Llama antibody fragments have good potential for application as HIV type 1 topical microbicides

There is an urgent global need for preventive strategies against HIV-1 infections. Llama heavy-chain antibody fragments (VHH) are a class of molecules recently described as potent cross-clade HIV-1 entry inhibitors. We studied the potential of a VHH-based microbicide in an application-oriented fashion. We show that VHH can be inexpensively produced in high amounts in the GRAS organism Saccharomyces cerevisiae, resulting in a very pure and endotoxin free product. VHH are very stable under conditions they might encounter during transport, storage, or use by women. We developed active formulations of VHH in aqueous gel and compressed and lyophilized tablets for controlled release from an intravaginal device. The release profile of the VHH from, e.g., a vaginal ring suggests sufficient bioavailability and protective concentration of the molecule at the mucosal site at the moment of the infection. The ex vivo penetration kinetics through human tissues show that the VHH diffuse into the mucosal layer and open the possibility to create a second defense layer either by blocking the HIV receptor binding sites or by blocking the receptors of immune cells in the mucosa. In conclusion, our data show that VHH have a high potential for HIV-1 microbicide application because of their low production costs, their high stability, and their favorable release and tissue penetration properties.     

Diagnostic evaluation of the MRP-8/14 for the emergency assessment of chest pain

Elevated levels of myeloid-related protein (MRP)-8/14 (S100A8/A9) are associated with first cardiovascular events in healthy individuals and worse prognosis in patients with acute coronary syndrome (ACS). The diagnostic utility of MRP-8/14 in patients presenting to the emergency room with symptoms concerning for ACS is uncertain. MRP-8/14 was measured in serial serum and plasma samples in a single center prospective cohort-study of patients presenting to the emergency room with non-traumatic chest pain concerning for ACS. Final diagnosis was adjudicated by an endpoint committee. Of patients with baseline MRP-8/14 results (n = 411), the median concentration in serum was 1.57 μg/ml (25th, 75th: 0.87, 2.68) and in plasma was 0.41 μg/ml (<0.4, 1.15) with only moderate correlation between serum and plasma (ρ = 0.40). A final diagnosis of MI was made in 106 (26%). Peak serum MRP-8/14 was higher in patients presenting with MI (p < 0.001). However, the overall diagnostic performance of MRP-8/14 was poor: sensitivity 28% (95% CI 20-38), specificity 82% (78-86), positive predictive value 36% (26-47), and negative predictive value 77% (72-81). The area under the ROC curve for diagnosis of MI with MRP-8/14 was 0.55 (95% CI 0.51-0.60) compared with 0.95 for cTnI. The diagnostic performance was not improved in early-presenters, patients with negative initial cTnI, or using later MRP-8/14 samples. Patients presenting with MI had elevated levels of serum MRP-8/14 compared to patients with non-cardiac chest pain. However, overall diagnostic performance of MRP-8/14 was poor and neither plasma nor serum MRP-8/14 offered diagnostic utility comparable to cardiac troponin.     

The effect of tobacco control policies on smoking prevalence and smoking-attributable deaths. Findings from the Netherlands SimSmoke Tobacco Control Policy Simulation Model

Aim To develop a simulation model projecting the effect of tobacco control policies in the Netherlands on smoking prevalence and smoking‐attributable deaths. Design, setting and participants Netherlands SimSmoke—an adapted version of the SimSmoke simulation model of tobacco control policy—uses population, smoking rates and tobacco control policy data for the Netherlands to predict the effect of seven types of policies: taxes, smoke‐free legislation, mass media, advertising bans, health warnings, cessation treatment and youth access policies. Measurements Outcome measures were smoking prevalence and smoking‐attributable deaths. Findings With a comprehensive set of policies, as recommended by MPOWER, smoking prevalence can be decreased by as much as 21% in the first year, increasing to a 35% reduction in the next 20 years and almost 40% by 30 years. By 2040, 7706 deaths can be averted in that year alone with the stronger set of policies. Without effective tobacco control policies, almost a million lives will be lost to tobacco‐related diseases between 2011 and 2040. Of those, 145 000 can be saved with a comprehensive tobacco control package. Conclusions Smoking prevalence and smoking‐attributable deaths in the Netherlands can be reduced substantially through tax increases, smoke‐free legislation, high‐intensity media campaigns, stronger advertising bans and health warnings, comprehensive cessation treatment and youth access laws. The implementation of these FCTC/MPOWER recommended policies could be expected to show similar or even larger relative reductions in smoking prevalence in other countries which currently have weak policies.     

Medical treatment for sphincter of oddi dysfunction:Can it replace endoscopic sphincterotomy?

AIM:To report the results of a medical management of sphincter of oddi dysfunction(SOD) after an intermediate follow-up period.METHODS:A total of 59 patients with SOD(2 men and 57 women,mean age 51 years old) were included in this prospective study.After medical treatment for one year,the patients were clinically re-evaluated after an average period of 30 mo.RESULTS:The distribution of the patients according to the Milwaukee's classification was the following:11 patients were type 1,34 were type 2 and 14 were type 3.Fourteen patients underwent an endoscopic sphincterotomy(ES) after one year of medical treatment.The median intermediate follow-up period was 29.8 ± 3 mo(3-72 mo).The initial effectiveness of the medical treatment was complete,partial and poor among 50.8%,13.5% and 35%,respectively,of the patients.At the end of the follow-up period,37 patients(62.7%) showed more than 50% improvement.The rate of improvement in patients who required ES was not significantly different compared with the patients treated conservatively(64.2% vs 62.2%,respectively).CONCLUSION:Our study confirms that conservative medical treatment could be an alternative to endoscopic sphincterotomy because,after an intermediate follow-up period,the two treatments show the same success rates.     

A Randomized Study of Defibrillator Lead Implantations in the Right Ventricular Mid-Septum versus the Apex: The SEPTAL Study(τ)

Impact of Recalls on ICD Utilization . Introduction: The study was designed to evaluate the feasibility and performance of right ventricular (RV) mid‐septal versus apical implantable defibrillator (ICD) lead placement. Methods and Results: SEPTAL is a randomized, noninferiority trial, which randomly assigned patients to implantation of ICD leads in the RV mid‐septum versus apex, with a primary objective of comparing the implant success rate of implant at each site, based on strict electrical predefined criteria. We also compared the (1) pacing lead characteristics, (2) rates of appropriate and inappropriate ICD therapies, and (3) all‐cause mortality between the 2 sites at 1 year. The trial enrolled 215 patients (mean age = 59.7 ± 12.4 years, mean LVEF = 34.0 ± 14.2%, 84.2% men), of whom 148 (68.8%) presented with ischemic heart disease. The ICD indication was primary prevention in 117 patients (54.4%). The lead was successfully implanted in 96/107 patients (89.7%) assigned to the RV mid‐septum, and in 99/108 (91.7%) assigned to the apex (ns). The 1‐year rate of lead‐related adverse events was similar in both groups. A total of 8 first inappropriate ICD therapies (7.9%) were delivered in the RV mid‐septal group, versus 8 (7.8%) in the apical group (ns), while first appropriate therapies were delivered to 22 (21.4%) and 24 patients (23.8%), respectively (ns). All‐cause mortality was 7.9% in the RV mid‐septal versus 2.9% in the RV apical group (ns). Conclusion: This study confirmed the technical feasibility and noninferior performance of ICD leads implanted in the RV mid‐septum versus the apex. (J Cardiovasc Electrophysiol, Vol. 23, pp. 853‐860, August 2012)     

Survival benefit of implantable cardioverter-defibrillators in left ventricular assist device-supported heart failure patients

BackgroundImplantable cardioverter-defibrillators (ICDs) reduce mortality in heart failure (HF). In patients requiring a ventricular assist device (VAD), the benefit from ICD therapy is not well established. The aim of this study was to define the impact of ICD on outcomes in VAD-supported patients.Methods and ResultsWe reviewed data for consecutive adult HF patients receiving VAD as a bridge to transplantation from 1996 to 2003. The primary outcome was survival to transplantation. A total of 144 VADs were implanted [85 left ventricular (LVAD), 59 biventricular (BIVAD), mean age 50 ± 12 years, 77% male, left ventricular ejection fraction 18 ± 9%, 54% ischemic]. Mean length of support was 119 days (range 1–670); 103 patients (72%) survived to transplantation. Forty-five patients had an ICD (33 LVAD, 12 BIVAD). More LVAD patients had an appropriate ICD shock before implantation than after (16 vs 7; P = .02). There was a trend toward higher shock frequency before LVAD implant than after (3.3 ± 5.2 vs 1.1 ± 3.8 shocks/y; P = .06). Mean time to first shock after VAD implant was 129 ± 109 days. LVAD-supported patients with an ICD were significantly more likely to survive to transplantation [1-y actuarial survival to transplantation: LVAD: 91% with ICD vs 57% without ICD (log-rank P = .01); BIVAD: 54% vs 47% (log-rank P = NS)]. An ICD was associated with significantly increased survival in a multivariate model controlling for confounding variables (odds ratio 2.54, 95% confidence interval 1.04–6.21; P = .04).ConclusionsShock frequency decreases after VAD implantation, likely owing to ventricular unloading, but appropriate ICD shocks still occur in 21% of patients. An ICD is associated with improved survival in LVAD-supported HF patients.