Signal-averaged P-wave analysis of normal controls and patients with paroxysmal atrial fibrillation: a study in gender differences,age dependence,and reproducibility

BACKGROUND: Atrial fibrillation is often first recognized after a complication such as embolic stroke has occurred. Limited data are available for the prospective identification of patients at risk for developing atrial fibrillation. HYPOTHESIS: Demonstration of areas of slow conduction in the atrium by means of P-wave signal averaging may identify individuals at risk for atrial fibrillation. METHODS: P-wave signal averaging from the surface electrocardiogram was performed in 199 normal controls and 81 patients with paroxysmal atrial fibrillation using an automated, P-triggered, high-resolution signal for analysis. RESULTS: Of the variables measured, the filtered P-wave duration and P-wave integral were significantly different between controls and patients (filtered P-wave duration 120 +/- 9 vs. 145 +/- 21 and P-wave integral 666 +/- 208 vs. 868 +/- 352), whereas the terminal root-mean-square (RMS) voltages (RMS 20, RMS 30, RMS 40) showed no significant differences between the two groups. Regression analysis of the first and second measurement of the filtered P-wave duration obtained during consecutive tests showed excellent reproducibility (r and r2 of 0.96 and 0.92). The duration of the filtered P wave showed no age dependence but was shorter in women. CONCLUSION: Utilizing the 90th percentile value of the filtered P-wave duration of 133 ms in men and 130 ms in women, the sensitivity was 80 and 81%, the specificity 92 and 90%, the positive predictive value 84 and 73%, and the negative predictive value 90 and 93%, respectively.     

Synthetic Glycopeptide-Based Delivery Systems for Systemic Gene Targeting to Hepatocytes

Purpose. To design, synthesize, and test synthetic glycopeptide-baseddelivery systems for gene targeting to hepatocytes by systemicadministration.Methods. All peptides were synthesized by the solid phase methoddeveloped using Fmoc chemistry on a peptide synthesizer. The bindingof galactosylated peptides to HepG2 cells and accessibility of thegalactose residues on particle surface was demonstrated by acompetition assay using ¹²⁵I-labeleld asialoorosomucoid and RCA lectinagglutination assay, respectively. DNA plasmid encoding chloramphenicolacetyl transferase (CAT) gene was complexed with a tri-galactosylatedpeptide (GM245.3) or tri-galactosylated lipopeptide (GM246.3) in thepresence of an endosomolytic peptide (GM225.1) or endosomolyticlipopeptide (GM227.3) to obtain DNA particles of 100–150 nm insize. The plasmid/peptide complexes were added to HepG2 cell culturesor intravenously administered by tail vein injection into normal miceor rats. Plasmid uptake and expression was quantified by qPCR andELISA, respectively.Results. Multiple antennary glycopeptides that have the ability tocondense and deliver DNA plasmid to hepatocytes were synthesized andcomplexed with DNA plasmid to obtain colloidally stable DNA/peptidecomplexes. Addition of DNA/GM245.3/GM225.1 peptide complexes(1:3:1 (–/+/–)) to HepG2 cell cultures yielded CAT expression intransfected cells. The transfection efficiency was significantly reducedin the absence of galactose ligand or removal of endosomolytic peptide.Intravenous administration of DNA/GM245.3 peptide complexes (1:0.5(–/+)) into the tail vein of normal rats yielded DNA uptake in theliver. Substitution of GM245.3 by galactosylated lipopeptide GM246.3resulted in more stable DNA particles, and a 10-fold enhancement inliver plasmid uptake. CAT expression was detectable in liver followingintravenous administration of DNA/GM246.3 complexes. Addition ofendosomolytic lipopeptide GM227.3 into the complexes(DNA/GM246.3/GM227.3 (1:0.5:1 (–/+/–))) yielded a 5-fold increase inCAT expression. Liver expression was 8-fold and 40-fold higher thanlung and spleen, respectively, and localized in the hepatocytes only.The transfection efficiency in liver was enhanced by increasing DNAdose and injection volume. The plasmid uptake and expression in liverusing DNA/GM246.3/GM227.3 complexes was 100-200-fold higherthan DNA formulated in glucose. Tissue examination and serumbiochemistry did not show any adverse effect of the DNA/GM246.3/GM227.3 (1:0.5:1 (–/+/–)) complexes after intravenous delivery.Conclusions. Gene targeting to hepatocytes was achieved by systemicadministration of a well-tolerated synthetic glycopeptide-baseddelivery system. The transfection efficiency of this glycopeptide deliverysystem was dependent on peptide structure, endosomolytic activity,colloidal particle stability, and injection volume.     

Targeted gene delivery: a two-pronged approach

The success of gene therapy relies on the ability of gene delivery systems to selectively deliver therapeutic genes to a sufficient number of target cells yielding expression levels that impact the diseased state. The gene delivery systems can be divided into two classes: viral and nonviral (or plasmid DNA-based). The present gene delivery technology being used in clinics today can be considered first generation, in that they possess the ability to transfect or infect target cells through their inherent chemical, biochemical, and molecular biological properties. Relying on these sole properties, however, limits therapeutic applications. Expansion of therapeutic applications or increased effectiveness of current therapies can be achieved by increasing the number of cells and cell types susceptible to gene transfer. This can be achieved through physical targeting and molecular biological targeting. Physical targeting relies on the attachment to the delivery vehicle of ligands that bind to cell surface receptors unique to the target cells. Molecular biological targeting refers to selective expression of the therapeutic gene by the target cell through the use of selective promoters. Selective expression can be further achieved by the use of expression systems controlled by extrinsic induction molecules. This review will describe in detail the advances that have been made in each of these areas of gene targeting.     

The implantable cardioverter defibrillator: technology, indications, and impact on cardiovascular survival

Since the introduction of the implantable cardioverter defibrillator (ICD) for the management of patients with high risk of arrhythmic SCD, there has been increasing use of this device. Its basic promise to effectively terminate ventricular tachycardia (VT)-ventricular fibrillation (VF) has been repeatedly met. In several randomized trials, the ICD has been shown to be superior to conventional anti-arrhythmic therapy, both in patients with documented VT-VF (secondary prevention) and those with high risk such as left ventricular ejection fraction and no prior sustained VT-VF (primary prevention). In both groups, the ICD showed overall and cardiac mortality reduction. The device now can more accurately detect VT-VF and differentiate these from other arrhythmias through a series of algorithms and direct-chamber sensing. Therapy options include painless antitachycardia pacing, low-energy cardioversion, and high-energy defibrillation. The technique implant is now simple as a pacemaker with one lead attached to an active (hot) can functioning as the other electrode. Among other improvements is its weight, volume, multiprogrammability, and storage of information,dual-chamber pacing and sensing, dual-chamber defibrillation, and addition of biventricular pacing for cardiac synchronization. It is anticipated that further improvement in ICD technology will take place and the list of indications will grow.     

Antioxidant properties of methanolic extracts from leaves of Rhazya stricta

Because of increased safety concerns about synthetic antioxidants, exploitation of cheaper and safer sources of antioxidants based on natural origin is the focus of research nowadays. Rhazya stricta is a medicinally important plant native to South Asia. Extraction of antioxidants was carried out in different solvent systems, i.e., water, 80% methanol, 70% ethanol, and diethyl ether. The methanolic extract exhibited the highest total phenolic content among the extracts; therefore for further studies the methanolic extract was employed. Antioxidant activity measurement in the linoleic acid system, metal chelating activity, reducing power, scavenging effect on 1,1-diphenyl-2-picrylhydrazyl free radical, and superoxide anion radical scavenging activity were taken as the parameters for assessment of antioxidant potential of methanolic extracts. Results were compared with alpha-tocopherol and the synthetic antioxidant butylated hydroxyanisole. The antioxidant potential of methanolic extracts of R. stricta leaves was comparable with previously exploited potent antioxidants and is strongly concentration dependent.     

Sudden cardiac death

SCD continues to be an important cause of death and morbidity. Despite expanding insight into the mechanisms causing SCD, the population at high risk is not being effectively identified. Although there is still much to do in the management phase of SCD (predicting the efficacy of various therapies), recent clinical trials have helped define the relative risks and benefits of therapies in preventing SCD. Trials are underway to determine whether treating other patient populations, including asymptomatic patients after MI, will improve survival rate. The approach to reducing mortality rate will always be multifaceted; primary prevention of coronary artery disease and prompt salvage of jeopardized myocardium are 2 important aspects of this approach. In addition to interventions for MI, such as myocardial revascularization when indicated, simple and easily administered therapies that are likely to remain the most effective prophylactic interventions are aspirin, ACE inhibitors, beta-blockers, and cholesterol-lowering agents. However, the MADIT and AVID data clearly demonstrate a role for ICD therapy in a subgroup of patients who have VT/VF and are at risk of cardiac arrest. Even though the absolute magnitude of benefit associated with ICDs is still to be determined, the AVID study and other recent reports provide convincing evidence that patients who have VT/VF fare better with ICDs than with antiarrhythmic drug therapy. For the high-risk population described in this article, in addition to aggressive anti-ischemic and heart failure therapy, ICDs are now a mainstay of life-saving treatment. Still to be surmounted is the challenge of identifying patients who have nonischemic substrates and of providing them with the appropriate therapy. Guided by genetic studies and new insight into the mechanisms of such problems as congenital long QT syndrome, life-saving and life-enhancing therapies may soon be available for the management of SCD.     

Characteristics of cocaine interaction with delta-9-tetrahydrocannabinol on glucose metabolism in the rat testis.

In this study, the characteristics of cocaine (COC) interaction with delta-9-tetrahydrocannabinol (THC) on glucose metabolism in the rat testis were investigated at different time points. Rats receiving 20 mg/kg IP COC at 0830 h and sacrificed at 15 min, 30 min and 60 min posttreatment showed no change in glucose metabolism. Moreover, 5 mg/kg, IV, COC treatment at 0900 h to rats and sacrificed 60 min postexposure, also produced no change in glucose metabolism. However, at 1300 h, the same protocol with IV COC treatment resulted in a significant increase in glucose utilization by the testis. Furthermore, a THC dose of 10 mg/kg, PO to the rats at 0830 or at 1130 h, followed by sacrifice 90 min later caused a significant decrease in glucose utilization at both time points. Similarly, when rats were given both THC and COC (THC at 0830 h, COC 90 min later) and sacrificed 60 min post-COC, it resulted in a further decrease in testicular glucose metabolism as compared to the rats treated by THC alone. On the other hand, concurrent exposure of rats to these drugs at 1300 h with same protocol, ended up with no change in glucose utilization in the testis. These data suggest that not only the route of administration but also the time of exposure plays an important role in defining the nature of the effects of COC/THC interaction on rat testicular glucose metabolism.     

Vacuolar change in Alzheimer's disease

A retrospective neuropathologic study of brains from 66 patients with Alzheimer's disease (AD) demonstrated the presence of a vacuolar change (VC) in 50 cases that was virtually indistinguishable histologically from the spongiform change characteristic of Creutzfeldt-Jakob disease (CJD). Indeed, in several instances, there was initial diagnostic confusion with CJD. Unlike the spongiform change in CJD, however, VC was almost entirely restricted to the medial temporal cortex and amygdala. Furthermore, the severity of VC was usually less intense than the spongiform change observed in cases of CJD with severe neurologic impairment. The VC could be readily distinguished from the fine microvacuolation of the upper layers of the isocortex reported in a number of different conditions, including AD. It also differed from the status spongiosus of the cerebral cortex that occurs in advanced AD and CJD as well as in other degenerative diseases. The artifactual rarefaction that occurs in improperly processed paraffin-embedded brain tissue was excluded as a contributory factor to the VC. Since VC does not invariably occur in AD, it conceivably could represent a subtype of this disorder or may represent a variant of the pathologic changes that can occur. Its relationship to CJD or other slow virus disorders is to date unknown but unlikely.     

Choledocholithiasis after Bariatric Surgery—More than a Stone’s Throw to Reach?

Background

Gallstone disease is common after bariatric surgery, and patients with bile duct stones in this cohort can be difficult to treat, due to the altered anatomy. This review aims to analyse the various management options available for choledocholithiasis in post-bariatric surgery patients.

Methods

A literature search of PubMed, Medline and Cochrane library databases was carried out for studies on this subject, between January 1970 and March 2017. After initial screening and further full text review, suitable studies were identified after applying the inclusion criteria.

Results

Twenty-nine studies were identified and analysed. Overtube-assisted endoscopy appears to be a popular technique, and 10 studies employing this technique were identified. Though there are minor variations between the three different types of overtube endoscopy, the success rate for ERCP with this approach is between 60 and 70%. Studies using a combination of radiological and endoscopic techniques report a success rate of 60–70%, though the endoscopic ultrasound-guided technique has been reported to have higher success rates (90–100%). Surgery-assisted ERCP also appears to be widely reported and has a consistently high ERCP success rate (80–100%), with an added advantage of the option to perform a concomitant cholecystectomy. There are very few reports on using surgery as the sole option in this scenario.

Conclusion

Both overtube-assisted endoscopy and laparoscopy-assisted ERCP appear to be safe, with good success rates. The other methods may be suitable for selected patients and centres with specific interest in such techniques.