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.     

Functional characterization of antineutrophil cytoplasmic antibodies in patients with cocaine-induced midline destructive lesions

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) binding to neutrophil elastase (NE) and proteinase 3 (PR3) are detectable in most patients with cocaine-induced midline destructive lesions (CIMDL), but the pathogenic role and antigen specificity of these antibodies are unknown. This study was undertaken to assess the effects of NE ANCA on the enzymatic activity of NE, to determine whether these antibodies interfere with the physiologic effect of secretory leukoprotease inhibitor (SLPI), and to investigate the antigen specificity of both NE and PR3 ANCA in patients with CIMDL. We also compared the binding of PR3 ANCA in patients with CIMDL with that in patients with Wegener's granulomatosis (WG). METHODS: PR3 ANCA and NE ANCA were detected by capture enzyme-linked immunosorbent assays (ELISAs) and by indirect immunofluorescence. IgG was purified from the patients' sera, and the influence of NE ANCA on the enzymatic activity of NE and on the inhibitory activity of SLPI was investigated by determining the hydrolysis of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide by NE. RESULTS: IgG from NE ANCA-positive sera of patients with CIMDL inhibited the enzymatic activity of NE and did not interfere with the activity of SLPI. In contrast to the findings in WG sera, measurement of PR3 ANCA in CIMDL sera showed only fair to moderate concordance between the 2 different capture ELISAs. Cross-inhibition experiments demonstrated that NE ANCA and PR3 ANCA represent distinct autoantibodies in patients with CIMDL. CONCLUSION: The functional effects of NE ANCA on the enzymatic activity of NE or on the activity of SLPI cannot be implicated in the pathogenesis of CIMDL. The autoimmune reaction that targets neutrophil serine proteases in patients with CIMDL is frequently directed against more than one antigen. The ANCA response, including the reactivity of PR3 ANCA, in patients with CIMDL differs from what has been described in patients with WG.     

Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8⁺ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8⁺ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.     

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.     

The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis

Journal of Neurology - Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional...     

Acute Flaccid Quadriparesis in a Recovering COVID-19 Patient: A Clinical Dilemma

How to cite this article: Sabharwal P, Chakraborty S, Tyagi N, Kumar A. Acute Flaccid Quadriparesis in a Recovering COVID-19 Patient: A Clinical Dilemma. Indian J Crit Care Med 2021;25(2):238–239.     

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.