α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans.

Preclinical studies implicate a role for α₁-noradrenergic receptors in the effects of psychostimulants, including 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The present study evaluated the effects of the α₁-noradrenergic receptor antagonist doxazosin on the acute pharmacodynamic and pharmacokinetic response to MDMA in 16 healthy subjects. Doxazosin (8 mg/d) or placebo was administered for 3 days before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, 4-session, crossover design. Doxazosin reduced MDMA-induced elevations in blood pressure, body temperature, and moderately attenuated positive mood but enhanced tachycardia associated with MDMA. The results indicate that α₁-adrenergic receptors contribute to the acute cardiostimulant and to a minor extent possibly also to the thermogenic and euphoric effects of MDMA in humans.

Oligoanalgesia in the emergency department: short-term beneficial effects of an education program on acute pain.

STUDY OBJECTIVE: Acute pain is the most frequent complaint in emergency department (ED) admissions, but its management is often neglected, placing patients at risk of oligoanalgesia. We evaluate the effect of the implementation of guidelines for pain management in ED patients with pain at admission or anytime during their stay in our ED. METHODS: This prospective pre-post intervention cohort study included data collection both before and after guideline implementation. Consecutive adult patients admitted with acute pain from any cause or with pain at any time after admission were enrolled. The quality of pain management was evaluated according to information in the ED medical records by using a standardized collection form, and its impact on patients was recorded with a questionnaire at discharge. RESULTS: Two hundred forty-nine and 192 patients were included during pre- and postintervention periods. Pain was documented in 61% and 76% of nurse and physician notes, respectively, versus 78% and 85% after the intervention (difference 17%/9%; 95% confidence interval [CI] 8% to 26%/2% to 17%, respectively). Administration of analgesia increased from 40% to 63% (difference 23%; 95% CI 13% to 32%) and of morphine from 10% to 27% (difference 17%; 95% CI 10% to 24%). Mean doses of intravenous morphine increased from 2.4 mg (95% CI 1.9 to 2.9 mg) to 4.6 mg (95% CI 3.9 to 5.3 mg); administration of nonsteroidal antiinflammatory drugs and acetaminophen increased as well. There was a greater reduction of visual analogue scale score after intervention: 2.1 cm (95% CI 1.7 to 2.4 cm) versus 2.9 cm (95% CI 2.5 to 3.3 cm), which was associated with improved patient satisfaction. CONCLUSION: Education program and guidelines implementation for pain management lead to improved pain management, analgesia, and patient satisfaction in the ED.

Citizens' preferences for brand name drugs for treating acute and chronic conditions: a pilot study.

Background: Generic drugs have been advocated to decrease the proportion of healthcare costs devoted to drugs, but are still underused. Objective: To assess citizens' preferences for brand name drugs (BNDs) compared with generic drugs for treating acute and chronic conditions. Methods: A questionnaire with eight hypothetical scenarios describing four acute and four chronic conditions was developed, with willingness to pay (WTP) determined using a payment card system randomized to ascending (AO) or descending order (DO) of prices. The questionnaire was distributed with an explanation sheet, an informed consent form and a pre-stamped envelope over a period of 3 weeks in 19 community pharmacies in Lausanne, Switzerland. The questionnaire was distributed to every third customer who also had health insurance, understood French and was aged =16 years (up to a maximum of ten customers per day and 100 per pharmacy). The main outcome measure was preferences assessed by WTP for BNDs as compared with generics, and impact of participants' characteristics on WTP. Results: Of the 1800 questionnaires, 991 were distributed and 393 returned (pharmacy participation rate?=?55%, subject participation rate?=?40%, overall response rate?=?22%); 51.7% were AO and 48.3% DO. Participants were predominantly women (62.6%) and of median age 62 years (range 16-90). The majority (70%) declared no WTP for BNDs as compared with generics. WTP was higher in people with an acute disease than in those with a chronic disease, did not depend on the type of chronic disease, and was higher in people from countries other than Switzerland. Conclusions: Most citizens visiting pharmacies attribute no added value to BNDs as compared with generics, although some citizen characteristics affected WTP. These results could be of interest to several categories of decision makers within the healthcare system.

Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndromes: Rational for "Double" and "Triple" Rule-Out Concepts

PURPOSE To evaluate the prevalence of acute coronary syndrome (ACS) in patients presenting initially with atypical chest pain and suspected to have pulmonary embolism (PE) or acute aortic syndromes (AAS). To evaluate the overlap between ACS, PE and AAS in routine practice and determine how many patients could have benefit from a single CT protocol to rule out ACS at the same time as PE and AAS. METHOD AND MATERIALS Our electronic hospital database revealed 1122 consecutive patients who underwent a thoracic CT angiography for PE or AAS from 2004 to 2006 (mean age, 63±13 years). Patients without chest pain were excluded from this study. Thus, 447 patients presented with isolated atypical chest were included in the analysis. All patients who underwent a thoracic CT scan previously received standard clinical care and were initially considered as non ACS. The final diagnosis was obtained by the hospital stay report. RESULTS Among the 447 patients with atypical chest pain, 25 (5.5%) were finally found to have ACS: 19 patients (4.2%) were suspected for PE and 6 (1. 3%) were suspected for AAS. There were 90 patients diagnosed to have PE, 89 (98.8%) of them were suspected for PE while only 1 (1%) was suspected for AAS. Eleven patients diagnosed to have AAS, 9 (82%) of them were suspected for AAS while 2 (18%) were suspected for PE. CONCLUSION In clinical practice, the overlap between PE, AAS and ACS is limited which make the triple rule-out studies less recommended to be done at the time being because of the high dose radiation. A double rule-out investigation is suggested to be done for patients being evaluated for atypical chest pain and suspected of having AAS or PE because of a significant overlap between the two entities as well it doesn't implicate any increment in radiation dose. CLINICAL RELEVANCE/APPLICATION With 64-slice CT, coronary circulation and total chest can be evaluated at the same time offering new opportunitie for the evaluation of three major life-threatening conditions :ACS,PE and AAS.

Magnitude of CD8 T-cell responses against hepatitis C virus and severity of hepatitis do not necessarily determine outcomes in acute hepatitis C virus infection.

Aim: We investigated the relationship between the magnitude of comprehensive hepatitis C virus (HCV)-specific CD8(+) T-cell responses and the clinical course of acute HCV infection. Methods: Six consecutive patients with acute HCV infection were studied. Analysis of HCV-specific CD8(+) T-cell responses was performed using an interferon-gamma-based enzyme-linked immunospot assay using peripheral CD8(+) T-cells, monocytes and 297 20-mer synthetic peptides overlapping by 10 residues and spanning the entire HCV sequence of genotype 1b. Results: Five patients presented detectable HCV-specific CD8(+) T-cell responses against a single and different peptide, whereas 1 patient showed responses against three different peptides. Neither the magnitude of HCV-specific CD8(+) T-cell responses nor the severity of hepatitis predicts the outcome of acute hepatitis. The maximum number of HCV-specific CD8(+) T-cells correlated with maximum serum alanine aminotransferase level during the course (r = 0.841, P = 0.036). Conclusions: HCV-specific CD8(+) T-cell responses were detectable in all 6 patients with acute HCV infection, and 6 novel HCV-specific CTL epitopes were identified. Acute HCV infection can resolve with detectable HCV-specific CD8(+) T-cell responses, but without development of antibody against HCV.

Impact of medical practice guidelines on the assessment of patients with acute coronary syndrome without persistent ST segment elevation.

OBJECTIVE: To assess the impact of introducing clinical practice guidelines on acute coronary syndrome without persistent ST segment elevation (ACS) on patient initial assessment. DESIGN: Prospective before-after evaluation over a 3-month period. SETTING: The emergency ward of a tertiary teaching hospital. PATIENTS: All consecutive patients with ACS evaluated in the emergency ward over the two 3-month periods. INTERVENTION: Implementation of the practice guidelines, and the addition of a cardiology consultant to the emergency team. MAIN OUTCOME MEASURES: Diagnosis, electrocardiogram interpretation, and risk stratification after the initial evaluation. RESULTS: The clinical characteristics of the 328 and 364 patients evaluated in the emergency ward for suspicion of ACS before and after guideline implementation were similar. Significantly more patients were classified as suffering from atypical chest pain (39.6% versus 47.0%; P = 0.006) after guideline implementation. Guidelines availability was associated with significantly more formal diagnoses (79.9% versus 92.9%; P < 0.0001) and risk stratification (53.7% versus 65.4%, P < 0.0001) at the end of initial assessment. CONCLUSION: Guidelines implementation, along with availability of a cardiology consultant in the emergency room had a positive impact on initial assessment of patients evaluated for suspicion of ACS. It led to increased confidence in diagnosis and stratification by risk, which are the first steps in initiating effective treatment for this common condition.

Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations.

Canakinumab vs triamcinolone acetonide for treatment of acute flares and prevention of recurrent flares in "difficult to treat" gouty arthritis

Monosodium urate crystal deposition seen in gout stimulates IL-1 beta OR IL-1_; release. Canakinumab, a long-acting, fully human anti- IL-1 beta OR IL-1_; monoclonal antibody, effectively neutralizes IL-1 beta OR IL-1_;. Methods: This was an 8-week, dose-ranging, multi-center, blinded, doubledummy, active-controlled trial. Patients (aged 18-80 years) with an acute gout flare, refractory to or contraindicated to NSAlDs and/or colchicine, were randomized to one dose of canakinumab 10, 25, 50, 90, 150 mg s.c. or triamcinolone acetonide (TA) 40 mg i.m. Primary variable was assessed as pain intensity at 72 h post-dose (0-100 mm VAS). Secondary variables included pain intensity 24 and 48 h post-dose, time to 50% reduction in pain intensity, time to recurrence of gout flares up to 8 weeks post-dose, and rescue medication use. Results: 191/200 enrolled patients (canakinumab, n_143; TA, n_57) completed the study. Canakinumab showed significant dose-dependent pain reduction at 72 h. Canakinumab 150 mg showed superior pain relief versus TA starting from 24 h: estimated mean difference in pain intensity on VAS was -11.5 (24 h), -18.2 (48 h), and -19.2 (72 h) (all p_0.05). Canakinumab 150 mg provided a rapid onset of pain relief: median time to 50% reduction in pain was reached at 1 day with canakinumab 150 mg versus 2 days with TA (p_0.0006). At Week 8, recurrent flares occurred in 1 patient (3.7%) on canakinumab 150 mg versus 25 (44.6%) patients on TA (relative risk reduction, 94%; p_0.006). During 7 days post-dose, 6 patients (22.2%) on canakinumab 150 mg, and 31 patients (55.4%) on TA, took rescue medication. Time to first rescue medication was significantly longer with canakinumab 150 mg versus TA (hazard ratio, 0.36; p_0.02). Serious adverse events (canakinumab _lsqb_n_4_rsqb_ and TA _lsqb_n_1_rsqb_) were considered not treatment-related by investigators and no patient discontinued due to adverse events. Conclusions: Canakinumab 150 mg was well-tolerated, provided rapid and sustained pain relief in patients with acute gout flares, and significantly reduced the recurrent flare risk by 94% at 8-weeks post-dose compared with triamcinolone acetonide.

Detection of CBP rearrangements in acute myelogenous leukemia with t(8;16).

The CREB-binding protein (CBP) is a large nuclear protein that regulates many signal transduction pathways and is involved in chromatin-mediated transcription. The translocation t(8;16)(p11;p13.3) consistently disrupts two genes: the CBP gene on chromosome band 16p13.3 and the MOZ gene on chromosome band 8p11. Although a fusion of these two genes as a result of the translocation is expected, attempts at detecting the fusion transcript by reverse transcriptase polymerase chain reaction (RT-PCR) have proven difficult; to date, only one in-frame CBP/MOZ fusion transcript has been reported. We therefore sought other reliable means of detecting CBP rearrangements. We applied fluorescence in situ hybridization (FISH) and Southern blot analyses to a series of AML patients with a t(8;16) and detected DNA rearrangements of both the CBP and the MOZ loci in all cases tested. All six cases examined for CBP rearrangements have breakpoints within a 13 kb breakpoint cluster region at the 5' end of the CBP gene. Additionally, we used a MOZ cDNA probe to construct a surrounding cosmid contig and detect DNA rearrangements in three t(8;16) cases, all of which display rearrangements within a 6 kb genomic fragment of the MOZ gene. We have thus developed a series of cosmid probes that consistently detect the disruption of the CBP gene in t(8;16) patients. These clones could potentially be used to screen other cancer-associated or congenital translocations involving chromosome band 16p13.3 as well.

Canakinumab (ACZ885) vs triamcinolone acetonide for treatment of acute flares and prevention of recurrent flares in gouty arthritis patients refractory to or contraindicated to nsaids and/or colchicine.

Purpose: Current treatments for arthritis flares in gout (gouty arthritis) are not effective in all patients and may be contraindicated in many due to underlying comorbidities. Urate crystals activate the NALP 3 inflammasome which stimulate production of IL-1β, driving inflammatory processes. Targeted IL-1β blockade may be an alternative treatment for gouty arthritis. Canakinumab (ACZ885) is a fully human monoclonal anti- IL-1β antibody with a long half-life (28 days). Method: This was an 8-weeks, dose-ranging, multicenter, blinded, double-dummy, active-controlled trial of patients ≥18 to ≤80 y with an acute gouty arthritis flare, refractory to or contraindicated to NSAIDs and/or colchicine. Patients were randomized to 1 subcutanous (sc) dose of canakinumab (10, 25, 50, 90, or 150 mg) or 1 intra muscular (im) dose of triamcinolone acetonide (TA) [40 mg]. The primary variable was assessed 72 h post-dose, measured on a 0-100 mm VAS pain scale. Secondary variables included pain intensity 24 and 48 h post dose, time to 50% reduction in pain intensity, and time to recurrence of gout flares up to 8 weeks post dose. Results: 200 patients were enrolled (canakinumab n=143, TA n=57) and 191 completed the study. A statistically significant dose response was observed at 72 h. The 150 mg dose reached superior pain relief compared to TA starting from 24h: estimated mean difference in pain intensity on 0-100 mm VAS was -11.5 at 24 h, -18.2 at 48 h, and -19.2 at 72 h (all p<0.05). Canakinumab 150 mg provided a rapid onset of pain relief: median time to 50% reduction in pain was reached at 1 day with canakinumab 150 mg vs 2 days for the TA group (p=0.0006). The probability of recurrent gout flares was 3.7% with canakinumab 150 mg vs. 45.4% with TA 8 weeks post treatment, a relative risk reduction of 94% (p=0.006). Serious AEs occurred in 2 patients receiving canakinumab (appendicitis and carotid artery stenosis) and 1 receiving TA (cerebrovascular disorder). Investigator's reported these events as not study drug related. There were no discontinuations due to AEs. Conclusion: Canakinumab 150 mg provided faster onset and superior pain relief compared to TA for acute flares in gouty arthritis patients refractory to or contraindicated to standard treatments. The 150 mg dose of canakinumab prevented recurrence of gout flares with a relative risk reduction compared to TA of 94% at 8 weeks post-dose, and was well tolerated.

Vasopressine lors d'infarctus myocardique aigu: implications cliniques [Vasopressin in acute myocardial infarct: clinical implications]

Since current data on vasopressin (AVP) secretion during the early phase of myocardial infarction is not extensive, plasma AVP was measured in 26 patients with acute myocardial infarction. Twelve had an increased AVP concentration (23.2 +/- 7.0 pg/ml; mean +/- SEM) whereas 14 had an AVP level less than 3 pg/ml (1.96 +/- 0.14 pg/ml). The patients with AVP greater than 3 pg/ml had higher heart rate and plasma osmolality than those with AVP less than 3 pg/ml. Blood pressure values were the same in both groups of patients. There was no difference in peak CPK and iso CPK activities between the two groups. Seven patients with AVP greater than 3 pg/ml died within the next few days, while only 1 patient with AVP less than pg/ml died. It thus appears that increased AVP concentration during acute myocardial infarction is associated with a poor prognosis. Whether it is a cause or a consequence of an unfavourable course of myocardial infarction remains to be determined.

Acute multivessel revascularization improves 1-year outcome in ST-elevation myocardial infarction: a nationwide study cohort from the AMIS Plus registry.

BACKGROUND: The optimal strategy for percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) in multi-vessel disease (MVD), i.e., multi-vessel PCI (MV-PCI) vs. PCI of the infarct-related artery only (IRA-PCI), still remains unknown. METHODS: Patients of the AMIS Plus registry admitted with an acute coronary syndrome were contacted after a median of 378 days (interquartile range 371-409). The primary end-point was all-cause death. The secondary end-point included all major adverse cardiovascular and cerebrovascular events (MACCE) including death, re-infarction, re-hospitalization for cardiac causes, any cardiac re-intervention, and stroke. RESULTS: Between 2005 and 2012, 8330 STEMI patients were identified, of whom 1909 (24%) had MVD. Of these, 442 (23%) received MV-PCI and 1467 (77%) IRA-PCI. While all-cause mortality was similar in both groups (2.7% both, p>0.99), MACCE was significantly lower after MV-PCI vs. IRA-PCI (15.6% vs. 20.0%, p=0.038), mainly driven by lower rates of cardiac re-hospitalization and cardiac re-intervention. Patients undergoing MV-PCI with drug-eluting stents had lower rates of all-cause mortality (2.1% vs. 7.4%, p=0.026) and MACCE (14.1% vs. 25.9%, p=0.042) compared with those receiving bare metal stents (BMS). In multivariate analysis, MV-PCI (odds ratio, OR 0.69, 95% CI 0.51-0.93, p=0.017) and comorbidities (Charlson index ≥ 2; OR 1.42, 95% CI 1.05-1.92, p=0.025) were independent predictors for 1-year MACCE. CONCLUSION: In an unselected nationwide real-world cohort, an approach using immediate complete revascularization may be beneficial in STEMI patients with MVD regarding MACCE, specifically when drug-eluting stents are used, but not regarding mortality. This has to be tested in a randomized controlled trial.