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Deposition of α-synuclein aggregates occurs widely in the central and peripheral nervous systems in Parkinson’s disease (PD). Although recent evidence has suggested that cell-to-cell transmission of α-synuclein aggregates is associated with the progression of PD, the mechanism by which α-synuclein aggregates spread remains undefined. Here, we show that α-synuclein aggregates are transmitted from cell to cell through a cycle involving uptake of external aggregates, co-aggregation with endogenous α-synuclein and exocytosis of the co-aggregates. Moreover, we find that glucocerebrosidase depletion, which has previously been strongly associated with PD and increased cognitive impairment, promotes propagation of α-synuclein aggregates. These studies define how α-synuclein aggregates spread among neuronal cells and may provide an explanation for how glucocerebrosidase mutations increase the risk of developing PD and other synucleinopathies. Transmission of alpha-synuclein aggregates between neurons has been observed in animal models of Parkinson’s disease, however, the mechanism of transmission remains unclear. Bae et al . report that a cycle of uptake, co-aggregation and exocytosis is enhanced by loss of glucocerebrosidase activity.

Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 ( GBA1 ) encodes β-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson’s disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When α-synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of α-synuclein aggregates. Genetics: Enzyme loss in Gaucher and Parkinson's diseases Loss of activity of the β-glucocerebrosidase 1 enzyme is sufficient to cause the defects responsible for Gaucher and Parkinson's diseases. Mutations in the GBA1 gene that encodes β-glucocerebrosidase 1 are known to cause Gaucher disease, an inherited lysosomal storage disorder, and to be risk factors for Parkinson's disease. Yet, despite the strong association between GBA1 mutations and these diseases, the mechanism responsible for pathology was not well understood. A research team led by Seung-Jae Lee of Konkuk University in Seoul, South Korea, generated human neuroblastoma cells harboring mutations in the GBA1 gene. The cell line without glucocerebrosidase 1 activity showed signs of lysosomal dysfunction, consistent with Gaucher disease, and a build-up of α-synuclein protein aggregates, a hallmark of Parkinson's disease. Mutant cells with normal enzyme activity did not show these problems.

Background Postoperative pain management after cardiac surgery involves a multimodal approach. Recently, the erector spinae plane (ESP) block has been incorporated into multimodal pain control protocols. These measures have been taken to increase patient satisfaction while minimizing opioid usage. Prospective data is lacking to guide decisions regarding optimal regional anesthetic agents. This randomized controlled pragmatic trial protocol seeks to determine the benefit of liposomal bupivacaine relative to plain bupivacaine hydrochloride at reducing postoperative opioid consumption and other clinical outcomes following cardiac surgery. Methods The investigators anticipate consenting 150 subjects to obtain 96 evaluable subjects undergoing minithoracotomy ( N  = 24 liposomal bupivacaine, N  = 24 bupivacaine hydrochloride) or open sternotomy ( N  = 24 liposomal bupivacaine, N  = 24 bupivacaine hydrochloride). The primary outcome will be postoperative opioid consumption, reported in morphine equivalents. Secondary outcomes will include postoperative nonopioid analgesic consumption, inpatient and outpatient postoperative pain scores, 30-day mortality and major morbidity rates, postoperative quality of life, and hospitalization costs. Double blinding will be conducted with necessary measures taken to mask electronic medical records and drug preparation. Discussion The trial is currently enrolling subjects at a single academic medical center in the northeastern United States. The current study aims to investigate the postoperative pain reported by patients undergoing cardiac surgery when receiving ESP blocks with liposomal bupivacaine (experimental) compared to its hydrochloride formulation (control). Trial registration ClinicalTrials.gov NCT06077422. Registered on October 2023.  https://clinicaltrials.gov/study/NCT06077422?tab=table .

Asian and Asian American students face culture-specific mental health risk factors, and the current study aims to examine whether a culture-specific community intervention in the form of a conference is an effective modality for psychoeducation in the Asian American community. Participants were assessed for reported changes in knowledge, attitudes, and behavior intentions related to mental health after attending the conference. A total of 118 conference participants filled out the survey. Participants reported changes in knowledge regarding mental health issues, generational differences, and the effects of culture. Participants also reported having a more open attitude towards mental health, having greater acceptance of mental health issues in themselves and others, and realizing that mental health issues are a community issue. Lastly, participants reported changes in behavior intentions such as communicating more with friends and family, engaging in perspective-taking, participating in advocacy and activism on mental health issues, and taking care of themselves and others.

Background and Aim of the Study. To investigate if mitral valve (MV) surgery quality differs by hospital volume in New Jersey (NJ). Methods. Using the NJ State Inpatient Database, patients ≥18 years undergoing MV repair or replacement from 2016–2019 were identified. Centers were considered high-volume if they performed more than 50 mitral operations annually. Baseline characteristics and outcomes (in-hospital mortality, seven-day readmission, hospital length of stay (LOS), and postoperative complications) were evaluated for the population and by center volume. Subanalysis by center volume within each procedure was conducted. Results. Among 2,560 mitral operations, MV replacement (92.3% (n = 2,362)) was performed more often than repair. High- (4) and low-volume (15) centers performed 1,180 (46.1%) and 1,380 (53.9%) mitral surgeries, respectively. Charlson Comorbidity Indices did not differ by center volume, including in subgroup analyses. Low-volume centers had higher rates of Hispanic patients, low-income patients, and readmission rates. High-volume centers had more transfers, urgent/emergent admissions, higher rates of in-hospital mortality, and longer LOS. Postoperative complications did not differ by volume. The MV replacement cohort reflected many of the differences seen in the total population, in addition to seeing higher rates of heart failure at high-volume centers and stroke at low-volume centers. Within MV repairs, significantly more Hispanic patients presented to low-volume centers and high-volume centers had longer LOS. Multivariable analysis indicated that hospital volume was not correlated to in-hospital mortality for the total population and within each procedure. Conclusions. MV replacement is performed more frequently than repair. Hospital volume is not correlated with MV surgical quality, and more representative quality measures are needed.

The association between low socioeconomic status (SES) and worse surgical outcomes has become an emerging area of interest. Literature has demonstrated that carotid artery stenting (CAS) poses greater risk of postoperative complications, particularly stroke, than carotid endarterectomy (CEA). This study aims to compare the impact of low SES on patients undergoing CAS vs. CEA. The National Inpatient Sample (NIS) was queried for patients undergoing CAS and CEA from 2010 to 2015. Patients were stratified by highest and lowest median income quartiles by zip code and compared through demographics, hospital characteristics, and comorbidities defined by the Charlson Comorbidity Index (CCI). Primary outcome was in-hospital mortality. Secondary outcomes included acute kidney injury (AKI), post-operative stroke, sepsis, and bleeding requiring reoperation.Multivariable logistic regression was used to determine the effect of SES on outcomes. Five thousand four hundred twenty-five patients underwent CAS (Low SES: 3,516 (64.8%); High SES: 1,909 (35.2%) and 38,399 patients underwent CEA (Low SES: 22,852 (59.5%); High SES: 15,547 (40.5%). Low SES was a significant independent predictor of mortality [OR = 2.07 (1.25-3.53);  = 0.005] for CEA patients, but not for CAS patients [OR = 1.21 (CI 0.51-2.30);  = 0.68]. Stroke was strongly associated with low SES, CEA patients (Low SES = 1.5% vs. High SES = 1.2%;  = 0.03), while bleeding was with high SES, CAS patients (Low SES = 5.3% vs. High SES = 7.1%;  = 0.01). CCI was a strong predictor of mortality for both procedures [CAS: OR1.45 (1.17-1.80);  < 0.001. CEA: OR1.60 (1.45-1.77);  < 0.001]. Advanced age was a predictor of mortality post-CEA [OR = 1.03 (1.01-1.06);  = 0.01]. While not statistically significant, advanced age and increased mortality trended towards a positive association in CAS [OR = 1.05 (1.00-1.10);  = 0.05]. Low SES is a significant independent predictor of post-operative mortality in patients who underwent CEA, but not CAS. CEA is also associated with higher incidence of stroke in low SES patients. Findings demonstrate the impact of SES on outcomes for patients undergoing carotid revascularization procedures. Prospective studies are warranted to further evaluate this disparity.

Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1)encodes β-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, themost common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson’s disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When α-synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of α-synuclein aggregates. KCI Citation Count: 32

Correction to: Experimental & Molecular Medicine (2015) 47, e153; doi:10.1038/emm.2014.128; published online 27 March 2015 The authors have noticed an error in publication of this paper. Throughout the article text, 'GTP-binding protein type A1 (GBA1) gene' should have been read as 'glucocerebrosidase (GBA1) gene'.

Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes β-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When α-synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of α-synuclein aggregates.