Postprocedural neuropathy after atrial fibrillation ablation

Purpose

Access-related neuropathy after atrial fibrillation (AF) ablation is underappreciated. We intend to describe the incidence, management, and prognosis of postprocedural neuropathy after AF ablation.

Methods

We performed a retrospective analysis of all consecutive patients with postprocedural neuropathy who underwent AF ablation in three high-volume tertiary care hospitals between January 2007 and April 2011.

Results

Of the 3,128 patients who underwent AF ablation during the study period, 25 (0.8 %) patients had postprocedural neuropathy and were included in the current study. Mean age was 58.5?±?11.5 years with 18 (72 %) being males and 14 (56 %) having paroxysmal AF. Ulnar nerve, lateral femoral cutaneous nerve manifesting as meralgia paresthetica, and femoral nerve were involved in 5 (20 %), 13 (54 %), and 7 (26 %) of the patients, respectively. Majority of neuropathies were associated with periprocedural hematomas (19, 76 %), and a quarter (19/72, 26 %) of all hematomas were associated with neuropathy. Initial treatment included warm and cold compresses followed by nonsteroidal anti-inflammatory and narcotic pain medications. In addition to the above regimen, in some patients (11, 44 %), oral gabapentin was used and it was associated with a shorter time to symptom resolution (9.4 vs. 14.1 days, p?=?0.007). All patients were symptom free within 90 days of the procedure.

Conclusion

Postprocedural neuropathy after AF ablation is rare and is frequently associated with a periprocedural hematoma. Patients typically become symptom free within 90 days of the procedure, and gabapentin may have a role in earlier symptom resolution.     

Impact of cachexia on outcomes in aggressive lymphomas

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87–93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into “non-cachectic” (CXI ≥49.8, n = 41) and “cachectic” (CXI <49.8, n = 40) groups. Cachectic patients had significantly worse PFS (HR 2.18, p = 0.044) and OS (HR = 4.05, p = 0.004) than non-cachectic patients. Cachexia as defined by the CXI is prognostic in aggressive lymphomas and implies that novel therapeutic strategies directed at reversing cachexia may improve survival in this population.     

Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

All positive-strand RNA viruses reorganize host intracellular membranes to assemble their viral replication complexes (VRCs); however, how these viruses modulate host lipid metabolism to accommodate such membrane proliferation and rearrangements is not well defined. We show that a significantly increased phosphatidylcholine (PC) content is associated with brome mosaic virus (BMV) replication in both natural host barley and alternate host yeast based on a lipidomic analysis. Enhanced PC levels are primarily associated with the perinuclear ER membrane, where BMV replication takes place. More specifically, BMV replication protein 1a interacts with and recruits Cho2p (choline requiring 2), a host enzyme involved in PC synthesis, to the site of viral replication. These results suggest that PC synthesized at the site of VRC assembly, not the transport of existing PC, is responsible for the enhanced accumulation. Blocking PC synthesis by deleting the CHO2 gene resulted in VRCs with wider diameters than those in wild-type cells; however, BMV replication was significantly inhibited, highlighting the critical role of PC in VRC formation and viral replication. We further show that enhanced PC levels also accumulate at the replication sites of hepatitis C virus and poliovirus, revealing a conserved feature among a group of positive-strand RNA viruses. Our work also highlights a potential broad-spectrum antiviral strategy that would disrupt PC synthesis at the sites of viral replication but would not alter cellular processes.All positive-strand RNA viruses [(+)RNA viruses], which include numerous important human, animal, and plant pathogens, share similar strategies for genomic replication. A highly conserved and indispensable feature of their replication is the proliferation and reorganization of host cellular membranes to assemble viral replication complexes (VRCs). Despite this central importance, it is largely unknown how cellular membranes are rearranged by the viral replication proteins and how cellular lipid metabolism is modulated to accommodate membrane proliferation and remodeling.Brome mosaic virus (BMV) serves as a model for understanding VRC formation of (+)RNA viruses (1). BMV is the type member of the plant virus family Bromoviridae and a representative member of the alphavirus-like superfamily, which includes many human, animal, and plant-infecting viruses (2). BMV encodes two replication proteins, 1a and 2a^pol. 2a^pol serves as the replicase, whereas 1a has an N-terminal methyltransferase domain (3, 4) and a C-terminal ATPase/helicase-like domain (5). Together, 1a and 2a^pol are necessary and sufficient for BMV replication. BMV induces vesicular structures in its surrogate host, the yeast Saccharomyces cerevisiae, and its natural host, barley (6, 7). These structures, termed spherules, have been shown to be the VRCs in yeast as 1a, 2a^pol, and nascent viral RNAs reside in the interior of these compartments. Spherules are invaginations of the outer perinuclear endoplasmic reticulum (ER) membrane into the ER lumen and are about 60–80 nm in diameter (6). Remarkably, expression of 1a alone in yeast induces spherule formation (6), which requires 1a’s amphipathic α-helix (1a amino acids 392–407) (8), helix A, and 1a–1a interactions (9, 10). In addition, several host proteins, including membrane-shaping reticulons (RTNs) (11) and an ESCRT (endosomal sorting complex required for transport) component, Snf7p (sucrose nonfermenting7) (12), are recruited by 1a to form spherules.Similar to other (+)RNA viruses, BMV promotes host lipid synthesis and requires balanced lipids for the formation and activity of VRCs. Expression of 1a in yeast induces a ∼30% increase in total fatty acids (FAs) per cell (13). BMV also requires a high level of unsaturated FA (UFA) because a ∼12% decrease of UFAs in the yeast ole1w mutant blocks its replication more than 20-fold (13). In addition, deleting host ACB1 (Acyl-CoA-binding 1) gene results in formation of spherules that are smaller in size but are in greater number than in wild-type (WT) cells (14). ACB1 encodes acyl-CoA binding protein, which binds long-chain fatty acyl-CoAs and is involved in maintaining lipid homeostasis. Supplemented long-chain UFAs largely complement the BMV replication defects in cells lacking ACB1, indicating that the altered lipid composition is primarily responsible for BMV replication defects (14).Cellular membranes are mainly composed of phospholipids, and in particular, phosphatidylcholine (PC) constitutes ∼50% of total phospholipids (15). PC is synthesized via the CDP–DAG (cytidine diphosphate–diacylglycerol) and Kennedy pathways in eukaryotes (16). PC synthesis is significantly enhanced during infection of Dengue virus (DENV) (17), Flock House virus (FHV) (18), and poliovirus (19, 20). A 70% and 35% increase of total PC levels was recorded in DENV-infected mosquito cells (17) and FHV-infected Drosophila cells (18), respectively. At the peak time of poliovirus replication in HeLa cells, a ∼37% increase of PC content was observed after a 30-min chase (19). It was further found that poliovirus promotes the import of FAs, which were subsequently channeled to the viral replication sites. In addition, FAs were mainly incorporated into PCs (20).One critical question based on the aforementioned research is whether the enhanced PC is synthesized in association with the VRCs or elsewhere in cells and subsequently transported into the VRCs. If PC is produced in association with the VRCs, what key enzymes are recruited? We report here that several (+)RNA viruses, including BMV, hepatitis C virus (HCV), and poliovirus, promote significantly enhanced accumulation of PC content at the viral replication sites, revealing a common feature of viral replication among a group of (+)RNA viruses. We further demonstrate that BMV 1a interacts with and redistributes the host enzyme, Cho2p (choline requiring 2), to the viral replication sites. As Cho2p converts phosphatidylethanolamine (PE) to PC in the CDP–DAG pathway, the relocalization of Cho2p suggests the VRC-localized PC synthesis. Deleting CHO2 inhibits BMV replication up to 30-fold and results in formation of spherules that are larger than those of WT cells. This work highlights the importance of PC in VRC formation and the possibility of developing a novel and broad-spectrum antiviral strategy by specifically disrupting PC synthesis at the viral replication sites but not general PC synthesis.     

Opposing mechanisms involving RNA and lipids regulate HIV-1 Gag membrane binding through the highly basic region of the matrix domain

Membrane binding of Gag, a crucial step in HIV-1 assembly, is facilitated by bipartite signals within the matrix (MA) domain: N-terminal myristoyl moiety and the highly basic region (HBR). We and others have shown that Gag interacts with a plasma-membrane-specific acidic phospholipid, phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P₂], via the HBR, and that this interaction is important for efficient membrane binding and plasma membrane targeting of Gag. Generally, in protein–PI(4,5)P₂ interactions, basic residues promote the interaction as docking sites for the acidic headgroup of the lipid. In this study, toward better understanding of the Gag–PI(4,5)P₂ interaction, we sought to determine the roles played by all of the basic residues in the HBR. We identified three basic residues promoting PI(4,5)P₂-dependent Gag-membrane binding. Unexpectedly, two other HBR residues, Lys25 and Lys26, suppress membrane binding in the absence of PI(4,5)P₂ and prevent promiscuous intracellular localization of Gag. This inhibition of nonspecific membrane binding is likely through suppression of myristate-dependent hydrophobic interaction because mutating Lys25 and Lys26 enhances binding of Gag with neutral-charged liposomes. These residues were reported to bind RNA. Importantly, we found that RNA also negatively regulates Gag membrane binding. In the absence but not presence of PI(4,5)P₂, RNA bound to MA HBR abolishes Gag-liposome binding. Altogether, these data indicate that the HBR is unique among basic phosphoinositide-binding domains, because it integrates three regulatory components, PI(4,5)P₂, myristate, and RNA, to ensure plasma membrane specificity for particle assembly.     

Messengers of tolerance

The use of immunosuppressant drugs after organ transplantation has brought great success in the field of organ transplantation with respect to short-term outcome. However, major challenges (i.e., limited improvement of long-term survival, immunosuppressant toxicity, infections and carcinoma) demand alternate treatment approaches that minimizes the use of immunosuppressants. Interestingly, few studies have identified groups of transplant patients who developed operational tolerance and thereby keep their allograft without complications in absence of immunosuppressants. These rare groups of patients are of particular interest as study subjects for understanding mechanisms of graft tolerance that could be leveraged in future for inducing tolerance and for understanding mechanisms involved in improving long-term allograft outcomes. Also, biomarkers from these studies could benefit the larger transplant population by their application in immunosuppressant tailoring and identification of tolerant patients among patients with stably functioning allografts. This review compiles several gene expression studies performed in samples from tolerant patients in different solid organ transplantations to identify key genes and associated molecular pathways relevant to tolerance. This review is aimed at putting forth all this important work done thus far and to identify research gaps that need to be filled, in order to achieve the greater purpose of these studies.     

Atrial fibrillation ablation in patients with gastroesophageal reflux disease or irritable bowel syndrome—the heart to gut connection!

Purpose

An association between atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) and/or irritable bowel syndrome (IBS) is increasingly being identified; yet the role of radiofrequency catheter ablation (RFA) of AF has not been systematically evaluated in these patient populations.

Methods

We performed a prospective matched case–control study of AF patients with GERD and/or IBS who underwent RFA for AF in two centers in North America. AF patients with GERD and/or IBS (gastrointestinal [GI] group) were matched by age, gender, and type of AF at each of the centers with an equal number of AF patients without GERD or IBS (non-GI group).

Results

Sixty patients were included in the study with 30 in each group. Mean age of the population was 45 years with 14 (47 %) males and 21 (87 %) patients with paroxysmal AF in each group. More patients in the GI group had identifiable GI triggers for AF episodes. During RFA, more patients in the GI group had a “vagal response” compared to non-GI group (60 vs 13 %; p?<?0.001). Left atrial scar as identified by electroanatomical mapping was more common in patients in the non-GI group compared to the GI group (57 vs 27 %; p?=?0.018). At 1-year follow-up, 56 (93 %) of the patients were free from AF with no difference between both groups.

Conclusions

Majority of AF patients with GERD and/or IBS have triggered AF and a positive vagal response during RFA. RFA is equally effective in this patient population when compared to those without GERD or IBS.