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1.
J Orthop ; 52: 129-132, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38596621

RESUMO

Objectives: The purpose of this study is to evaluate the outcomes of operatively treated Mason Type III radial head fractures. Additionally, this project seeks to assess efficacy of PROMIS in evaluating post-operative outcomes for this patient population. Methods: A total of 143 patients who underwent operative treated Mason Type III radial head fractures were analyzed retrospectively. PROMIS physical function (PF), PROMIS upper extremity (UE), PROMIS pain interference (PI), demographic variables, and range of motion were collected and analyzed over 12-month follow-up. Results: Radial head arthroplasty (RHA) was performed on 89 patients, open reduction and internal fixation (ORIF) was performed on 47 patients, and radial head excision was performed on 7 patients. Among the RHA patients, PROMIS PF, PI and UE demonstrated a change of -1.33 (p < 0.05), -1.48 (p < 0.05), and 2.23 (p < 0.05) respectively from injury to 12-months. Among the ORIF patients, PROMIS PF, PI and UE demonstrated a change of 3.22 (p < 0.05), -1.56 (p < 0.05), and 2.09 (p < 0.05) respectively from injury to 12-months. At the pre-operative and 12-month visits, the RHA group demonstrated lower PROMIS PF scores 34.75 vs 38.02 (p < 0.05) and 33.42 vs 41.24 (p < 0.05) respectively. Ther was no difference in PROMIS PI, UE, or elbow range of motion between the two groups at 6- or 12-month follow-up (p > 0.05). Conclusion: Comparing the RHA and ORIF groups, there was no difference in PROMIS PI or UE scores nor was there a clinically significant improvement at the 6- or 12-month mark. The ORIF group demonstrated improved PROMIS PF at all follow-up periods and did show a clinically significant improvement. Patient Acceptable Symptom State (PASS) correlated only with PROMIS UE at 6- and 12- months for both groups.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38634133

RESUMO

The Dietary Approach to Stop Hypertension (DASH) diet, with its low sodium and high potassium content, acts like a diuretic by reducing sodium reabsorption in the kidney's distal convoluted tubule but without the side effects. Previous studies based on animal models didn't explore changes in human ion channel proteins. Recent insights into urinary extracellular vesicles (uEVs) suggest they reflect kidney tissue and physiological modifications. In our inpatient study, we shifted hypertensive volunteers from an American diet to the DASH diet, examining changes in those with stage 1 untreated hypertension. We analyzed a large range of pure uEVs, from small to large, in urine samples from nine volunteers over three time points. Mass spectrometry of these uEVs identified 1,800 proteins, revealing an increase in SCL12A3 (NCC) and a decrease in aquaporin 2 (AQP2). Immunoblotting showed an increase in activated (phosphorylated) NCC ratio to total NCC and a decrease in AQP2 from day 5 to 11, indicating the DASH diet induces measurable kidney responses via uEV protein abundance changes. This non-invasive method offers new insights into the diet's renal mechanism. Future studies should confirm these findings in a larger cohort, clarify the drivers behind NCC and AQP2 changes, their impact on hypertension, and investigate if uEVs also act as a waste pathway for inactive proteins, expanding our understanding of dietary effects on kidney physiology.

3.
J Orthop ; 54: 5-9, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38516390

RESUMO

Background: Distal radius fractures with severely osteoporotic bone or articular comminution can provide challenges to fixation with traditional volar locked plating alone. The purpose of this study was to evaluate the clinical, radiographic, and patient reported outcomes of patients undergoing distal radius fixation with volar locked plating and adjunctive dorsal bridge plating. Methods: We retrospectively identified 16 patients with distal radius fractures who underwent our preferred surgical technique for fixation. Patients underwent volar locked plate fixation as well as dorsal bridge fixation at time of surgery. Seven patients were indicated for severe articular comminution with volar rim fragmentation (44%), three patients were revised for nonunion after previous volar locked late fixation (19%), and six patients had severely osteoporotic bone with articular comminution (38%). Two patients (13%) sustained AO/OTA 23-A3 distal radius fracture, two patients (13%) had a 23-B3 fracture, two patients (13%) had a 23-C2 fracture and ten patients (63%) had a 23-C3 fracture. Results: The average patient age was 51.8 years ± 20.6. Patients were followed for an average of 12.2±6.3 months. The dorsal bridge plate was removed at an average of 11.1±2.4 weeks. The average post-operative radial inclination was 18.9±2.4°, radial height 12.4 mm ± 2.6 mm, and volar tilt 7.1±1.9°. There were no cases of deep or superficial infection. After dorsal bridge plate removal, patients demonstrated an average wrist extension of 55.3±9.5°, flexion 54.4±12.8°, radial deviation 15.7±3.2°, 25.2±3.9 degrees of ulnar deviation. Conclusion: Distal radius fractures in the setting of severely osteoporotic bone, salvage procedures, articular comminution, volar rim fractures, and revision surgery present uniquely difficult surgical challenges. Volar locked plating with adjunctive dorsal bridge plating can be used with good short- and long-term results.

4.
J Voice ; 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38519334

RESUMO

OBJECTIVES: Silk-hyaluronic acid (silk-HA) is a novel vocal fold augmentation material used in humans since July 2020. We aim to describe indications, voice outcomes, and longevity data for silk-HA injectable when used for vocal fold injection (VFI) augmentation in a large cohort of patients with longer-term follow-up than preliminary clinical studies. METHODS: Retrospective chart review of Silk-HA injections for glottic insufficiency (GI) and follow-up between July 2020 and November 2023. Subject demographics, diagnoses, volume of material injected, VHI-10 data, time from injection, need for reinjection, and complications were collected. Blinded perceptual voice analysis of randomly selected pre- and post-intervention voice samples for unilateral vocal fold paralysis patients was performed by three voice-specialized speech-language pathologists, and changes in VHI-10 determined at various time intervals up to 1year and beyond. RESULTS: A total of 160 silk-HA injection procedures were performed: 59% female, with a mean age of 66± 13 (range 21-90) years. Ninety-four subjects had unilateral paralysis (58.4%); the remainder had scar, atrophy, paresis, or a combination thereof. Mean volume of silk-HA injected was 0.24± 0.14 cc. Major complications were rare, most notable for laryngoscopic evidence of hemilaryngeal edema (n = 6, 3.8%), with a readmission rate to hospital of 1.3% (n = 2). There was a statistically significant decrease in paired ΔVHI-10 and CAPE-V ratings for each of the postoperative follow-up intervals. A total of 24 (27.2%) repeat medialization procedures were recommended following silk-HA injection for unilateral paralysis. CONCLUSIONS: This study demonstrates that silk-HA is a safe product for VFI augmentation, and effective injectable for the treatment of GI due to unilateral vocal fold paralysis. Based on the current data, it is reasonable to counsel patients that they should expect benefit for several months following the injection. If patients reach 1year from their injection with a stable and satisfactory outcome, the majority experience ongoing benefit without need for additional procedures, however, the final duration of clinical effect appears to be years, but it is yet to be determined.

5.
J Orthop Trauma ; 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38457769

RESUMO

OBJECTIVES: To test the hypothesis that primary osteosynthesis of humeral shaft fractures may lead to more favorable clinical, functional, and patient-reported outcomes than fixation following a trial of nonoperative management. DESIGN: Retrospective Cohort Review. SETTING: Academic Level I Trauma Center. PATIENT SELECTION CRITERIA: Adult patients who presented with humeral shaft fractures, and ultimately underwent open reduction and internal fixation (ORIF) from 05/2011 to 05/2021. Patients who underwent ORIF within 2 weeks of injury were grouped into the primary osteosynthesis cohort, and patients who underwent ORIF >4 weeks from date of injury were grouped into the trial of nonoperative cohort. OUTCOME MEASURES AND COMPARISONS: Post-operative complications, elbow arc of motion, time to radiographic union, and patient-reported outcomes were investigated and compared between the primary osteosynthesis and trial of nonoperative management cohorts.Results: 127 patients fit the study criteria, 84 underwent primary osteosynthesis and 43 trialed initial non-operative treatment. No differences were found in patient demographics between the primary osteosynthesis and trial of non-operative management cohorts, including age (53±19 vs. 57±18; p=0.25), sex (39% vs. 44% male, 61% vs. 56% female; p=0.70), and BMI (30±6 vs. 32±9; p=0.38) . The average time to operative intervention in the primary osteosynthesis group was 4 days (0-14 days), and 105 days (28-332 days) in the trial of non-operative treatment group (p<0.01). No differences were found with regards to intra-operative blood loss, total operative time, time to radiographic union (determined using the RUSHu scoring system), or overall complication rates, including primary and secondary radial nerve injuries (P=0.23 and 0.86, respectively). Patients reported similar PROMIS Pain Interference (PI) (P=0.73), Depression (D) (P=0.99), and Physical Function (PF) (P=0.66) scores at their 6-month post-surgical follow up visits. CONCLUSION: Patients who attempted a trial of non-operative management for humeral shaft fractures prior to open reduction and internal fixation had similar clinical, functional, and patient reported outcomes as those who underwent primary osteosynthesis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

6.
Nucleic Acids Res ; 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38477352

RESUMO

Alterations in the tumor suppressor ATRX are recurrently observed in mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) that Atrx deficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks. We additionally observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Finally, we demonstrated that loss of ATRX in a mesenchymal malignancy, undifferentiated pleomorphic sarcoma, results in similar epigenetic disruption and de-repression of transposable elements. Together, our results reveal a role for ATRX in maintaining epigenetic states and transcriptional repression in mesenchymal progenitors and tumor cells and in preventing aberrant differentiation in the progenitor context.

7.
Eur Arch Otorhinolaryngol ; 281(5): 2547-2552, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38492008

RESUMO

INTRODUCTION: Chatbot Generative Pre-trained Transformer (ChatGPT) is an artificial intelligence-powered language model chatbot able to help otolaryngologists in practice and research. The ability of ChatGPT in generating patient-centered information related to laryngopharyngeal reflux disease (LPRD) was evaluated. METHODS: Twenty-five questions dedicated to definition, clinical presentation, diagnosis, and treatment of LPRD were developed from the Dubai definition and management of LPRD consensus and recent reviews. Questions about the four aforementioned categories were entered into ChatGPT-4. Four board-certified laryngologists evaluated the accuracy of ChatGPT-4 with a 5-point Likert scale. Interrater reliability was evaluated. RESULTS: The mean scores (SD) of ChatGPT-4 answers for definition, clinical presentation, additional examination, and treatments were 4.13 (0.52), 4.50 (0.72), 3.75 (0.61), and 4.18 (0.47), respectively. Experts reported high interrater reliability for sub-scores (ICC = 0.973). The lowest performances of ChatGPT-4 were on answers about the most prevalent LPR signs, the most reliable objective tool for the diagnosis (hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring (HEMII-pH)), and the criteria for the diagnosis of LPR using HEMII-pH. CONCLUSION: ChatGPT-4 may provide adequate information on the definition of LPR, differences compared to GERD (gastroesophageal reflux disease), and clinical presentation. Information provided upon extra-laryngeal manifestations and HEMII-pH may need further optimization. Regarding the recent trends identifying increasing patient use of internet sources for self-education, the findings of the present study may help draw attention to ChatGPT-4's accuracy on the topic of LPR.


Assuntos
Refluxo Laringofaríngeo , Humanos , Refluxo Laringofaríngeo/diagnóstico , Refluxo Laringofaríngeo/tratamento farmacológico , Inteligência Artificial , Reprodutibilidade dos Testes , Educação de Pacientes como Assunto , Endoscopia , Monitoramento do pH Esofágico
8.
Nat Commun ; 15(1): 1943, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431617

RESUMO

DNA replication through a challenging genomic landscape is coordinated by the replisome, which must adjust to local conditions to provide appropriate replication speed and respond to lesions that hinder its progression. We have previously shown that proteasome shuttle proteins, DNA Damage Inducible 1 and 2 (DDI1/2), regulate Replication Termination Factor 2 (RTF2) levels at stalled replisomes, allowing fork stabilization and restart. Here, we show that during unperturbed replication, RTF2 regulates replisome localization of RNase H2, a heterotrimeric enzyme that removes RNA from RNA-DNA heteroduplexes. RTF2, like RNase H2, is essential for mammalian development and maintains normal replication speed. However, persistent RTF2 and RNase H2 at stalled replication forks prevent efficient replication restart, which is dependent on PRIM1, the primase component of DNA polymerase α-primase. Our data show a fundamental need for RTF2-dependent regulation of replication-coupled ribonucleotide removal and reveal the existence of PRIM1-mediated direct replication restart in mammalian cells.


Assuntos
Replicação do DNA , DNA , Animais , DNA/genética , DNA/metabolismo , Dano ao DNA , Proteínas de Ciclo Celular/metabolismo , RNA/genética , Ribonucleases/metabolismo , Mamíferos/genética
9.
J Clin Invest ; 134(7)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38386415

RESUMO

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Recém-Nascido , Humanos , Carcinoma de Células Renais/patologia , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Fatores de Transcrição/genética , Genômica , Neoplasias Renais/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Translocação Genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Ligação a RNA/genética
10.
Nat Metab ; 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413806

RESUMO

Post-translational modifications (PTMs) on histones are a key source of regulation on chromatin through impacting cellular processes, including gene expression1. These PTMs often arise from metabolites and are thus impacted by metabolism and environmental cues2-7. One class of metabolically regulated PTMs are histone acylations, which include histone acetylation, butyrylation, crotonylation and propionylation3,8. As these PTMs can be derived from short-chain fatty acids, which are generated by the commensal microbiota in the intestinal lumen9-11, we aimed to define how microbes impact the host intestinal chromatin landscape, mainly in female mice. Here we show that in addition to acetylation, intestinal epithelial cells from the caecum and distal mouse intestine also harbour high levels of butyrylation and propionylation on lysines 9 and 27 of histone H3. We demonstrate that these acylations are regulated by the microbiota and that histone butyrylation is additionally regulated by the metabolite tributyrin. Tributyrin-regulated gene programmes are correlated with histone butyrylation, which is associated with active gene-regulatory elements and levels of gene expression. Together, our study uncovers a regulatory layer of how the microbiota and metabolites influence the intestinal epithelium through chromatin, demonstrating a physiological setting in which histone acylations are dynamically regulated and associated with gene regulation.

11.
Patient Educ Couns ; 123: 108203, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38359588
12.
J Hand Surg Glob Online ; 6(1): 58-61, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38313628

RESUMO

Purpose: Perilunate fracture dislocation (PLFD) injuries are associated with the development of acute carpal tunnel syndrome (CTS). The purpose of our study was to identify the factors that increase the likelihood of developing CTS in patients with PLFD. Additionally, we attempted to classify patients who did not initially undergo carpal tunnel release (CTR) at the time of injury but eventually underwent CTR within the follow-up period. Methods: Patients presenting to a level-1 trauma center with isolated PLFDs (Mayfield III-IV) were retrospectively identified by using CPT and ICD-10 codes. Polytraumatized patients, those with a history of previous wrist trauma, or those with previous carpal tunnel symptoms or surgery were excluded. Outcomes of interest included the development of acute CTS, pre- and post-reduction changes in CTS symptoms, and associated hand and wrist fractures. Chi-square tests, Kruskal-Wallis tests, and multivariate logistic regression were used to examine the predictors of developing CTS after a PLFD. Results: In total, 43 patients were included in the final cohort, with a mean age of 44 years, of which 77% were men. The most common fracture of the carpus included scaphoid fractures (9/43, 21%). The average time from presentation to reduction was 636 minutes. Acute CTS symptoms before reduction were present in 26% of the patients and increased post-reduction to 28%. No difference exists between the time to sedation and the presence of acute carpal tunnel symptoms (P >.05). During initial surgical intervention, 79% underwent CTR (27/34). Of the seven patients who did not initially undergo a CTR, 57% (4/7) required a CTR within the follow-up period. Conclusion: Reduction of PLFDs did not significantly improve the number of patients with acute CTS. More than 50% of the patients who did not undergo a CTR at the initial surgery required a CTR within the follow-up period. Type of study/level of evidence: Prognostic III.

13.
Acta Otorhinolaryngol Ital ; 44(1): 27-35, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38420719

RESUMO

Objective: The aim of this study was to compare the efficacy of voice therapy combined with standard anti-reflux therapy in reducing symptoms and signs of laryngopharyngeal reflux (LPR). Methods: A randomised clinical trial was conducted. Fifty-two patients with LPR diagnosed by 24 h multichannel intraluminal impedance-pH monitoring were randomly allocated in two groups: medical treatment (MT) and medical plus voice therapy (VT). Clinical symptoms and laryngeal signs were assessed at baseline and after 3 months of treatment with the Reflux Symptom Index (RSI), Reflux Finding Score (RFS), Voice Handicap Index (VHI) and GRBAS scales. Results: Groups had similar scores at baseline. At 3-month follow-up, a significant decrease in RSI and RFS total scores were found in both groups although it appeared to be more robust in the VT group. G and R scores of the GRBAS scale significantly improved after treatment in both groups, with better results in the VT group. The VHI total score at 3 months improved more in the VT group (VHI delta 9.54) than in the MT group (VHI delta 5.38) (p < 0.001). Conclusions: The addition of voice therapy to medications and diet appears to be more effective in improving treatment outcomes in subjects with LPR. Voice therapy warrants consideration in addition to medication and diet when treating patients with LPR.


Assuntos
Refluxo Laringofaríngeo , Voz , Humanos , Refluxo Laringofaríngeo/diagnóstico , Refluxo Laringofaríngeo/tratamento farmacológico , Projetos Piloto , Inibidores da Bomba de Prótons/uso terapêutico , Qualidade da Voz
15.
J Orthop ; 51: 54-59, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38304145

RESUMO

Introduction: Coronal Plane Alignment of the Knee (CPAK), is an informative way to classify native knee alignment types, but does not consider posterior tibial slope, an important variable in knee kinematics. We hypothesized that tibial slope would have a significant effect on knee kinematics and warrant consideration in addition to the CPAK system. Methods: We examined 335 adult patients with osteoarthritis receiving total knee arthroplasty. We measured the lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), and posterior tibial slope angle (PTS). Knees were categorized into CPAK classes and subdivided into types 'A' (PTS 8°) or 'B' (PTS >8°). We recorded pre-and-post operative knee flexion, and extension/flexion gaps in all subjects. Results: CPAK classes VII-IX were not seen. Classes I and II comprised a plurality of all knees. One-third of all knees were type B. CPAK classes III, IV, and VI had greater type B proportions, but this was not statistically significant. Type B knees had greater flexion both pre-op (p < .001) and post-op (p = .043); type A knees had greater flexion improvement pre-to-post operatively (p = .045). Type A knees had greater medial and lateral flexion-extension gap change pre-operatively (p = .021) and (p = .027), respectively. Type B knees had greater medial-lateral gap imbalance preoperatively in both flexion and extension. Discussion/conclusion: Our results suggest that there are important pre and post-operative differences in medial and lateral femorotibial gap balance between type A and B knees that require consideration for intra-operative balancing. Differences in knee flexion further solidify that PTS is an important variable that affects kinematics before and after TKA. We propose the addition of PTS types A and B to the existing CPAK classes. This is an easy and logical way to create a comprehensive classification system in both coronal and sagittal planes that captures further differences in knee kinematics.

16.
Nat Genet ; 56(3): 383-394, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38291334

RESUMO

Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington's disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSß), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.


Assuntos
Corpo Estriado , Doença de Huntington , Humanos , Animais , Cerebelo/metabolismo , Doença de Huntington/genética , Modelos Animais de Doenças
17.
Neuron ; 112(6): 924-941.e10, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38237588

RESUMO

The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex.


Assuntos
Doença de Huntington , Animais , Doença de Huntington/metabolismo , Neurônios/metabolismo , Células Piramidais/metabolismo , Córtex Cerebral/metabolismo , Núcleo Solitário/metabolismo , Modelos Animais de Doenças , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo
18.
J Voice ; 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38182497

RESUMO

OBJECTIVES: This case report aims to histologically examine human vocal fold tissue 9 months after silk-hyaluronic acid (silk-HA) injection. INTRODUCTION: Silk-HA is an engineered injectable implant made from natural protein biomaterial, silk, crosslinked with hyaluronic acid to provide long-lasting, dynamic office-based vocal fold injection augmentation to restore glottic competency. METHODS: We report the case of an adult female with left vocal fold immobility and bilateral atrophy that was treated with silk-HA injections with biopsy taken 9 months after injection for histological examination. CONCLUSION: Silk-HA injection in human true vocal fold demonstrates slow degradation of particles and intended cellular infiltration 9 months after injection.

19.
Indian J Orthop ; 58(1): 62-67, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38161407

RESUMO

Background: First tarsometatarsal joint arthrodesis is a common procedure performed by podiatrists and orthopedic surgeons. There remains debate on how useful CT scans are in assessing fusion status in the post-operative patient. The purpose of our study was to determine the reliability among both orthopedic surgeons and radiologists in reviewing both postoperative radiographs and CT in order to determine if fusion had occurred in patients undergoing 1st tarsometatarsal arthrodesis. A secondary purpose of this study was to determine if CT offered improved inter- and intra-rater reliability when compared to plain radiographs. Methods: Patients who underwent 1st tarsometatarsal arthrodesis were retrospectively reviewed and those who underwent CT post-operatively for persistent pain were identified. Orthopedic surgeons and radiologists then analyzed the radiographs and CT of these patients for union with a threshold for union being set at 50% of the joint being fused. Imaging was then re-evaluated by the same provider 6 months later. Results: 24 patients were identified meeting inclusion criteria. Inter-rater reliability and intra-rater reliability for assessment of 1st tarsometatarsal arthrodesis were better with CT compared to radiographs; however, this association was not deemed reliable. Both imaging modalities were not able to assess union status confidently and reliably across reviewers, although CT scan had better intra-rater reliability. Conclusions: While CT is frequently used to assess fusion in patients who have underwent 1st tarsometatarsal arthrodesis, it was not found to be better than radiographs. Practitioners should reconsider the use CT as the gold standard when assessing fusion in this population.

20.
J Am Chem Soc ; 146(2): 1423-1434, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38171910

RESUMO

Cu-based catalysts hold promise for electrifying CO2 to produce methane, an extensively used fuel. However, the activity and selectivity remain insufficient due to the lack of catalyst design principles to steer complex CO2 reduction pathways. Herein, we develop a concept to design carbon-supported Cu catalysts by regulating Cu active sites' atomic-scale structures and engineering the carbon support's mesoscale architecture. This aims to provide a favorable local reaction microenvironment for a selective CO2 reduction pathway to methane. In situ X-ray absorption and Raman spectroscopy analyses reveal the dynamic reconstruction of nitrogen and hydroxyl-immobilized Cu3 (N,OH-Cu3) clusters derived from atomically dispersed Cu-N3 sites under realistic CO2 reduction conditions. The N,OH-Cu3 sites possess moderate *CO adsorption affinity and a low barrier for *CO hydrogenation, enabling intrinsically selective CO2-to-CH4 reduction compared to the C-C coupling with a high energy barrier. Importantly, a block copolymer-derived carbon fiber support with interconnected mesopores is constructed. The unique long-range mesochannels offer an H2O-deficient microenvironment and prolong the transport path for the CO intermediate, which could suppress the hydrogen evolution reaction and favor deep CO2 reduction toward methane formation. Thus, the newly developed catalyst consisting of in situ constructed N,OH-Cu3 active sites embedded into bicontinuous carbon mesochannels achieved an unprecedented Faradaic efficiency of 74.2% for the CO2 reduction to methane at an industry-level current density of 300 mA cm-2. This work explores effective concepts for steering desirable reaction pathways in complex interfacial catalytic systems via modulating active site structures at the atomic level and engineering pore architectures of supports on the mesoscale to create favorable microenvironments.

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