Citations

Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson’s disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.

Abstract To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. Significance: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor. This article is highlighted in the In This Issue feature, p. 2355

Background and purpose Deep brain stimulation of the thalamus is an effective treatment for multiple neurological disorders. The centromedian and parafascicular nuclei are recently emerging targets for multiple conditions, such as epilepsy and Tourette syndrome; however, their limited visibility on conventional magnetic resonance imaging sequences has been a major obstacle. The goal of this study was to demonstrate the feasibility of a high-resolution and high-contrast targeting sequence for centromedian-parafascicular deep brain stimulation using a recently described magnetic resonance imaging sequence, three-dimensional edge-enhancing gradient echo. Methods The three-dimensional edge-enhancing gradient echo sequence was performed on a normal volunteer for a total of six acquisitions. Multi-image co-registration and averaging was performed by first co-registering each of the six scans and then averaging to produce an edge-enhancing gradient echo-multi-image co-registration and averaging scan. The averaging was also performed for two, three, four and five scans to assess the change in the signal-to-noise ratio and identify the ideal balance of image quality and scan time. Results The edge-enhancing gradient echo-multi-image co-registration and averaging scan allowed clear boundary delineation of the centromedian and parafascicular nuclei. The signal-to-noise ratio increased as a function of increasing scan number, but the added gain was small beyond four scans for the imaging parameters used in this study. Conclusions The recently described three-dimensional edge-enhancing gradient echo sequence provides an easily implementable approach, using widely available magnetic resonance imaging technology without complex post-processing techniques, to delineate centromedian and parafascicular nuclei for deep brain stimulation targeting.

High salt diet (HS) impairment of endothelial nitric oxide (NO) signaling has been described in human and rodents. The mechanisms which mediate this dysfunction remain unknown. We and others have previously shown histone deacetylase 1 (HDAC1) decreases endothelial NO production. We therefore sought to investigate the mechanisms by which HS initiates endothelial dysfunction and if it is HDAC1‐dependent. We first investigated if HS induced endothelial dysfunction is acutely regulated by a circulating factor. Male Sprague Dawley rats were fed normal salt diet (NS; 0.49% NaCl) or 2 weeks of HS (4.0% NaCl). Afferent arteriole vasoconstrictor responses to the NOS inhibitor, L‐NAME, were monitored using the in vitro, blood perfused juxtamedullary nephron preparation. Arterioles from HS fed rats perfused with blood from HS fed rats demonstrated blunted constriction to L‐NAME (96 ± 2% of Con) compared to arterioles from NS fed rats perfused with blood from NS fed rats (76.2 ± 2% of Con; P=0.0017). Perfusing arterioles from NS fed rats with blood HS fed rats blunted constriction to L‐NAME (88 ± 1% of Con) compared to perfusing with blood from NS fed rats (P=0.0003), but not to the same extent as arterioles from HS fed rats perfused with blood from HS fed rats (P=0.0095). HS arterioles perfused with blood from NS fed rats had similar L‐NAME‐induced constriction (75 ± 2% of Con) compared to arterioles from NS fed rats perfused with blood from NS fed rats (P=0.9107). In short, the impaired constriction to L‐NAME is dependent up on the diet of the blood donor and not the diet of the arteriole donor suggesting HS impairs endothelial function through an acute‐acting circulating factor. This was not due to increased plasma arginase activity (NS: 7.96 ± 3.73 U/L vs HS: 5.42 ± 1.83 U/L P=0.5813), changes in plasma tetrahydrobiopterin (NS: 65.09 ± 11.57 pmol/ml vs HS: 53.54 ± 5.59 pmol/ml, P=0.311) or changes in plasma dihydrobiopterin (NS: 98.18 ± 7.84 pmol/ml vs HS: 87.45 ± 13.28 pmol/ml, P=0.530). We then investigated if HS increased endothelial HDAC1 activity. Renal endothelial cells were isolated from NS and HS fed rats and incubated in plasma from the same rat. HDAC1 activity was defined as the MS‐275 (HDAC1 specific inhibitor) inhibitable portion of total HDAC activity. We found HS significantly increased renal endothelial HDAC1 activity (NS: 0.38 ± 0.03 pmol/min vs HS:0.94 ± 0.19 pmol/min, P=0.01). Furthermore, in vitro HDAC1 inhibition with 300 nM MS‐275 restored the arteriolar vasoconstrictor responses in HS rats (79 ± 3% of Con) to values similar to NS fed rats (P=0.969) and to NS rats + MS‐275 (79 ± 1% of Con; P>0.998). When plasma from HS fed rats was combined with erythrocytes from NS fed rats and perfused through arterioles from NS fed rats, constriction to L‐NAME was blunted (85 ± 3% of Con; P=0.0129). Under these same conditions, HDAC1 inhibition restored constriction (75.7 ± 0.95 % of Con) similar to controls (P=0.979). We conclude that HS disruption of renal microvascular NO signaling is initiated by a circulating factor(s) that increases endothelial HDAC1 activity.

Abstract Objective The purpose of this study was to determine the association between fear-avoidance beliefs and disability in 3 months in people with vestibular disorders while accounting for demographic and clinical characteristics. Methods This prospective cohort study included people aged 18 to 100 years who reported dizziness. Participants were recruited from a balance disorders clinic and outpatient physical therapy clinics. All participants completed the Vestibular Activities Avoidance Instrument (VAAI) and the Hospital Anxiety and Depression Scale at baseline and the Vestibular Activities and Participation measure (VAP), dizziness Visual Analogue Scale (VAS), and 12-item Short Form Health Questionnaire at baseline and 3-month follow-up. A modified version of the VAAI included 9 items abstracted from the 81-item VAAI. The relationships between 9-item VAAI scores and follow-up measures of disability were assessed using Spearman correlation coefficients. Linear regression models were analyzed to determine the effect of fear-avoidance beliefs on follow-up VAP score while accounting for baseline outcome measures. Results All participants (n = 404) completed the baseline assessment (mean age = 54 years), and 286 (71%) completed the 3-month assessment. The mean 9-item VAAI score was 25 (SD = 14) at baseline and was significantly associated with VAP (ρ = 0.54), 12-item Short Form Health Questionnaire component scores (ρ = −0.53; −0.44), and dizziness VAS at follow-up (ρ = 0.37). Approximately 38% of the variation in VAP score at follow-up was predicted by age, number of medications, 9-item VAAI score, dizziness VAS, and Hospital Anxiety and Depression Scale-depression score when considered together (R2 = 0.38). Conclusion Fear-avoidance beliefs are associated with measures of disability at 3 months and are predictive of activity limitations and participation restrictions at 3 months when controlling for age, medications, baseline dizziness, and depression symptom severity in people with vestibular disorders. Impact Measurement of fear-avoidance beliefs may provide important prognostic information, suggesting that an assessment of fear-avoidance beliefs could be used by clinicians to identify individuals at greater risk of disability after a vestibular disorder. Lay Summary Fear-avoidance beliefs in people who have vestibular disorders are associated with disability at 3 months and predict limitations in daily activities at 3 months.

Adequate dietary protein is important for many aspects of health with current evidence suggesting that exercising individuals need greater amounts of protein. When assessing protein quality, animal sources of protein routinely rank amongst the highest in quality, largely due to the higher levels of essential amino acids they possess in addition to exhibiting more favorable levels of digestibility and absorption patterns of the amino acids. In recent years, the inclusion of plant protein sources in the diet has grown and evidence continues to accumulate on the comparison of various plant protein sources and animal protein sources in their ability to stimulate muscle protein synthesis (MPS), heighten exercise training adaptations, and facilitate recovery from exercise. Without question, the most robust changes in MPS come from efficacious doses of a whey protein isolate, but several studies have highlighted the successful ability of different plant sources to significantly elevate resting rates of MPS. In terms of facilitating prolonged adaptations to exercise training, multiple studies have indicated that a dose of plant protein that offers enough essential amino acids, especially leucine, consumed over 8–12 weeks can stimulate similar adaptations as seen with animal protein sources. More research is needed to see if longer supplementation periods maintain equivalence between the protein sources. Several practices exist whereby the anabolic potential of a plant protein source can be improved and generally, more research is needed to best understand which practice (if any) offers notable advantages. In conclusion, as one considers the favorable health implications of increasing plant intake as well as environmental sustainability, the interest in consuming more plant proteins will continue to be present. The evidence base for plant proteins in exercising individuals has seen impressive growth with many of these findings now indicating that consumption of a plant protein source in an efficacious dose (typically larger than an animal protein) can instigate similar and favorable changes in amino acid update, MPS rates, and exercise training adaptations such as strength and body composition as well as recovery.

OBJECTIVES: Investigate the challenges experienced by survivors of critical illness and their caregivers across the transitions of care from intensive care to community, and the potential problem-solving strategies used to navigate these challenges. DESIGN: Qualitative design—data generation via interviews and data analysis via the framework analysis method. SETTING: Patients and caregivers from three continents, identified through the Society of Critical Care Medicine’s THRIVE international collaborative sites (follow-up clinics and peer support groups). SUBJECTS: Patients and caregivers following critical illness. INTERVENTIONS: Nil MEASUREMENTS AND MAIN RESULTS: From 86 interviews (66 patients, 20 caregivers), we identified the following major themes: 1) Challenges for patients—interacting with the health system and gaps in care; managing others’ expectations of illness and recovery. 2) Challenges for caregivers—health system shortfalls and inadequate communication; lack of support for caregivers. 3) Patient and caregiver-driven problem solving across the transitions of care—personal attributes, resources, and initiative; receiving support and helping others; and acceptance. CONCLUSIONS: Survivors and caregivers experienced a range of challenges across the transitions of care. There were distinct and contrasting themes related to the caregiver experience. Survivors and caregivers used comparable problem-solving strategies to navigate the challenges encountered across the transitions of care.