Cardioneuroablation for pediatric patients with functional sinus node dysfunction and paroxysmal atrioventricular block.

INTRODUCTION: Severe transitory episodes of bradycardia with subsequent syncope in children are common, and generally portend a benign prognosis. Rarely, patients may experience prolonged asystolic episodes secondary to significant sinus pauses (SP) or paroxysmal atrioventricular block (AVB). Cardioneuroablation (CNA) is a catheter-based intervention, used to identify and ablate the epicardial ganglionated plexi (GP), which results in disruption of the vagal-mediated parasympathetic input to the sinus and atrioventricular node. OBJECTIVE: Describe the methodology and role of CNA for treatment of pediatric patients with functional AVB or SP. METHODS: This is a single-center, case series study. Patients with SP or AVB, 21 years of age or younger, who underwent CNA between 2015 and 2021 were included. CNA was performed via anatomically guided and high-frequency stimulation methods. RESULTS: Six patients were included. The median age was 18.9 years (range 12.3-20.9 years), 33% female. Two patients had prolonged SP, two had paroxysmal AVB, and two had both SP and AVB. Four patients had prior syncope. The median longest pause was 8.9 s (range 3.9-16.8) with 11 total documented pauses (range 2-231) during the 6 months pre-CNA. Post-CNA, the median longest pause was 1.3 s (range 0.8-2.2) with one documented SP after termination of atrial tachycardia at the 3-month follow-up. At 6 months, the median longest pause was 1.1 s (0.8-1.3) with 0 documented pauses. No patients had syncope post-CNA. CONCLUSION: CNA may be an effective alternative to pacemaker implantation in pediatric patients with syncope or significant symptoms secondary to functional SP or AVB.

Cardiac arrhythmias in postural tachycardia syndrome and orthostatic intolerance.

BACKGROUND AND OBJECTIVES: There is sparse literature on cardiac arrhythmias and the utility of ambulatory rhythm monitoring in patients with postural tachycardia syndrome and orthostatic intolerance. This study's primary aim was to investigate the prevalence of arrhythmias in this population. Knowing the prevalence and types of arrhythmias in dysautonomia patients could influence the decision to pursue ambulatory rhythm monitoring and ultimately guide therapy. METHODS: This retrospective descriptive study examined the frequency of cardiac arrhythmias, as detected by ambulatory rhythm monitoring, in children with postural tachycardia syndrome/orthostatic intolerance or syncope who were seen at the Children's National Hospital Electrophysiology Clinic between January 2001 and December 2020. RESULTS: In postural tachycardia syndrome/orthostatic intolerance patients, arrhythmia was detected on 15% of 332 ambulatory rhythm monitors. In syncope patients, arrhythmia was detected on 16% of 157 ambulatory rhythm monitors, not significantly different from the postural tachycardia syndrome/orthostatic intolerance group. The difference in rate of arrhythmia detection between 24-hour Holter and 2-week Zio® monitoring was not statistically significant. CONCLUSION: This study suggests that a substantial proportion of postural tachycardia syndrome/orthostatic intolerance patients may have concomitant underlying cardiac arrhythmias, at a frequency similar to what is seen in patients undergoing primary evaluation for cardiac symptoms such as chest pain, palpitations, and syncope. In the appropriate clinical context, physicians caring for postural tachycardia syndrome/orthostatic intolerance patients should consider additional evaluation for arrhythmias beyond sinus tachycardia.

NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis.

OBJECTIVE: NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate, fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory networks. DESIGN: Using the first genetic-screen to identify NFκB-specific lncRNAs, we performed RNA-seq from the p65-/- and Ikkß-/- mouse embryonic fibroblasts and report the identification of an evolutionary conserved lncRNA designated mNAIL (mice) or hNAIL (human). hNAIL is upregulated in human inflammatory disorders, including UC. We generated mNAILΔNFκB mice, wherein deletion of two NFκB sites in the proximal promoter of mNAIL abolishes its induction, to study its function in colitis. RESULTS: NAIL regulates inflammation via sequestering and inactivating Wip1, a known negative regulator of proinflammatory p38 kinase and NFκB subunit p65. Wip1 inactivation leads to coordinated activation of p38 and covalent modifications of NFκB, essential for its genome-wide occupancy on specific targets. NAIL enables an orchestrated response for p38 and NFκB coactivation that leads to differentiation of precursor cells into immature myeloid cells in bone marrow, recruitment of macrophages to inflamed area and expression of inflammatory genes in colitis. CONCLUSION: NAIL directly regulates initiation and progression of colitis and its expression is highly correlated with NFκB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases.

Transcatheter mechanical manipulation of obstructed prosthetic mitral valve in an infant.

Prosthetic valve thrombosis is a serious complication of prosthetic heart valves that typically requires either surgical intervention or systemic thrombolysis. In patients with contraindications to both treatment modalities, options can be limited. We describe an alternative approach to managing prosthetic valve thrombosis in an infant presenting in extremis with pulmonary haemorrhage. Using transoesophageal echocardiography and fluoroscopic guidance, we restored function to the infant's obstructed St. Jude prosthetic mitral valve through percutaneous transcatheter manipulation of the valve's leaflets.

Rabbit Fungal Keratitis Model of Fusarium solani Tested Against Three Commercially Available Antifungal Drugs.

OBJECTIVES: The purpose of this study was to develop a reproducible preclinical Fusarium solani keratitis model, which would allow comparative testing of currently available antifungals (NATACYN [Alcon, Fort Worth, TX], voriconazole 1%, and amphotericin B 0.1%) as well as efficacy testing of new antifungals for translation into clinical practice in the future. METHODS: The rabbit F. solani keratitis model was developed in New Zealand white rabbits using local and systemic immunosuppression. Infection was introduced by intrastromal injection of F. solani spores into one of the immunosuppressed rabbit eyes while the contralateral eye was a control. Progress of the infection was assessed by the clinical features, histopathology, and viable fungal counts. In this study, the efficacy of currently available antifungals (NATACYN [Alcon], voriconazole 1%, and amphotericin B 0.1%) was compared. Rabbits were randomly divided (n=4 in each group), and the respective antifungal was instilled topically 5 times/day for 7 days. Treatment effects were analyzed by evaluating the anterior segment with the help of slit-lamp, histopathological findings and viable fungal culture at the end of the experiment. RESULTS: We report the development of a reproducible and progressive rabbit F. solani keratitis model as shown by the substantial viable fungal counts (3 log CFU), the presence of large patchy lesions and substantial hypopyon in the 12-day model correlated with specific histopathological analysis for fungus (extended F. solani hyphae from midcorneal stroma into the anterior chamber and traverse Descemet membrane with anterior chamber suppurative plaque). Voriconazole 1% and NATACYN revealed significant reduction of the fungal wound area (P=0.02 and 0.021), respectively, while amphotericin B 0.1% exhibited P value of 0.083 compared with their infected nontreated controls. Voriconazole 1% and amphotericin B 0.1% showed significant viable fungal count differences (P=0.004 and 0.01), respectively, whereas P value of NATACYN was 0.337 compared with control infected corneas. CONCLUSION: The reported rabbit fungal keratitis model can be used for screening new antifungals and evaluating currently available antifungals to facilitate better clinical outcomes. Voriconazole 1% showed the best efficacy among the three tested currently available antifungals by showing the significant differences in both wound size and viable fungal count comparisons in our F. solani rabbit keratitis model.

Rap1 regulates hematopoietic stem cell survival and affects oncogenesis and response to chemotherapy.

Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.

Discovery of novel antimycobacterial drug therapy in biofilm of pathogenic nontuberculous mycobacterial keratitis.

PURPOSE: The potential of slow-growing mycobacteria to form biofilms in human tissues contributes to the problem of establishing an effective treatment strategy. The purpose of this study was to examine new antibiotic strategies to enhance current treatment options for these infections. METHODS: Sensitivities of Mycobacterium fortuitum ATCC 49404 and Mycobacterium chelonae ATCC 35752 were evaluated for different antimicrobials singly and in combination using broth microdilution and FICI (Fractional Inhibitory Concentration Index) synergy screening. Anti-biofilm effects were evaluated in an 8-well chamber slide biofilm model. The efficacy of a new treatment strategy was validated using the novel neutropenic mouse keratitis model and monitored by slit-lamp microscopy, confocal microscopy, and colony forming unit measurements. RESULTS: We reported the very first evidence that these organisms develop corneal biofilms by the accumulation of extracellular DNA (eDNA) and the presence of microcolonies using a novel mycobacterial neutropenic mouse keratitis model. The combination of amikacin and gatifloxacin or besifloxacin was more effective than the current gold-standard drug, amikacin, and we developed a novel treatment strategy (amikacin + gatifloxacin + DNase), the destruction of biofilm matrix component, eDNA, which increased the efficacy of the new antibiotic combination for treating mycobacterial infection in in vitro (P = 0.002) and in vivo (P = 0.001) compared to its respective control. CONCLUSION: Biofilms have a role in mycobacterial keratitis leading to poor treatment outcomes in clinical practice and the use of combination therapy (amikacin + gatifloxacin + DNase) could be a useful new treatment option.

Cough and expiration reflexes elicited by inhaled irritant gases are intensified in ovalbumin-sensitized mice.

This study was designed to determine the effect of active sensitization with ovalbumin (Ova) on cough responses to inhaled irritant gases in mice. Conscious mice moved freely in a recording chamber, while the pressure change in the chamber and audio and video signals of the mouse movements were recorded simultaneously to measure the frequencies of cough reflex (CR) and expiration reflex (ER). To further verify the accuracy of cough analysis, the intrapleural pressure was also recorded by a telemetry sensor surgically implanted in the intrapleural space in a subgroup of mice. During the irritant gas inhalation challenge, sulfur dioxide (SO2; 200 and 400 ppm) or ammonia (NH3; 0.1% and 0.2%) was drawn into the chamber at a constant flow rate for 8 min. Ova sensitization and sham sensitization with vehicle (Veh) were performed over a 25-day period in separate groups of mice. Our results showed that 1) both SO2 and NH3 inhalation challenges increased CR and ER frequencies in a concentration-dependent manner before Ova sensitization; 2) the baseline CR frequency was significantly elevated after Ova sensitization, accompanied by pronounced airway inflammation; and 3) Ova sensitization also markedly augmented the responses of CR and ER to both SO2 and NH3 inhalation challenges; in sharp contrast, the cough responses did not change after sham sensitization in the Veh group. In conclusion, Ova sensitization caused distinct and lingering increases in baseline cough frequency, and also intensified both CR and ER responses to inhaled irritant gases, which probably resulted from an allergic inflammation-induced hypersensitivity of airway sensory nerves.