Arc Oligomerization Is Regulated by CaMKII Phosphorylation of the GAG Domain: An Essential Mechanism for Plasticity and Memory Formation.

Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc's canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc's synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse.

BACKGROUND: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

Outcomes and atrial substrate analysis in patients with HIV undergoing atrial fibrillation ablation.

INTRODUCTION: Patients with HIV infection have increased risk of atrial fibrillation, but the pathophysiologic mechanisms and the utility of catheter ablation in this population are not well-studied. We aimed to characterize outcomes of atrial fibrillation ablation and left atrial substrate in patients with HIV. METHODS: The study was a retrospective propensity score-matched analysis of patients with and without HIV undergoing atrial fibrillation ablation. A search was performed in the electronic medical record for all patients with HIV who received initial atrial fibrillation ablation from 2011 to 2020. After calculating propensity scores for HIV, matching was performed with patients without HIV by using nearest-neighbor matching without replacement in a 1:2 ratio. The primary outcome was freedom from atrial arrhythmia and secondary outcomes were freedom from atrial fibrillation, freedom from atrial tachycardia, and freedom from repeat ablation, compared by log-rank analysis. The procedures of patients with HIV who underwent repeat ablation at our institution were further analyzed for etiology of recurrence. To further characterize the left atrial substrate, a subsequent case-control analysis was then performed for a set of randomly chosen 10 patients with HIV matched with 10 without HIV to compare minimum and maximum voltage at nine pre-specified regions of the left atrium. RESULTS: Twenty-seven patients with HIV were identified. All were prescribed antiretroviral therapy at time of ablation. These patients were matched with 54 patients without HIV by propensity score. 86.4% of patients with HIV and 76.9% of controls were free of atrial fibrillation or atrial tachycardia at 1 year (p = .509). Log-rank analysis showed no difference in freedom from atrial arrhythmia (p value .971), atrial fibrillation (p-value .346), atrial tachycardia (p value .306), or repeat ablation (p value .401) after initial atrial fibrillation ablation in patients with HIV compared to patients without HIV. In patients with HIV with recurrent atrial fibrillation, the majority had pulmonary vein reconnection (67%). There were no significant differences in minimum or maximum voltage at any of the nine left atrial regions between the matched patients with and without HIV. CONCLUSIONS: Ablation to treat atrial fibrillation in patients with HIV, but without overt AIDS is frequently successful therapy. The majority of patients with recurrence of atrial fibrillation had pulmonary vein reconnection, suggesting infrequent nonpulmonary vein substrate. In this population, the left atrial voltage in patients with HIV is similar to that of patients without HIV. These findings suggest that the pulmonary veins remain a critical component to the initiation and maintenance of atrial fibrillation in patients with HIV.

Diagnosis, differential diagnosis and misdiagnosis of Susac syndrome.

BACKGROUND AND PURPOSE: Susac syndrome (SuS) is an inflammatory condition of the brain, eye and ear. Diagnosis can be challenging, and misdiagnosis is common. METHODS: This is a retrospective review of the medical records of 32 adult patients from an Australasian cohort of SuS patients. RESULTS: An alternative diagnosis prior to SuS was made in 30 patients (94%) with seven patients receiving two or more diagnoses. The median time to diagnosis of SuS was 3 months (range 0.5-100 months). The commonest misdiagnoses were migraine in 10 patients (31%), cerebral vasculitis in six (19%), multiple sclerosis in five (16%) and stroke in five (16%). Twenty-two patients were treated for alternative diagnoses, 10 of whom had further clinical manifestations prior to SuS diagnosis. At presentation seven patients (22%) met criteria for definite SuS, 19 (59%) for probable SuS and six (19%) for possible SuS. Six patients (19%) presented with brain-eye-ear involvement, 14 with brain-ear (44%), six with brain-eye (19%) and six (19%) with only brain involvement. In patients with the complete triad of symptoms the median delay to diagnosis was 3 months (range 1-9 months) compared to 5.25 months (range 0.5-100 months) for patients with encephalopathy and ocular symptoms at presentation. CONCLUSIONS: Susac syndrome patients are frequently misdiagnosed at initial presentation, despite many having symptoms or radiological features that are red flags for the diagnosis. Delayed diagnosis can lead to patient morbidity. The varied ways in which SuS can present, and clinician failure to consider or recognize SuS, appear to be the main factors leading to misdiagnosis.

Interactions between the mRNA and Rps3/uS3 at the entry tunnel of the ribosomal small subunit are important for no-go decay.

No-go Decay (NGD) is a process that has evolved to deal with stalled ribosomes resulting from structural blocks or aberrant mRNAs. The process is distinguished by an endonucleolytic cleavage prior to degradation of the transcript. While many of the details of the pathway have been described, the identity of the endonuclease remains unknown. Here we identify residues of the small subunit ribosomal protein Rps3 that are important for NGD by affecting the cleavage reaction. Mutation of residues within the ribosomal entry tunnel that contact the incoming mRNA leads to significantly reduced accumulation of cleavage products, independent of the type of stall sequence, and renders cells sensitive to damaging agents thought to trigger NGD. These phenotypes are distinct from those seen in combination with other NGD factors, suggesting a separate role for Rps3 in NGD. Conversely, ribosomal proteins ubiquitination is not affected by rps3 mutations, indicating that upstream ribosome quality control (RQC) events are not dependent on these residues. Together, these results suggest that Rps3 is important for quality control on the ribosome and strongly supports the notion that the ribosome itself plays a central role in the endonucleolytic cleavage reaction during NGD.

Rapid pacing and high-frequency jet ventilation additively improve catheter stability during atrial fibrillation ablation.

INTRODUCTION: Catheter stability during atrial fibrillation ablation is associated with higher ablation success rates. Rapid cardiac pacing and high-frequency jet ventilation (HFJV) independently improve catheter stability. Simultaneous modulation of cardiac and respiratory motion has not been previously studied. The objective of this study was to determine the effect of simultaneous heart rate and respiratory rate modulation on catheter stability. METHODS: Forty patients undergoing paroxysmal atrial fibrillation ablation received ablation lesions at 15 prespecified locations (12 left atria, 3 right atria). Patients were randomly assigned to undergo rapid atrial pacing for either the first or the second half of each lesion. Within each group, half of the patients received HFJV and the other half standard ventilation. Contact force and ablation data for all lesions were compared among the study groups. Standard deviation of contact force was the primary endpoint defined to examine contact force variability. RESULTS: Lesions with no pacing and standard ventilation had the greatest contact force standard deviation (5.86 ± 3.08 g), compared to lesions with pacing and standard ventilation (5.45 ± 3.28 g; P < .01) or to lesions with no pacing and HFJV (4.92 ± 3.00 g; P < .01). Lesions with both pacing and HFJV had the greatest reduction in contact force standard deviation (4.35 ± 2.81 g; P < .01), confirming an additive benefit of each maneuver. Pacing and HFJV together was also associated with a reduction in the proportion of lesions with excessive maximum contact force (P < .001). DISCUSSION: Rapid pacing and HFJV additively improve catheter stability. Simultaneous pacing with HFJV further improves catheter stability over pacing or HFJV alone to optimize ablation lesions.

Neisseria gonorrhoeae infects the human endocervix by activating non-muscle myosin II-mediated epithelial exfoliation.

Colonization and disruption of the epithelium is a major infection mechanism of mucosal pathogens. The epithelium counteracts infection by exfoliating damaged cells while maintaining the mucosal barrier function. The sexually transmitted bacterium Neisseria gonorrhoeae (GC) infects the female reproductive tract primarily from the endocervix, causing gonorrhea. However, the mechanism by which GC overcome the mucosal barrier remains elusive. Using a new human tissue model, we demonstrate that GC can penetrate into the human endocervix by inducing the exfoliation of columnar epithelial cells. We found that GC colonization causes endocervical epithelial cells to shed. The shedding results from the disassembly of the apical junctions that seal the epithelial barrier. Apical junction disruption and epithelial exfoliation increase GC penetration into the endocervical epithelium without reducing bacterial adherence to and invasion into epithelial cells. Both epithelial exfoliation and junction disruption require the activation and accumulation of non-muscle myosin II (NMII) at the apical surface and GC adherent sites. GC inoculation activates NMII by elevating the levels of the cytoplasmic Ca2+ and NMII regulatory light chain phosphorylation. Piliation of GC promotes, but the expression of a GC opacity-associated protein variant, OpaH that binds to the host surface proteins CEACAMs, inhibits GC-induced NMII activation and reorganization and Ca2+ flux. The inhibitory effects of OpaH lead to reductions in junction disruption, epithelial exfoliation, and GC penetration. Therefore, GC phase variation can modulate infection in the human endocervix by manipulating the activity of NMII and epithelial exfoliation.

Cost-Effectiveness Analysis of the Clear Cell Likelihood Score Against Renal Mass Biopsy for Evaluating Small Renal Masses.

OBJECTIVE: To examine the cost-effectiveness of the clear cell likelihood score compared to renal mass biopsy (RMB) alone. METHODS: The clear cell likelihood score, a new grading system based on multiparametric magnetic resonance imaging, has been proposed as a possible alternative to percutaneous RMB for identifying clear cell renal carcinoma in small renal masses and expediting treatment of high-risk patients. A decision analysis model was developed to compare a RMB strategy where all patients undergo biopsy and a clear cell likelihood score strategy where only patients that received an indeterminant score of 3 undergo biopsy. Effectiveness was assigned 1 for correct diagnoses and 0 for incorrect or indeterminant diagnoses. Costs were obtained from institutional fees and Medicare reimbursement rates. Probabilities were derived from literature estimates from radiologists trained in the clear cell likelihood score. RESULTS: In the base case model, the clear cell likelihood score was both more effective (0.77 vs 0.70) and less expensive than RMB ($1629 vs $1966). Sensitivity analysis found that the nondiagnostic rate of RMB and the sensitivity of the clear cell likelihood score had the greatest impact on the model. In threshold analyses, the clear cell likelihood score was the preferred strategy when its sensitivity was greater than 62.7% and when an MRI cost less than $5332. CONCLUSION: The clear cell likelihood score is a more cost-effective option than RMB alone for evaluating small renal masses for clear cell renal carcinoma.

DHDDS and NUS1: A Converging Pathway and Common Phenotype.

BACKGROUND: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis. CASES: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles. LITERATURE REVIEW: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific. CONCLUSIONS: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

Comparison of microwave ablation and partial nephrectomy for T1a small renal masses.

OBJECTIVE: To compare the oncological and renal function outcomes of microwave ablation (MWA) compared to partial nephrectomy (PN) in two small renal mass (SRM) tumor size cohorts, <3 cm and 3-4 cm. MATERIALS AND METHODS: This study included retrospective data from 2009 to 2015 and prospective data since 2015 from a single-institution database. Patient demographics, renal mass characteristics, and treatment outcomes were collected. Survival curves and hazard analysis were used to assess oncological outcomes. Changes in eGFR and CKD stage following surgery were used to assess renal function outcomes. RESULTS: A total of 80 PN and 126 MWA patients were analyzed. Median age and Charlson Comorbidity Index (CCI) of MWA patients were greater than PN for each tumor size cohort. Cumulative progression free survival at 36-months was 91% for MWA and 90% for PN. Preoperative renal function was significantly lower in patients undergoing MWA for both tumor sizes, however there was no significant difference in the postoperative change in renal function between MWA and PN for tumors up to 4 cm. CONCLUSIONS: Oncological outcomes and renal preservation were comparable between MWA and PN cohorts for SRMs <3cm and 3-4cm despite the MWA cohort being older and having more comorbidities. Our findings suggest that MWA can be used as a safe and effective alternative to PN for T1a renal tumors up to 4 cm.

Microwave ablation of the T1a small renal mass: expanding beyond 3 cm.

PURPOSE: To compare the oncological and renal function outcomes for patients receiving microwave ablation (MWA) in tumors < 3 and 3-4 cm. METHODS: Retrospective analysis of a prospectively maintained database identified patients with < 3 or 3-4 cm renal cancers undergoing MWA. Radiographic follow-up occurred at approximately 6 months post-procedure and annually thereafter. Serum creatinine and estimated glomerular filtration rate (eGFR) were calculated before and 6-months post-MWA. Local recurrence-free survival (LRFS) was estimated using the Kaplan-Meier method. Tumor size was evaluated as a prognostic factor using Cox proportional-hazards regression. Predictors for change in eGFR and chronic kidney disease (CKD) stage were modeled using linear and ordinal logistic regression. RESULTS: A total of 126 patients fit the inclusion criteria. Overall recurrences were 2/62 (3.2%) and 6/64 (9.4%) for < 3 versus 3-4 cm. Both recurrences in the < 3 cm group were local, 4/6 in the 3-4 cm group were local and 2/6 were metastatic without local progression. For < 3 versus 3-4 cm, cumulative LRFS at 36 months was 94.6% versus 91.4%. Tumor size was not a significant prognostic factor for LRFS. Renal function did not change significantly after MWA. Patient comorbidities and RENAL nephrometry score significantly affected change in CKD. CONCLUSION: With comparable oncological outcomes, complication rates, and renal function preservation, MWA is a promising management strategy for renal masses of 3-4 cm in select patients. Our findings suggest that current AUA guidelines, which recommend thermal ablation for tumors < 3 cm, may need review to include T1a tumors for MWA, regardless of size.

An approach to acute clinical deterioration in patients with late-stage Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease is a slowly progressive neurodegenerative disease. In the absence of disease-modifying therapies, patients inevitably progress to late-stage disease, characterised by a shift towards increasing disability from predominantly non-motor symptoms, which may be poorly levodopa responsive. OBJECTIVE: The aim of this article is to provide general practitioners (GPs) with a practical approach to the diagnosis and management of acute clinical deterioration in patients with late-stage Parkinson's disease. The authors outline common causes for such change and an approach to their workup and management. DISCUSSION: With an ageing population, we are seeing an increased prevalence of Parkinson's disease at all stages. Neurologists, geriatricians and GPs alike should therefore be familiar with the syndrome of late-stage Parkinson's disease and be equipped with treatment strategies to address acute non-motor and motor deteriorations.

Challenges in managing late-stage Parkinson's disease: Practical approaches and pitfalls.

BACKGROUND: Parkinson's disease is a universally progressive neurodegenerative disease. People living with Parkinson's disease for many years face progression from early- to mid- to late-stage Parkinson's disease (LSPD). While levodopa-responsive, predominantly motor features constitute the majority of symptom burden in early-stage Parkinson's disease, the disability in LSPD is characterised mainly by non-motor symptoms, which may be poorly levodopa responsive. OBJECTIVE: The aim of this article is to discuss recognition of LSPD and suggest strategies that may assist patients with LSPD in the community. DISCUSSION: The milestones of frequent falls, cognitive dysfunction, hallucinations and the need for residential care signal LSPD and predict time to death. Treatment aims shift to focus on patient comfort and conscientious prevention of exacerbations. In this article, challenges such as autonomic dysregulation, pain, cognitive decline and psychosis are addressed. These authors advocate a holistic approach, including supporting not only the patient with LSPD but also their carers.

Dystonia Responsive to Dopamine: POLG Mutations Should Be Considered If Sensory Neuropathy Is Present.

The POLG gene encodes mitochondrial DNA polymerase, and mutations in this gene cause a spectrum of disorders related to mitochondrial DNA depletion or deletion. Dystonia has only rarely been reported as an early and prominent manifestation of POLG mutations. We report a case of a 30-year-old male presenting with lower limb dystonia with peripheral neuropathy and demonstrate that the dystonia was levodopa responsive (with video findings). Whole-genome sequencing revealed biallelic variants in the POLG gene: a known pathogenic variant [NM_001126131.2:c.2209G>C (p.Gly737Arg)] and a novel likely pathogenic variant [NM_001126131.2:c.3305A>C (p.Gln1102Pro)]. A genetic diagnosis was made before the appearance of more readily recognizable features of mitochondrial disease, allowing us to avoid invasive tissue biopsies or potentially deleterious treatments, such as sodium valproate. A POLG-related disorder should be suspected in cases of dystonia with peripheral neuropathy, and this diagnosis may have implications for further investigations and management.

The neuro-otology of Susac syndrome.

OBJECTIVE: We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. METHODS: The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. RESULTS: Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. CONCLUSIONS: Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

Ribosome Collisions Result in +1 Frameshifting in the Absence of No-Go Decay.

During translation, an mRNA is typically occupied by multiple ribosomes sparsely distributed across the coding sequence. This distribution, mediated by slow rates of initiation relative to elongation, ensures that they rarely collide with each other, but given the stochastic nature of protein synthesis, collision events do occur. Recent work from our lab suggested that collisions signal for mRNA degradation through no-go decay (NGD). We have explored the impact of stalling on ribosome function when NGD is compromised and found it to result in +1 frameshifting. We used reporters that limit the number of ribosomes on a transcript to show that +1 frameshifting is induced through ribosome collision in yeast and bacteria. Furthermore, we observe a positive correlation between ribosome density and frameshifting efficiency. It is thus tempting to speculate that NGD, in addition to its role in mRNA quality control, evolved to cope with stochastic collision events to prevent deleterious frameshifting events.

Utilization of a Radiation Safety Time-Out Reduces Radiation Exposure During Electrophysiology Procedures.

OBJECTIVES: This study sought to determine whether a radiation safety time-out reduces radiation exposure in electrophysiology procedures. BACKGROUND: Time-outs are integral to improving quality and safety. The authors hypothesized that a radiation safety time-out would reduce radiation exposure levels for patients and the health care team members. METHODS: The study was performed at the New York University Langone Health Electrophysiology Lab. Baseline data were collected for 6 months prior to the time-out. On implementation of the time-out, data were collected prospectively with analyses to be performed every 3 months. The primary endpoint was dose area product. The secondary endpoints included reference point dose, fluoroscopy time, use of additional shielding, and use of alternative imaging such as intracardiac and intravascular ultrasound. RESULTS: A total of 1,040 patient cases were included. The median dose area product prior to time-out was 18.7 Gy∙cm2, and the median during the time-out was 14.7 Gy∙cm2, representing a 21% reduction (p = 0.007). The median reference point dose prior to time-out was 163 mGy, and during the time-out was 122 mGy (p = 0.011). The use of sterile disposable protective shields and ultrasound imaging for access increased significantly during the time-out. CONCLUSIONS: A radiation safety time-out significantly reduces radiation exposure in electrophysiology procedures. Electrophysiology laboratories, as well as other areas of cardiovascular medicine using fluoroscopy, should strongly consider the use of radiation safety time-outs to reduce radiation exposure and improve safety.