Publications

BACKGROUND

Heart disease is a major cause of death in industrialized nations, with approximately 50% of these deaths attributable to sudden cardiac arrest. If patients at high risk for sudden cardiac arrest can be identified, their odds of surviving fatal arrhythmias can be significantly improved through prophylactic implantable cardioverter defibrillator placement. This review summarizes the current knowledge pertaining to surface electrocardiogram (ECG) predictors of sudden cardiac arrest.

METHODS

We conducted a literature review focused on methods of predicting sudden cardiac arrest through noninvasive electrocardiographic testing.

RESULTS

Several electrocardiographic-based methods of risk stratification of sudden cardiac arrest have been studied, including QT prolongation, QRS duration, fragmented QRS complexes, early repolarization, Holter monitoring, heart rate variability, heart rate turbulence, signal-averaged ECG, T wave alternans, and T-peak to T-end. These ECG findings have shown variable effectiveness as screening tools.

CONCLUSION

At this time, no individual ECG finding has been found to be able to adequately stratify patients with regard to risk for sudden cardiac arrest. However, one or more of these candidate surface ECG parameters may become useful components of future multifactorial risk stratification calculators.

BACKGROUND

The lipopolysaccharide (LPS) molecule is composed of a hydrophobic lipid region (Lipid A), an oligosaccharide core, and an O-Antigen chain. Lipid A has been described as the molecular region responsible for inducing activation of immune cells. We hypothesize that the O-Antigen plays a critical role in the activation and responsiveness of mononuclear cell immune function.

METHODS

Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with LPS, LPS with attenuated O-Antigen (RF5), or Lipid A (DPL), which lacks an O-Antigen. Selected cells were pretreated with a blocking antibody to CD14. Western blots were performed to determine activation of mitogen-activated protein kinases (MAPK) p38, ERK, and JNK at selected time-points. RNA was extracted for RT-PCR quantification of TNF-α and IL-10 gene transcription. Supernatants were harvested and analyzed by ELISA for tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10).

RESULTS

LPS elicited maximal response, including phosphorylation of p38, ERK, and JNK, synthesis of TNF-α and IL-10 mRNA, and secretion of TNF-α and IL-10. Stimulation with RF5 activated the same pathways to a lesser degree. DPL led to increased phosphorylation of p38 and ERK and increased secretion of IL-10. CD14 blockade was associated with a significant decrease in cytokine secretion by LPS, and abolished cytokine secretion in cells stimulated with RF5 or DPL.

CONCLUSIONS

Structural variants of LPS activate monocytes differentially. The complete O-Antigen is important for maximal activation of MAPK, cytokine synthesis, and cytokine secretion. LPS with attenuated O-Antigen and Lipid A activate only certain components of these pathways. LPS with a complete O-Antigen stimulates cytokine secretion that is partially independent of CD14, but shortening or removal of the O-Antigen inhibits this secretion.

INTRODUCTION

As the most common major neurocognitive disorder, Alzheimer's disease (AD) will play an increasingly important role both socially and financially as the population ages. Approved treatments for AD are symptomatic in nature and show modest improvements in cognition and global functioning among patients with AD.

AREAS COVERED

This article focuses on the pharmacokinetics, pharmacodynamics, efficacy, and safety of the transdermal patch form of the cholinesterase inhibitor rivastigmine. The rivastigmine transdermal system is approved for the treatment of patients with mild, moderate, and severe AD. Three randomized trials have shown the rivastigmine patch to be efficacious and tolerable across all stages of AD.

EXPERT OPINION

The rivastigmine patch offers several advantages over the capsule form, including decreased peak to trough plasma fluctuations, reduced rates of nausea and vomiting, better treatment adherence, higher probability of reaching the target dose, ease of administration, and greater satisfaction among caregivers. These factors may be especially important in patients with severe AD, in which patients are more vulnerable to adverse side effects from higher doses. While the patch is more expensive than generic therapies, patient populations that may benefit from the patch include those that are particularly sensitive to GI side effects, have chronic gastrointestinal problems, have difficulty swallowing medications, or have failed to respond with high doses of other generic options.