Efficacy and safety of a high loading dose of clopidogrel administered prehospitally to improve primary percutaneous coronary intervention in acute myocardial infarction: the randomized CIPAMI trial

Objectives

To compare a loading dose of 600?mg clopidogrel given in the prehospital phase versus clopidogrel administered only after the diagnostic angiogram in patients with STEMI scheduled for primary PCI.

Background

The optimal time and dose for the initiation of clopidogrel therapy in patients with STEMI scheduled for primary PCI has not been studied in prospective randomized trials.

Methods

The primary efficacy endpoint was the TIMI 2/3 patency of the infarct-related artery in the diagnostic angiography immediately prior to PCI.

Results

We randomized 337 patients to prehospital (n?=?166) loading dose versus standard therapy (n?=?171). The time interval between initiation of clopidogrel therapy and diagnostic angiography was 47?min. TIMI 2/3 patency before PCI was not different between the groups (49.3 vs. 45.1%, P?=?0.5). We observed a trend towards a reduction of the combined endpoint death, re-infarction, and urgent target vessel revascularization in the prehospital-treated patients (3.0 vs. 7.0%, P?=?0.09), this difference was significant if patients were classified as treated (4/161 vs. 13/174; 2.5 vs. 7.5%, P?P?=?0.8).

Conclusions

Early inhibition of the platelet ADP-receptor with a high loading dose of 600?mg clopidogrel given in the prehospital phase in patients with STEMI scheduled for primary PCI is safe, did not increase pre-PCI patency of the infarct vessel, but was associated with a trend towards a reduction in clinical events.     

A cautionary note on experimental artefacts induced by fetal calf serum in a viral model of pulmonary eosinophilia

In BALB/c mice, sensitization with the attachment protein (G) of respiratory syncytial virus (RSV) leads to CD4(+) T cell-mediated lung eosinophilia during subsequent challenge with RSV. In this study, we originally intended to test whether activation of RSV-specific cytotoxic T cells by peptide-pulsed dendritic cells (DC) after G protein sensitization could prevent this eosinophilic response. Peptide-pulsed dendritic cells activated CTL, which could mediate protective immunity to RSV. However, DC vaccination aggravated, rather than prevented, pulmonary eosinophilia in G-sensitized mice and also enhanced weight loss upon RSV infection. This was accompanied by preferential pulmonary recruitment of CD4(+) T cells secreting IL-5. The same enhanced Th2-mediated eosinophilic response could be observed in mice that received unloaded dendritic cells and this response occurred even in the absence of prior G sensitization. Since both dendritic cells and RSV were grown in fetal calf serum (FCS)-containing medium, we suspected that FCS had provoked this response. Indeed, neither eosinophilia nor enhanced pathology were observed in mice treated with DC raised in mouse serum. This observation calls for meticulous controls for artefacts induced by fetal calf serum particularly in mouse models of allergic responses of the respiratory tract.     

Hepatocyte polarization is essential for the productive entry of the hepatitis B virus

Human hepatitis B virus (HBV) is characterized by a high species specificity and a distinct liver tropism. Within the liver, HBV replication occurs in differentiated and polarized hepatocytes. Accordingly, the in vitro HBV infection of primary human hepatocytes (PHHs) and the human hepatoma cell line, HepaRG, is restricted to differentiated, hepatocyte-like cells. Though preparations of PHH contain up to 100% hepatic cells, cultures of differentiated HepaRG cells are a mixture of hepatocyte-like and biliary-like epithelial cells. We used PHH and HepaRG cells and compared the influence of virus inoculation dose, cell differentiation, and polarization on productive HBV infection. At multiplicities of genome equivalents (mge) >8,000, almost 100% of PHHs could be infected. In contrast, only a subset of HepaRG cells stained positive for HBcAg at comparable or even higher mge. Infection predominantly occurred at the edges of islands of hepatocyte-like HepaRG cells. This indicates a limited accessibility of the HBV receptor, possibly as a result of its polar sorting. Multidrug resistance protein 2 (MRP2), a marker selectively transported to the apical (i.e., canalicular) cell membrane, revealed two polarization phenotypes of HepaRG cells. HBV infection within the islands of hepatocyte-like HepaRG cells preferentially occurred in cells that resemble PHH, exhibiting canalicular structures. However, disruption of cell-cell junctions allowed the additional infection of cells that do not display a PHH-like polarization. CONCLUSION: HBV enters hepatocytes via the basolateral membrane. This model, at least partially, explains the difference of PHH and HepaRG cells in infection efficacy, provides insights into natural HBV infection, and establishes a basis for optimization of the HepaRG infection system.     

Fully covered self-expandable metal stents for treatment of malignant and benign biliary strictures

AIM:To present a series of covered self-expandable metal stents(CSEMS) placed for different indications and to evaluate the effectiveness,complications and extractability of these devices.METHODS:We therefore retrospectively reviewed the courses of patients who received CSEMS due to malignant as well as benign biliary strictures and postsphincterotomy bleeding in our endoscopic unit between January 2010 and October 2011.RESULTS:Twenty-six patients received 28 stents due to different indications(20 stents due to malignant biliary strictures,six stents due to benign biliary strictures and two stents due to post-sphincterotomy bleeding).Biliary obstruction was relieved in all cases,regardless of the underlying cause.Hemostasis could be achieved in the two patients who received the stents for this purpose.Complications occurred in five patients(18%).Two patients(7%) developed cholecystitis,stents dislocated/migrated in other two patients(7%),and in one patient(3.6%) stent occlusion was documented during the study period.Seven stents were extracted endoscopically.Removal of stents was easily possible in all cases in which it was desired using standard forceps.Twelve patients underwent surgery with pylorus preserving duodenopancreatectomy.In all patients stents could be removed during the operation without difficulties.CONCLUSION:Despite the higher costs of these devices,fully covered self-expanding metal stents may be suitable to relief biliary obstruction due to bile duct stenosis,regardless of the underlying cause.CSEMS may also represent an effective treatment strategy of severe post-sphincterotomy bleeding,not controlled by other measures.     

The mutagenically separated polymerase chain reaction is a rapid and reliable method for genotyping of the tumour necrosis factor-alpha promoter polymorphism (-308 G/A)

BACKGROUND: The tumour necrosis factor-alpha (TNF alpha) promoter polymorphism (-308 G/A) has been shown to be associated with the susceptibility to and/or the severity of diverse diseases such as infections, autoimmunity, and malignancies. We developed a genotyping technique based on the mutagenically separated polymerase chain reaction (MS-PCR) which may be useful in the clinical risk assessment. METHODS: Different length allele-specific primers and an unspecific complementary strand primer were used in a one-tube assay. At least one PCR product was generated in a single reaction obviating the need for an internal control amplification. Introduction of additional base substitutions into the allele-specific primers led to a clear-cut separation between the alleles through the reduction of cross-reactions during amplification. The only post-PCR step required was the separation of allelic PCR products by size upon agarose gel electrophoresis. RESULTS: The allele frequencies in 300 German healthy Caucasians were 0.84 for TNF1 (-308 G) and 0.16 for TNF2 (-308 A) in accordance with published data obtained with the conventional RFLP method. No significant deviation from Hardy-Weinberg equilibrium was observed. The specificity of MS-PCR was confirmed by sequence-based typing. CONCLUSIONS: MS-PCR is a rapid, reliable, and cost-effective technique for genotyping of the TNF alpha promoter polymorphism (-308 G/A).     

Off-pump surgery for the poor ventricle?

Severely decreased ejection-fraction is an established risk-factor for worse outcome after cardiac surgery. We compare outcomes of off-pump coronary artery bypass grafting (OPCAB) and on-pump CABG (ONCABG) in patients with severely compromised EF. From 2004 to 2009, 478 patients with a decreased EF ??35% underwent myocardial-revascularization. Patients received either OPCAB (n?=?256) or ONCABG (n?=?222). Propensity score (PS), including 50 preoperative risk-factors, was used to balance characteristics between groups. PS adjusted logistic regression analysis was performed to assess mortality and major adverse cardiac and cerebrovascular events (MACCE). A composite endpoint for major non-cardiac complications such as respiratory failure, renal failure, rethoracotomy was applied. Complete revascularization (CR) was assumed when the number of distal anastomoses was larger than that of diseased vessels. There was no difference for mortality (2.3 vs. 4.1%; PS-adjusted odds ratio (PS-OR)?=?1.05; p?=?0.93) and MACCE (13.7 vs. 17.6%; PS-OR?=?1.22; p?=?0.50) including myocardial-infarction (1.4 vs. 4.9%; PS-OR?=?0.39; p?=?0.26), low cardiac output (2.3 vs. 4.7%; PS-OR?=?0.75; p?=?0.72) and stroke (2.3 vs. 2.7%; PS-OR?=?0.69; p?=?0.66). OPCAB patients presented with a trend to less frequent occurrence of the non-cardiac composite (12.1 vs. 22.1%; PS-OR?=?0.54; p?=?0.059) including renal dysfunction (PAOR?=?0.77; 95% CI 0.31?C1.9; p?=?0.57), bleeding (PAOR?=?0.42; 95% CI 0.14?C1.20; p?=?0.10) and respiratory failure (PAOR?=?0.39; 95% CI 0.05?C3.29; p?=?0.39). The rate of complete revascularization was similar (92.2 vs. 92.8%; PS-OR?=?0.75; p?=?0.50). OPCAB in patients with severely decreased EF is safe and feasible. It may even benefit these patients in regard to non-cardiac complications and does not come at cost of less complete revascularization.