Heart failure, diastolic dysfunction and atrial fibrillation; mechanistic insight of a complex inter-relationship

Atrial fibrillation (AF) and heart failure (HF) commonly coexist, and their co-presence is associated with adverse outcomes relating to thromboembolic events, HF progression, hospitalisation and death. Diastolic dysfunction (DD) is also frequently present in patients with HF and is an independent predictor of hospitalisation and mortality. The presence of DD is a strong predictor of incident AF in patients with HF. In this review, we provide mechanistic insight into pathophysiological processes that frequently promote the occurrence of AF, HF and DD and outline the yin-yang relationship between AF, DD and HF. More recently, invasive studies have also shown that asymptomatic paroxysmal atrial fibrillation (PAF) is a common phenomenon in HF patients. We examine complex inter-relationships between PAF, HF and DD and speculate upon the possible clinical influence of undiagnosed PAF in HF patients.     

Ablation of Complex Fractionated Atrial Electrograms in Catheter Ablation for AF; Where have we been and where are we going?

Catheter ablation for persistent AF remains a challenge to the ablator as the disease is now outside the veins and cannot be tackled by pulmonary vein isolation alone. In this article we describe targeting complex fractionated atrial electrograms (CFAE) as a method to guide atrial substrate modification.     

Optical read-out and modulation of peripheral nerve activity

Numerous clinical and research applications necessitate the ability to interface with peripheral nerve fibers to read and control relevant neural pathways. Visceral organ modulation and rehabilitative prosthesis are two areas which could benefit greatly from improved neural interfacing approaches. Therapeutic neural interfacing, or ‘bioelectronic medicine', has potential to affect a broad range of disorders given that all the major organs of the viscera are neurally innervated. However, a better understanding of the neural pathways that underlie function and a means to precisely interface with these fibers are required. Existing peripheral nerve interfaces, consisting primarily of electrode-based designs, are unsuited for highly specific(individual axon) communication and/or are invasive to the tissue. Our laboratory has explored an optogenetic approach by which optically sensitive reporters and actuators are targeted to specific cell(axon) types. The nature of such an approach is laid out in this short perspective, along with associated technologies and challenges.     

Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage

Resistance to cytarabine and anthracycline‐based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl‐2, Bcl‐xL, and/or Mcl‐1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti‐apoptotic Bcl‐2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan‐Bcl‐2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double‐strand breaks (DSBs) preceded a decrease of Mcl‐1 levels, nuclear translocation of Bcl‐2, Bcl‐xL, and Mcl‐1, and apoptosis. These results indicate that obatoclax enhances cytarabine‐induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA‐damaging agents in AML and possibly a broader range of malignancies.     

Balloon Retrograde Transvenous Obliteration Versus Endoscopic Cyanoacrylate in Bleeding Gastric Varices: Comparison of Rebleeding and Mortality with Extended Follow-up

Purpose

To assess short- and long-term mortality and rebleeding with endoscopic cyanoacrylate (EC) versus balloon-occluded retrograde transvenous obliteration (BRTO).

The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis

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A Predictable Worm: Application of <Emphasis Type="Italic">Caenorhabditis elegans</Emphasis> for Mechanistic Investigation of Movement Disorders

Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson’s disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (α-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C. elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.