An Update on Electrical Cardioversion of Atrial Fibrillation

Atrial fibrillation is the most frequently encountered sustained arrhythmia in clinical practice. Electrical cardioversion of atrial fibrillation using damped sine wave shocks has been a mainstay of therapy for nearly 4 decades; its limitation remains a failure rate that approaches 20%. Although several alternatives have been proposed, including delivering 720 J shocks using dual monophasic defibrillators, ibutilide pretreatment and internal cardioversion, each of these approaches has significant limitations, which preclude its routine use. Recent data demonstrate that routine use of biphasic shocks for cardioversion of atrial fibrillation is associated with a marked improvement in cardioversion efficacy and suggest that biphasic shocks may be the preferred method for the transthoracic electrical cardioversion of atrial fibrillation.     

An unusual case of Holt-Oram syndrome

An unusual case of Holt-Oram syndrome with arachnodactyly, high arch palate, thoracic scoliosis and hypoplasia of the left radial artery is reported. The relevant literature is discussed and the importance of vascular hypoplasia in genesis and localization of the skeletal deformities of this syndrome is stressed.     

Sparing of the Dystrophin-Deficient Cranial Sartorius Muscle Is Associated with Classical and Novel Hypertrophy Pathways in GRMD Dogs

Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top-ranked network included α-dystroglycan and like-acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, α-dystroglycan/like-acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement.Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene and occurs in approximately 1 in 3500 live male births.¹ DMD boys show signs of skeletal muscle weakness, evidenced by a delay in walking until approximately 18 months and loss of ambulation by the teenage years. Necrotic muscle ultimately fails to regenerate and is replaced with fibrous connective tissue and fat. Molecular and cellular mechanisms underlying gradual muscle deterioration are poorly understood.Animal models of DMD include the mdx mouse and golden retriever muscular dystrophy (GRMD) dog.^2,3 Despite sharing the same fundamental genetic and biochemical lesions, remarkable phenotypic variation occurs among dystrophin-deficient individuals and muscles. Mdx mice have a relatively mild phenotype,⁴ whereas affected dogs have clinical and pathological features consistent with those of DMD.⁵ Even among DMD patients, who all lack dystrophin except for rare revertant fibers, symptoms can vary markedly.⁶ Dogs with GRMD also demonstrate pronounced phenotypic variation, as some dogs lose the ability to walk within the first 6 months of life, whereas others remain ambulatory to 10 years of age or older.^7–9In GRMD neonatal dogs, flexor muscles such as the sartorius are generally more severely involved than extensors, potentially due to their role in crawling.^10,11 Early dystrophic histopathological changes seen in these diseased muscles include myofiber necrosis evidenced by hyaline fibers, mineralization, edema, and inflammation, with associated regeneration.¹⁰ Presumably, as dogs subsequently begin to walk, weight-bearing extensor muscles such as the vastus lateralis (VL) are more predisposed to injury and display these same acute dystrophic changes. With regard to individual muscle variation in DMD, extensors that undergo eccentric contraction (eg, quadriceps femoris) are particularly vulnerable to early weakness and wasting.¹² On the other hand, the extraocular muscles are largely spared.¹³In DMD patients, most muscles atrophy over time, but some, such as the gastrocnemius, undergo gross enlargement.¹⁴ On the basis of early histological studies of dystrophic muscle biopsies, this calf hypertrophy was initially attributed to deposition of fat and fibrotic tissue and was termed pseudohypertrophy.¹⁵ However, in a series of 350 neuromuscular patients, including 9 with Becker muscular dystrophy, quantitative ultrasound demonstrated that calf hypertrophy was most often due to an actual increase in contractile tissue.¹⁶ Mdx mice¹⁷ and dystrophin-deficient cats¹⁸ also have muscle hypertrophy in the absence of significant fat and connective tissue infiltration. The sartorius muscle is particularly intriguing in both DMD and GRMD. Humans have a single muscle, whereas dogs have cranial and caudal bellies. Serving principally as a hip flexor, the sartorius extends from the pelvis to the proximal tibia in people. Both heads of the canine sartorius also arise from the pelvis, but they insert at different sites (caudal, proximal tibia; cranial, distal femur). The cranial sartorius (CS) muscle of neonatal GRMD dogs sustains extensive necrosis¹⁹ and then regenerates, often undergoing dramatic true hypertrophy.^9,20 In DMD patients, the sartorius muscle is relatively spared and may hypertrophy late in the disease process.^21,22Studies showing variable phenotypes among dystrophin-deficient species, individuals, and muscles suggest that factors other than dystrophin deficiency, so-called secondary effects, are involved in the disease process.²³ Determining the molecular underpinnings of the variable clinical and histopathological response to dystrophin deficiency should provide insight into disease pathogenesis and an opportunity to identify potential targets for therapy. Phenotypic–molecular correlations are inherently limited in DMD patients due to unavoidable restrictions of muscle sampling. Animal studies are potentially more powerful because multiple muscles can be sampled at different ages, thus allowing clearer distinction of factors contributing to disease progression. We chose to use the GRMD model of DMD for this study because of the availability of archived biopsy samples of multiple muscles from affected dogs at two ages and corresponding systematic functional data that could be correlated with mRNA and protein expression findings.Hierarchical clustering of several phenotypic markers, including CS muscle size, tibiotarsal joint angle,⁷ and flexor and extensor torque,⁸ was first performed in a group of GRMD and normal dogs. Consistent with our prior studies,⁹ severely affected dogs tended to have larger CS muscles. To achieve a better understanding of the molecular signals that drive muscle hypertrophy, we extended a prior, largely pathological study of differential muscle involvement in the GRMD model.¹⁹ Proteins that are well known to influence muscle size [myostatin (MSTN)]^24,25 or potentially compensate for dystrophin deficiency [utrophin (UTRN)]²⁶ were assessed in a subset of the dogs evaluated by hierarchical clustering. MSTN showed an age-dependent decrease and an inverse correlation with the degree of CS hypertrophy. Regulators of MSTN at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) level were altered, consistent with down-regulation of MSTN signaling, CS hypertrophy, and functional rescue of this muscle. The growth factor myotrophin (MTPN) was increased in the CS. These studies were augmented by analysis of mRNA, miRNA, and proteomic profiles from several GRMD muscles at two different ages to elucidate additional hypertrophic pathways. Although UTRN was also uniformly increased in GRMD muscles, there was no association with CS size. Other membrane-associated proteins, including α-dystroglycan, like-acetylglucosaminyltransferase (LARGE), and β-spectrin, were increased in the GRMD CS, consistent with a role in membrane stabilization. These results indicate that several muscle proteins may act together to stabilize myofibers and promote muscle growth. Our findings also further substantiate that differential muscle involvement can exaggerate the GRMD phenotype. This suggests that care should be taken with treatments targeting specific pathways, such as MSTN, that could selectively exaggerate muscle hypertrophy.     

Infection imaging using [18F]FDG-labelled white blood cell positron emission tomography–computed tomography

Localizing the sites of infection in the body is possible in nuclear medicine using a variety of radiopharmaceuticals that target different components of the infective and inflammatory cascade. Gamma(γ)-emitting agents such as [67Ga]gallium citrate were among the first tracers used, followed by development of positron-emitting tracers like 2-deoxy-2-[18F]fluoro-D-glucose (¹⁸F-FDG). Though these tracers are quite sensitive, they have limited specificity for infection due to their concentration in sites of non-infective inflammation. White blood cells (WBC) labelled with γ or positron emitters have higher accuracy for differentiating the infective processes from the non-infective conditions that may show positivity with tracers such as ¹⁸F-FDG. We present a pictorial review of potential clinical applications of PET/CT using ¹⁸F-FDG labelled WBC.     

Oligo-glycerol based non-ionic amphiphilic nanocarriers for lipase mediated controlled drug release

A new class of non-ionic amphiphiles is synthesized using a diaryl derivative of diglycerol as a central core and functionalizing it with long alkyl chains (C-12/C-15) and monomethoxy PEG moiety (M_n: 350/550) by following a chemo-enzymatic approach. The aggregation behavior of the amphiphiles in aqueous medium is studied by using dynamic light scattering (DLS) and fluorescence spectroscopy, whereas the size and morphology of the aggregates are studied by transmission electron microscopy (TEM). A hydrophobic dye, Nile red and a hydrophobic drug, nimodipine, are used to demonstrate the nano-carrier capability of these non-ionic amphiphilic systems and the results are compared with amphiphilic analogues obtained from the triaryl derivatives of triglycerol. The in vitro controlled release of the encapsulated dye is successfully carried out in the presence of immobilized Candida antarctica lipase (Novozym 435). Furthermore, cytotoxicity data is also collected which suggests that the amphiphiles are suitable for biomedical applications.

A new series of oligo-glycerol based amphiphiles have been synthesized for drug delivery.     

Epigenetics in the Pathogenesis of Esophageal Adenocarcinoma

Epigenetic influences, such as DNA methylation, histone acetylation, and up‐regulation/down‐regulation of genes by microRNAs, change the genetic makeup of an individual without affecting DNA base‐pair sequences. Indeed, epigenetic changes play an integral role in the progression from normal esophageal mucosa to Barrett''s esophagus to esophageal adenocarcinoma via dysplasia–metaplasia–neoplasia sequence. Many genes involved in esophageal adenocarcinoma display hypermethylation, leading to their down‐regulation. The classes of these genes include cell cycle control, DNA and growth factor repair, tumor suppressors, antimetastasis, Wnt‐related genes, and proapoptotic genes. Histone acetylation in the pathophysiology of esophageal diseases has not been thoroughly investigated, and its critical role in the development of esophageal adenocarcinoma is less defined. Many microRNAs have been associated with the development of Barrett''s esophagus and esophageal adenocarcinoma. Here, we critically addressed the specific steps most closely influenced by microRNAs in the progression from Barrett''s esophagus to esophageal adenocarcinoma. However, microRNAs can target up to hundreds of genes, making it difficult to correlate directly with a given phenotype of the disease. Esophageal adenocarcinoma progressing from premalignant condition of Barrett''s esophagus carries an extremely poor prognosis. Risk stratification for patients based on their epigenetic profiles may be useful in providing more targeted and directed treatment to patients.