Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.

Survey of public attitudes towards imminent death donation in the United States.

Imminent death donation (IDD) is described as living organ donation prior to a planned withdrawal of life-sustaining care in an imminently dying patient. Although IDD was ethically justified by United Network for Organ Sharing, the concept remains controversial due to presumed lack of public support. The aim of this study was to evaluate the public's attitudes towards IDD. A cross-sectional survey was conducted of US adults age >18 years (n = 2644). The survey included a case scenario of a patient with a devastating brain injury. Responses were assessed on a 5-point Likert scale. Results showed that 68% - 74% of participants agreed or strongly agreed with IDD when posed as a general question and in relation to the case scenario. Participants were concerned about "recovery after a devastating brain injury" (34%), and that "doctors would not try as hard to save a patient's life" (33%). Only 9% of participants would be less likely to trust the organ donation process. In conclusion, our study demonstrates strong public support for IDD in the case of a patient with a devastating brain injury. Notably, participants were not largely concerned with losing trust in the organ donation process. These results justify policy change towards imminent death donation.

A rare case of isolated thoracic AL-amyloidoma causing complete atelectasis of the right lung.

Tumoral amyloidosis, or amyloidoma, is a benign, but rare form of amyloidosis that has been reported with a favorable prognosis following surgical resection in some case reports. We present a case of acute on chronic respiratory failure secondary to extensive growth of a thoracic amyloidoma causing atelectasis of the right lung. Our case patient had greater morbidity due to late presentation and extensive disease at diagnosis, precluding any surgical intervention. Radiation therapy and medical management were unsuccessful in reducing disease burden. Early diagnosis and detection are pivotal to improving survival in patients with isolated thoracic amyloidoma.

Electrostatic Discharge (ESD) as a Cause of Facial Nerve Stimulation After Cochlear Implantation: A Case Report.

OBJECTIVE: To discuss persistent facial nerve stimulation (FNS) related to repeated electrostatic discharge (ESD) shock following cochlear implantation. METHODS: Single case report with literature review. RESULTS: FNS is a feared complication after cochlear implantation, occurring in approximately 7% of cases, with most patients having anatomic abnormalities. The presented case has no anatomical abnormalities but reported frequent environmental static shock. FNS during the first 1 to 3 seconds of processor attachment caused a significant decrease in the patient's quality of life, requiring subsequent re-implantation with full resolution. CONCLUSIONS: FNS is a complication of cochlear implantation that can cause a great deal of distress and discomfort. Frequent electrostatic discharge (ESD) contributed to device malfunctioning and FNS in a patient with otherwise normal anatomy and should be avoided if possible.

Extracapsular versus intracapsular tonsillectomy: Outcomes in children with a focus on developmental delay.

INTRODUCTION: Outcomes following intracapsular tonsillectomy (IT) have not been well established in children with developmental delays. The objective of this study was to compare outcomes and complications between intracapsular and extracapsular tonsillectomy (TT) in pediatric patients with developmental delay (DD) in comparison to non-developmentally delayed children. METHODS: This is a retrospective study of pediatric patients with DD undergoing tonsillectomy between 2016 and 2019 at a tertiary care hospital. This group included patients with Down Syndrome, Autism Spectrum Disorder, other genetic syndromes, and patients with a diagnosis of global developmental delay. Outcomes and complications were analyzed for IT and TT. RESULTS: 2267 charts were reviewed, and 320 patients were identified with DD. Of those, 72 patients underwent IT and 248 underwent TT. In the DD cohort, the IT group had a shorter length of stay (0.97 vs 1.7 days, p < .0001) and was less likely to receive post-operative narcotic medication (2.8% vs 35%, p < .0001) and corticosteroids (9.7% vs 64%, p < .0001) during their hospital stay. Reductions in emergency room (ER) visits (5.6% vs 10%, p = .21) and post-op bleeding (PTH) (1.4% vs 4.8%, p = .31) for IT vs TT were not statistically significant in the DD group. In the NDD group, fewer patients undergoing IT returned to the ER (11% vs 2.3%, p < .0001) or had PTH (4.8% vs 0.25%, p, 0.0001) as compared to those children undergoing TT. There was no difference between parental report of symptom improvement between the groups (39% vs 33%, p = .39). Analysis of 180 patients with preoperative and postoperative sleep study data revealed post-op Apnea Hypopnea Index (AHI) improved with both techniques (74% TT vs 79% IT, p = .7). There were no differences noted for persistent obstructive sleep apnea (OSA) among the two techniques for both study groups (p = .63). CONCLUSION: Children with DD undergoing IT have reduced length of stay and reduced inpatient administration of post-operative opioids and steroids. IT has comparable efficacy to TT in treating symptoms of pediatric sleep apnea with a better safety profile. Overall, children undergoing IT return to the operating room less frequently than those undergoing TT. Longer follow-up studies will be needed to evaluate rate of tonsil regrowth, risk of revision surgery and persistence of OSA in these patients.

Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1.

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length-dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.

Comparison of proton therapy techniques for treatment of the whole brain as a component of craniospinal radiation.

BACKGROUND: For treatment of the entire cranium using passive scattering proton therapy (PSPT) compensators are often employed in order to reduce lens and cochlear exposure. We sought to assess the advantages and consequences of utilizing compensators for the treatment of the whole brain as a component of craniospinal radiation (CSI) with PSPT. Moreover, we evaluated the potential benefits of spot scanning beam delivery in comparison to PSPT. METHODS: Planning computed tomography scans for 50 consecutive CSI patients were utilized to generate passive scattering proton therapy treatment plans with and without Lucite compensators (PSW and PSWO respectively). A subset of 10 patients was randomly chosen to generate scanning beam treatment plans for comparison. All plans were generated using an Eclipse treatment planning system and were prescribed to a dose of 36 Gy(RBE), delivered in 20 fractions, to the whole brain PTV. Plans were normalized to ensure equal whole brain target coverage. Dosimetric data was compiled and statistical analyses performed using a two-tailed Student's t-test with Bonferroni corrections to account for multiple comparisons. RESULTS: Whole brain target coverage was comparable between all methods. However, cribriform plate coverage was superior in PSWO plans in comparison to PSW (V95%; 92.9 ± 14 vs. 97.4 ± 5, p < 0.05). As predicted, PSWO plans had significantly higher lens exposure in comparison to PSW plans (max lens dose Gy(RBE): left; 24.8 ± 0.8 vs. 22.2 ± 0.7, p < 0.05, right; 25.2 ± 0.8 vs. 22.8 ± 0.7, p < 0.05). However, PSW plans demonstrated no significant cochlear sparing vs. PSWO (mean cochlea dose Gy(RBE): 36.4 ± 0.2 vs. 36.7 ± 0.1, p = NS). Moreover, dose homogeneity was inferior in PSW plans in comparison to PSWO plans as reflected by significant alterations in both whole brain and brainstem homogeneity index (HI) and inhomogeneity coefficient (IC). In comparison to both PSPT techniques, multi-field optimized intensity modulated (MFO-IMPT) spot scanning treatment plans displayed superior sparing of both lens and cochlea (max lens: 12.5 ± 0.6 and 12.9 ± 0.7 right and left respectively; mean cochlea 28.6 ± 0.5 and 27.4 ± 0.2), although heterogeneity within target volumes was comparable to PSW plans. CONCLUSIONS: For PSPT treatments, the addition of a compensator imparts little clinical advantage. In contrast, the incorporation of spot scanning technology as a component of CSI treatments, offers additional normal tissue sparing which is likely of clinical significance.