we evaluated our ceramic-on-ceramic cohort, we noticed squeaking primarily in patients receiving an acetabular system designed with an elevated titanium rim.
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Probes for narcotic receptor mediated phenomena. Part 42: synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans.
Bioorg. Med. Chem.
PUBLISHED: 01-25-2011
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A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan(rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)) was found to have the highest ?-opioid receptor affinity (K(i)=1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([³?S]GTP-?-S) showed that the racemate 12 was more than three times more potent than naloxone as an ?-opioid antagonist.
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Reverse transcription polymerase chain reaction and electrospray ionization mass spectrometry for identifying acute viral upper respiratory tract infections.
Diagn. Microbiol. Infect. Dis.
PUBLISHED: 01-22-2011
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Diagnosis of respiratory viruses traditionally relies on culture or antigen detection. We aimed to demonstrate capacity of the reverse transcription polymerase chain reaction/electrospray ionization mass spectrometry (RT-PCR/ESI-MS) platform to identify clinical relevant respiratory viruses in nasopharyngeal aspirate (NPA) samples and compare the diagnostic performance characteristics relative to conventional culture- and antigen-based methods. An RT-PCR/ESI-MS respiratory virus surveillance kit designed to detect respiratory syncytial virus, influenza A and B, parainfluenza types 1-4, Adenoviridae types A-F, Coronaviridae, human bocavirus, and human metapneumovirus was evaluated using both mock-ups and frozen archived NPA (N = 280), 95 of which were positive by clinical virology methods. RT-PCR/ESI-MS detected 74/95 (77.9%) known positive samples and identified an additional 13/185 (7%) from culture-negative samples. Viruses that are nondetectable with conventional methods were also identified. Viral load was semiquantifiable and ranged from 2400 to >320?000 copies/mL. Time to results was 8 h. RT-PCR/ESI-MS showed promise in rapid detection of respiratory viruses and merits further evaluation for use in clinical settings.
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Probes for narcotic receptor mediated phenomena. 41. Unusual inverse ?-agonists and potent ?-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans.
J. Med. Chem.
PUBLISHED: 01-19-2011
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Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher ?-affinity than the compound with an N-phenylpropyl substituent (K(i) = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [(35)S]GTP-?-S functional binding assay using nondependent cells that stably express the cloned human ?-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent ?-opioid antagonists ((+)-29, K(e) = 0.17 and (-)-30, K(e) =0.3) in the [(35)S]GTP-?-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their ?-opioid receptor affinity in terms of the spatial position of N-substituents.
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In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat.
J. Pharmacol. Exp. Ther.
PUBLISHED: 01-12-2011
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Evidence suggests that elevations in extracellular serotonin (5-HT) in the brain can diminish stimulant effects of dopamine (DA). To assess this proposal, we evaluated the pharmacology of amphetamine analogs (m-fluoroamphetamine, p-fluoroamphetamine, m-methylamphetamine, p-methylamphetamine), which display similar in vitro potency as DA releasers (EC(50) = 24-52 nM) but differ in potency as 5-HT releasers (EC(50) = 53-1937 nM). In vivo microdialysis was used to assess the effects of drugs on extracellular DA and 5-HT in rat nucleus accumbens, while simultaneously measuring ambulation (i.e., forward locomotion) and stereotypy (i.e., repetitive movements). Rats received two intravenous injections of drug, 1 mg/kg at time 0 followed by 3 mg/kg 60 min later. All analogs produced dose-related increases in dialysate DA and 5-HT, but the effects on DA did not agree with in vitro predictions. Maximal elevation of dialysate DA ranged from 5- to 14-fold above baseline and varied inversely with 5-HT response, which ranged from 6- to 24-fold above baseline. All analogs increased ambulation and stereotypy, but drugs causing greater 5-HT release (e.g., p-methylamphetamine) were associated with significantly less forward locomotion. The magnitude of ambulation was positively correlated with extracellular DA (p < 0.001) and less so with the ratio of DA release to 5-HT release (i.e., percentage DA increase divided by percentage 5-HT increase) (p < 0.029). Collectively, our findings are consistent with the hypothesis that 5-HT release dampens stimulant effects of amphetamine-type drugs, but further studies are required to address the precise mechanisms underlying this phenomenon.
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Perinatal lead exposure alters locomotion induced by amphetamine analogs in rats.
Life Sci.
PUBLISHED: 01-11-2011
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The precise neurochemical perturbations through which perinatal (gestation/lactation) lead exposure modifies the reinforcement efficacy of various psychoactive drugs (e.g., cocaine, opiates) are unknown. The present study considers the role of altered serotonin and dopamine functionality in perinatal lead-psychostimulant interactions.
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Rapid identification viruses from nasal pharyngeal aspirates in acute viral respiratory infections by RT-PCR and electrospray ionization mass spectrometry.
J. Virol. Methods
PUBLISHED: 01-06-2011
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Diagnosis of the etiologic agent of respiratory viral infection relies traditionally on culture or antigen detection. This pilot evaluation compared performance characteristics of the RT-PCR and electrospray ionization mass spectrometry (RT-PCR/ESI-MS) platform to conventional virologic methods for identifying multiple clinically relevant respiratory viruses in nasopharyngeal aspirates. The RT-PCR/ESI-MS respiratory virus surveillance kit was designed to detect respiratory syncytial virus, influenza A and B, parainfluenza types 1-4, adenoviridae types A-F, coronaviridae, human bocavirus, and human metapneumovirus. Patients (N=192) attending an emergency department during the 2007-2008 respiratory season consented, and "excess" frozen archived nasopharyngeal aspirates were analysed; 46 were positive by conventional virology and 69 by RT-PCR/ESI-MS, among which there were six samples with multiple viral pathogens detected. The sensitivity and specificity of the assay were 89.1% and 80.3%, respectively. Additional viruses that were not identified by conventional virology assays were detected (4 human bocaviruses and 7 coronaviruses). Samples in which the RT-PCR/ESI-MS results disagreed with conventional virology were sent for analysis by a third method using a commercial RT-PCR-based assay, which can identify viruses not detectable by conventional virologic procedures. Time to first result of RT-PCR/ESI-MS was 8h. RT-PCR/ESI-MS demonstrated capacity to detect respiratory viruses identifiable and unidentifiable by conventional methods rapidly.
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Anabolic androgenic steroid induced myocardial toxicity: an evolving problem in an ageing population.
BMJ Case Rep
PUBLISHED: 01-01-2011
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Widespread use of anabolic androgenic steroid (AAS) abuse is a rapidly increasing public health concern with an expanding demographic. Previous studies and reports have been exclusive to young individuals at low risk for traditional, non-AAS associated, cardiovascular disease. To date, the impact of AAS use on older patients has not been well characterised. The patient herein presented documents a dramatic case of an older individual who developed decompensated heart failure secondary to illicit use of AAS, highlighting an evolving problem among a rapidly expanding demographic and illustrating that a) AAS, used to alter appearance or augment performance, is no longer an issue confined to young adults; b) older individuals with ageing myocardium may be particularly susceptible to AAS toxicity and may present with fulminate congestive heart failure; and that c) AAS abstinence coupled with traditional heart failure pharmacotherapy may be an effective treatment for this condition.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.